ES3034905T3 - Deuterated domperidone compounds for use in ameliorating gastroesophageal reflux disease - Google Patents

Abstract

Compositions of deuterated domperidone, synthesis methods, methods of use, and dosage formulations that provide beneficial safety and other effects. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

Deuterated domperidone compounds for use in the improvement of gastroesophageal reflux disease Background

Gastroparesis (GP) is a condition in which stomach motility does not work or does not work properly, preventing the stomach from emptying and interfering with digestion.

GP can be caused by damage to the vagus nerve, which regulates digestive processes. Damage to the vagus nerve can be caused by diseases, such as type 1 or type 2 diabetes, or by stomach or small intestine surgery, and can limit the nervous system's ability to send signals to the stomach muscles. Viral infections, certain medications, certain cancer treatments, scleroderma, nervous system disorders such as Parkinson's disease or multiple sclerosis, or hypothyroidism can also cause or result in GP.

The diagnosis of GP is typically made by upper gastrointestinal (GI) endoscopy, computed tomography (CT) scan, enterography, magnetic resonance enterography, upper GI series (X-rays), gastric emptying study, and/or a breath test. Symptoms of GP include nausea, vomiting, blood glucose disturbances, abdominal pain, bloating, feeling full after only a few bites, poor appetite, weight loss, and malnutrition. Untreated GP can lead to severe dehydration, malnutrition, hardening of undigested food in the stomach (bezoar), and erratic blood glucose disturbances that can exacerbate diabetes.

Treatment of PG involves identifying and treating the underlying pathology. PG resulting from diabetes can be treated with dietary modifications. It can be treated with medications that stimulate the stomach muscles, such as metoclopramide, erythromycin, and cisapride. Metoclopramide has serious side effects, such as the development of movement disorders or adverse interactions with other medications; erythromycin is susceptible to loss of effectiveness as the patient's tolerance to the drug increases; and cisapride has limited availability. Medications to control nausea and vomiting include prochlorperazine, thiethylperazine, diphenhydramine, and ondansetron.

GP symptoms can be treated surgically, such as by placing a jejunostomy tube in the small intestine or by inserting a gastric ventilation tube. In severe cases, a feeding tube can be inserted orally or nasally directly into the small intestine, or it can be administered parenterally.

Domperidone is an effective dopamine antagonist that does not readily cross the blood-brain barrier; as such, domperidone exhibits only minimal extrapyramidal side effects. Domperidone exhibits both gastrokinetic and antiemetic activity and exerts its gastrokinetic action by acting on peripheral dopamine receptors in the stomach. Domperidone acts as a selective peripheral antagonist of dopamine D2 and D3 receptors and works to block dopamine receptors that register nausea. Domperidone can block dopamine receptors in the pyloric antrum and duodenum to increase motility in the upper GI tract. Domperidone can also block dopamine receptors in the pituitary gland, which may increase prolactin release and lead to increased lactation, so it is used to treat insufficient lactation. Domperidone has been evaluated for use in the treatment of nausea and vomiting, gastroparesis, Parkinson's disease, functional dyspepsia, inadequate lactation, pediatric reflux, gastroesophageal reflux disease, and other GI motility disorders or conditions.

WO2008134540 discloses domperidone compositions formulated for transmucosal administration. The document also discloses methods for treating nausea, vomiting, and gastrointestinal motility disorders, and methods for enhancing breast milk production. The methods utilize domperidone compositions formulated for transmucosal administration, administered to patients in an amount effective to treat nausea, vomiting, or gastrointestinal motility disorders, or to enhance breast milk production.

Summary

The invention is defined by the claims. Any material beyond the scope of the claims is provided for informational purposes only.

The present disclosure is directed to a compound that is d4-domperidone 2, d6-domperidone 3 or d<10>-domperidone 5, or a pharmaceutically acceptable salt:

for use in the improvement of gastroesophageal reflux disease.

References to methods of treatment by therapeutic methods in the present disclosure should be construed as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in such methods.

Brief description of the figures

FIGS. 1A-1B show a plasma profile of orally administered domperidone and deuterated domperidone (FIG. 1A) and an analysis of the data shown in FIG. 1A (FIG. 1B).

FIG. 2 shows a representative drug release profile for an immediate release (IR) formulation and an extended release (XR) formulation.

FIG. 3 is a simulated plasma profile of deuterated domperidone of an immediate-release portion and an extended-release portion.

FIG. 4 shows a bilayer tablet with IR and ER layers.

FIG. 5 shows a tri-layer tablet containing IR, ER and a buffer layer.

FIG. 6 shows a tablet with an ER matrix and an IR coating.

FIG. 7 shows a capsule containing an IR tablet, a cap and an ER tablet with an osmotic system.

FIG. 8 shows a capsule containing IR and ER beads.

FIG. 9 shows a capsule containing IR and ER mini-tablets.

FIG. 10 shows a capsule containing IR and ER granules.

FIG. 11 shows a capsule containing an ER bead coated with an IR layer.

FIG. 12 shows a compressed tablet containing IR granules and a coated ER tablet embedded within the compressed tablet.

FIG. 13 shows an IR tablet in compressed form with an ER tablet embedded within the IR tablet.

FIG. 14 shows an ER tablet suspended in an IR liquid.

FIG. 15 shows a sachet containing a mixture of IR and ER granules or beads.

FIG. 16 shows a sachet containing IR effervescent granules or beads and coated ER granules or beads.

FIG. 17 shows a tablet with interlayers separated by bands.

FIG. 18 shows an orally disintegrating tablet containing coated delayed-release/ER drug particles, beads, or granules; the inset shows a drug in a polymer matrix.

FIG. 19 shows a capsule containing drug solution and coated delayed-release/ER drug particles, beads, or granules,

FIG. 20 shows a soft capsule containing drug solution and coated delayed-release/ER drug particles, beads, or granules.

FIG. 21 shows a soft capsule containing coated delayed-release/ER drug particles, beads, or granules.

FIGS. 22A-22B are line graphs showing the effect of domperidone or d4-domperidone suspensions on Cmax and AUC, respectively.

Detailed description

In the description, the singular forms "a," "an," and "the" include plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a material" is a reference to at least one such material and equivalents thereof known to those skilled in the art, and so on. When a value is expressed as an approximation by use of the descriptor "approximately," it will be understood that the particular value constitutes another embodiment. In general, the use of the term "approximately" indicates approximations that may vary depending on the desired properties sought to be obtained by the described subject matter and should be interpreted in the specific context in which it is used, based on its function. One skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be a non-limiting procedure for determining the scope of the word "approximately." In other cases, the gradations used in a series of values can be used to determine the expected range available for the term "approximately" for each value. All ranges are inclusive and combinable. That is, references to values stated in the ranges include each and every value within that range.

When a list is presented, unless otherwise indicated, it should be understood that each individual item in that list and each combination of that list should be construed as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be construed as including embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

It is appreciated that certain features of the invention which, for clarity, are described herein in the context of separate embodiments, may also be provided in combination within a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is considered to be combined with any other embodiment, and such combination is considered another embodiment. Conversely, various features of the invention which, for brevity, are described within the context of a single embodiment, may also be provided separately or in a subcombination. It is further noted that claims may be drafted to exclude an optional element. As such, this statement is intended to serve as background for the use of such exclusive terminology as "solely," "only," and the like in connection with the reciting of claim elements, or the use of a "negative" limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each such step may also be considered an independent embodiment in and of itself.

Unless otherwise specified herein, percentages refer to weight/volume.

The terms "subject" and "patient" are used interchangeably and typically refer to mammals. In some embodiments, the patient or individual is a human. In other embodiments, the patient or subject is a farm or veterinary animal, a domestic animal or pet, or an animal used to conduct clinical research.

"Ameliorate" or variations thereof refer to eliminating or reducing the development of a disease or disorder, i.e., delaying the onset of the disease. In other embodiments, "treat" refers to eliminating or reducing at least one physical parameter of the disease or disorder.

"Domperidone" as referred to in this invention refers to 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one, which has the following structure:

Any reference to domperidone also includes pharmaceutically acceptable salts, esters, hydrates, solvates, prodrug forms, and derivatives thereof, which are broadly defined as modified or partially substituted domperidone compounds. Examples include, but are not limited to, the addition of a single atom, the addition of a reactive group, the addition of a functional group, the formation of a dimer or multimer, conjugation with another molecule such as an antibody, etc.

"Pharmaceutically acceptable" refers to properties and/or substances that are acceptable to the patient from a pharmacological/toxicological advantage, and to the pharmaceutical manufacturer from a physical/chemical advantage in relation to composition, formulation, stability, patient acceptance and bioavailability.

A pharmaceutically acceptable salt includes salts with a pharmaceutically acceptable acid or base, for example, inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acids, and organic acids, for example, citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic (cyclamic) or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metals, for example, sodium or potassium, and alkaline earth metals, for example, calcium or magnesium, hydroxides, and organic bases, for example, alkyl amines, arylalkyl amines and heterocyclic amines.

The abbreviation "D" as used herein refers to a stable hydrogen isotope which is deuterium (heavy hydrogen or 2H). These instances of "D" include an amount of deuterium that is above the natural distribution of deuterium. In some embodiments, D has a deuterium enrichment of not less than about 1%. In some embodiments, D has a deuterium enrichment of not less than about 5%. In some embodiments, D has a deuterium enrichment of not less than about 10%. In some embodiments, D has a deuterium enrichment of not less than about 20%. In some embodiments, D has a deuterium enrichment of not less than about 30%. In some embodiments, D has a deuterium enrichment of not less than about 40%. In some embodiments, D has a deuterium enrichment of not less than about 50%. In some embodiments, D has a deuterium enrichment of not less than about 60%. In some embodiments, D has a deuterium enrichment of not less than about 70%. In some embodiments, D has a deuterium enrichment of not less than about 80%. In even some embodiments, D has a deuterium enrichment of not less than about 90%. In even some embodiments, D has a deuterium enrichment of not less than about 98% deuterium. In even some embodiments, D has a deuterium enrichment of not less than about 99% deuterium.

Like all drugs, the safety of domperidone depends on its metabolism. Decreased metabolism causes a drug to remain in the body longer. The doses of domperidone required to treat gastroparesis—10 mg administered three times a day for a total of 30 mg, and up to 60 mg—can produce dose-related prolongation of the cardiac QT interval. Because of this effect, it is not approved for this indication in the United States, but it is approved in Europe and Canada.

Domperidone is extensively metabolized; its major metabolic pathways produce a 5-hydroxy form, an N-dealkylated form, and a hydroxylated form. Methods that decrease domperidone metabolism would allow a lower dose to be administered to achieve the same degree of efficacy in a patient, thereby diminishing or eliminating the cardiac effect and/or decreasing the number of doses required and/or providing more consistent exposure, which could improve patient tolerance or efficacy.

The overall peak plasma levels of domperidone depend on its route of administration. Intramuscular (IM) and oral administration in a fasted individual resulted in peak plasma levels at 10 and 30 minutes postdose; suppository administration resulted in peak plasma levels 1–2 hours postdose. Plasma concentrations were lower two hours after oral administration than after IM administration, probably due to first-pass metabolism in the liver and gut wall. The peak plasma concentration was 40 ng/mL after a 10 mg IM injection, 20 ng/mL after oral ingestion of a 10 mg tablet, and 70–100 ng/mL after oral ingestion of a 60 mg tablet or drops. The human plasma protein binding of tritiated domperidone at 10 and 100 ng/mL was 91.7% and 93.0%, respectively. Bioavailability was relatively high at 90% after IM injection and relatively low at 13%–17% after oral administration, and was further decreased by the use of antacids due to increased gastric pH. RxMed: Drug Facts-MOTILIUM®, Janssen-Ortho, Domperidone Maleate.

Compared with tritiated spiperone, the classic ligand used in central nervous system (CNS) models, domperidone binds selectively and specifically to striatal dopamine receptors. However, intravenous (IV) administration of domperidone, even at high doses, does not displace labeled spiperone in animal brain models due to its poor penetration of the blood-brain barrier (Reddymasu et al., Am. J. Gastroenterology). Domperidone also has a high affinity for GI tissue; high concentrations are found in the esophagus, stomach, and small intestine. Domperidone blocks dopaminergic inhibition of GI transit. It is rapidly metabolized by the liver; after oral administration, 32% is excreted in the urine and 66% is excreted in the feces. The elimination half-life is 7.5 h in healthy individuals and approximately three times longer in individuals with renal dysfunction.

The efficacy of domperidone is based on its ability to increase the amplitude of esophageal motor function, improve antroduodenal contractions, and better coordinate peristalsis through the pylorus, thereby accelerating gastric emptying. Domperidone has effective antiemetic activity at the chemoreceptor trigger zone (CTZ) in the fourth ventricle of the brain, but outside the blood-brain barrier. It has no cholinergic activity and is not inhibited by atropine.

Domperidone modulates gastric emptying of solids and liquids and does not alter gastric acid secretion, secretory volume, intragastric pH, or serum gastrin concentration.

At doses ranging from 10 mg to 30 mg orally, four times daily, half an hour before meals and at bedtime, domperidone significantly reduced gastrointestinal symptoms and hospitalizations for gastroparesis, had a positive effect on central control of vomiting and nausea, and accelerated emptying of a solid meal (Buckels et al., Medscape General Medicine. 2003; 5(4) www.medscape.com).

One method to decrease domperidone metabolism is to administer a deuterated form of domperidone. Domperidone is extensively metabolized. Deuteration slows metabolism at key metabolic sites and pathways, resulting in greater efficacy at a lower dose. A deuterated form of a small molecule increases its retention and therefore decreases its metabolism, allowing a lower dose to be administered and achieve the same efficacy as the higher dose without cardiac symptoms.

Deuterated domperidone can be synthesized or prepared by several routes. In general, any hydrogen in the chemical structure of domperidone can be hydrogen or deuterium. Beneficially, the sites of domperidone metabolism, i.e., all unsubstituted sites on the aromatic rings, can be blocked by adding a commercially available deuterated alkyl halide, and the metabolite can be blocked by adding a commercially available deuterated alkyl halide to the propyl linker. This can significantly reduce domperidone metabolism and improve its bioavailability.

Deuteration of a drug increases the drug’s half-life, allowing for less frequent dosing and improved pharmacokinetics, i.e., absorption, distribution, and metabolism. The kinetic isotope effect (KIE) and the deuterium kinetic isotope effect (DKIE) are used to incorporate deuterium into drugs. Gant, J. Med. Chem. (2014) 57, 3595–3611.

Deuterium forms more stable bonds with carbon than hydrogen. In some cases, deuterium substitution can result in altered drug metabolism. Altered drug metabolism can take many forms, e.g., improved metabolite stability, reduced formation of toxic metabolites, and/or increased formation of active metabolites. Deuterated compounds may have a longer half-life and increased systemic exposure compared to the corresponding non-deuterated forms. The longer half-life and decreased metabolism may provide increased efficacy, tolerability, safety, and convenience, such that lower doses of the deuterated form may produce similar results to higher doses of the non-deuterated form. Deuterated compounds generally retain the biochemical potency and selectivity of the corresponding non-deuterated forms. Any effect of deuterium substitution on metabolic parameters is highly dependent on the specific molecular positions at which deuterium replaces hydrogen.

The metabolic effects of deuterium substitution are neither obvious nor predictable, even in compounds that have similar chemical structures. For example, U.S. Publication No. 2009/0076010 discloses deuterium-enriched lamotrigine, an anticonvulsant. Deuteration ranges from 14% to 100%, depending on the position of the hydrogen replaced by deuterium. Enrichment methods can be by proton exchange with deuterium or by synthesis of molecules with deuterium-enriched starting materials. U.S. Publication No. 2009/0131485 describes deuterium-enriched pirfenidone, a collagen production inhibitor that blocks fibroblast proliferation and stimulation in response to cytokines, investigated for the treatment of neurofibromatosis, multiple sclerosis, and other fibroid-related diseases. Describes synthesis and isotope methods, and methods for improving bioavailability and dosage. Deuterated pirfenidone has a half-life ranging from 110% to 140% or more depending on the degree of deuteration. The effective amount is in the range of 80% to 40% or less compared to non-deuterated forms. U.S. Publication No. 2011/0160253 describes deuterium-enriched tizanidine, a benzothiazole that acts as a centrally acting α<2> adrenoceptor agonist, used to treat muscle hypertonia and muscle spasticity associated with multiple sclerosis, spinal cord injury, etc. Describes deuteration methods; enrichment is in the range of 52.5% to 99.5%, and pharmaceutical compositions, effective amounts, and dosages are described. Harbeson and Tung, MECHEM NEWS No. 2 May 2014, 8 22 describe that deuterium substitution can improve the safety, efficacy and/or tolerability of a therapeutic agent.

Deuterated drugs have been used in nonclinical settings and as metabolic and pharmacokinetic probes, but none are approved as human therapeutics. Depending on the desired deuteration sites, DO can be exchanged directly in finished drug compounds or in reagents used to synthesize drugs. Deuterium has low systemic toxicity. Deuterium in the gaseous state can be used as a starting material to incorporate deuterium. Catalytic deuteration of olefinic and acetylenic bonds can rapidly incorporate deuterium. Metal catalysts such as Pd, Pt, and Rh in the presence of deuterium in the gaseous state can be used to directly exchange deuterium for hydrogen in hydrocarbons containing functional groups. Deuterated reagents and synthetic building blocks are commercially available. The shape and size of a molecule are very similar in the deuterated and undeuterated forms. Minor changes in the physical properties of partially or fully deuterated compounds include reduced hydrophobicity, decreased acidity of carboxylic acids and phenols, and increased basicity of amines, but most of these small differences have negligible effects on biochemical potency or target selectivity. Isotope binding effects are well known and can contribute positively or negatively to a measured deuterium kinetic isotope effect. Reduced metabolic rates and metabolic shifts also occur, where the ratio of metabolites is altered. Changes in an individual's exposure to the parent drug and its metabolites can have ramifications for the pharmacodynamics, tolerance, and efficacy of the deuterated drug. Deuteration reduces the formation of unwanted or toxic metabolites, in addition to enhancing the formation of desired metabolites. An example of the positive effects of metabolic switching is deuterated nevirapine, which resulted in a reduction in the incidence and severity of rashes, and deuterated efavirenz, indilon, and odanacatib each resulted in fewer side effects with increased efficacy in a rat model. Deuterated rofecoxib, also known as BDD-11602, had an improved pharmacokinetic profile in a rat model compared with non-deuterated rofecoxib. Deuterated telaprevir, a hepatitis C virus NS3-4A protease inhibitor, had a 13% increase in the epimerization rate but a negligible effect on antiviral activity. The effects of deuteration on the metabolic profile of a particular drug are not predictable, although there is potential for improved safety, tolerability, efficacy, and dosage.

One method of decreasing domperidone metabolism is to administer a deuterated form of domperidone. A deuterated form of a small molecule can increase its retention and thus decrease its metabolism, allowing a lower dose to be administered and achieve the same efficacy as the higher dose, but without cardiac symptoms. Domperidone is extensively metabolized, so deuteration slows metabolism at key sites and pathways of metabolism, resulting in greater efficacy at a lower dose. This is demonstrated in FIGS. 1A and 1B, described below, where the area under the curve is greater for deuterated compounds. Table 1, described below, shows the reduction in metabolite formation for compound 2 over a 60-minute time period.

Compound 1 shows a general deuterated form of domperidone where R = H or D, independently, allowing for the presence of 1 to 10 deuteriums. Any and all permutations of deuterated sites may be used without limitation. The most significant sites for deuteration are the aromatics, as shown, and the methylene of the alpha alkyl linker to the piperidine nitrogen. The primary hydroxylated metabolites are on this aromatic ring, and the presence of deuterium can reduce the rate at which these metabolites are formed. The dealkylation metabolic pathway involves those alpha protons via an N-oxide elimination mechanism; deuterium is slower to eliminate, slowing this metabolic pathway.

Domperidone can be deuterated at any hydrogen site, as exemplified below. In compound 2, deuteration of the aromatic H atoms of the unsubstituted aromatic ring yields domperidone-d4. Further deuteration of one or more methylene sites on the linking propyl group yields compound 3 (domperidone-d6) or domperidone-d8 (not shown) or compound 5 (domperidone-d<10>). It is also possible to deuterate one or more of the methylene sites while retaining H at the aromatic sites. For example, deuteration of one methylene group yields compound 4 (domperidone-d<2>), deuteration of H from two methylene groups yields domperidone-d4 (not shown), and deuteration of H from all three methylene groups yields compound 6.

In one embodiment, any one of compounds 2, 3 or 5 is administered. Any one of compounds 2 and 3 act by reducing the metabolic rate and are preferred.

Raw materials with deuterium only in the alpha methylene are probably more expensive and less readily available than those in which the propyl group is fully deuterated.

Compound 2 is used and preferred in one embodiment.

Compound 3 is used and preferred in another embodiment.

Compound 5 is used and preferred in one embodiment.

Compounds 2 and 5 are used and preferred in one embodiment.

Thus, the present disclosure provides methods for ameliorating gastroesophageal reflux disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound that is d4-domperidone 2, d6-domperidone 3, or d<10>-domperidone 5, or a pharmaceutically acceptable salt thereof to the patient:

In some embodiments, the compound d4-domperidone 2 or a pharmaceutically acceptable salt thereof:

In other embodiments, the compound d6-domperidone 3 or a pharmaceutically acceptable salt thereof:

In other embodiments, the compound d<10>-domperidone 5 or a pharmaceutically acceptable salt thereof:

In some embodiments, deuterated compounds can be used in the methods described herein to ameliorate gastroesophageal reflux disease.

Scheme 1 shows a general synthesis for preparing various deuterated domperidone compounds shown generally as compound 1. The synthesis is based on the non-deuterated analog in Vandenberk U.S. Patent No. 4,066,772. The process begins with 1,2-diaminobenzene substituted with 0 to 4 deuteriums on the aromatic ring. The imide is closed using ethyl chloroformate, or other similar reactive carbonyl species, in an appropriate solvent, such as, but not limited to, an ether, such as, tetrahydrofuran (THF), halocarbons, such as, dichloromethane, ketones such as acetone, hydrocarbons, such as, heptane, and amides, such as, N,N-dimethylformamide (DMF). Compound 8 is then protected once with an appropriate protecting group, such as, but not limited to, carbamates, sulfonamides, and vinylalkyls. The second nitrogen is then reacted with a 1,3-bifunctional propyl derivative containing 0 to 6 deuterium. The functionality may independently be halogen (Br, Cl, I), hydroxyl, or an appropriate leaving group, such as, tosylate or mesylate. The remaining leaving group X of compound 10 may optionally be exchanged for a more reactive species, e.g., if X is chloride, the chloride may be exchanged for an iodide, or if X is a tosylate, the tosylate may be exchanged for a trifluoromethanesulfonate (triflate). The protecting group P may also be removed at this step.

Intermediate 10 or 12 is then reacted with compound 14 using a base or other appropriate coupling procedure. Compound 14 is prepared using methods known in the art. Removal of the protecting group yields the desired deuterated domperidone derivative 1. Alternatively, the protecting group P can be removed prior to alkylation with 14. All compounds are prepared according to this general scheme using the appropriately substituted deuterated starting materials.

Scheme 1: General Synthesis of Deuterated Domperidone

Scheme 2 shows an alternative synthesis for deuterated domperidone. A suitably deuterated 1,2-aminobenzene is reacted with tetraethyl orthocarbonate in the presence of a catalyst and in a suitable solvent, resulting in compound 15. A 1,3-bifunctional propyl derivative containing 0-6 deuterium is then reacted with the protonated N-nitrogen of imide 15 in the presence of base and in a solvent to provide compound 16. Substitution of compound 14 and deprotection of the benzimidazole results in deuterated domperidone 1.

Scheme 2: Synthesis of Deuterated Domperidone

The synthesis of deuterated domperidone in Scheme 2 involves only three steps, each of which results in high product yields. The overall yield of deuterated domperidone in Scheme 2 greatly improves the yield of deuterated domperidone in Scheme 1.

The deuterated domperidone compounds may be administered by any route determined by one of skill in the art, including, but not limited to, oral, rectal, nasal, parenteral (i.e., subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous, intraarticular, intramedullary), intraperitoneal, transmucosal, transdermal, or topical (i.e., dermal, buccal, sublingual, intraocular). In some embodiments, the deuterated domperidone compounds are administered in the form of pharmaceutical compositions.

The formulations can be administered orally in solid form, such as a tablet, capsule, lozenge, or chewing gum, or in liquid form as a syrup, emulsion, solution, or suspension in an aqueous or non-aqueous vehicle. In solid forms, the formulations can be controlled-release or rapid-release for rapid onset. The formulations can also be administered by injection, which may be subcutaneous, intradermal, intramuscular, intravenous, or other injection methods. Formulations for administration by injection may include suspensions, solutions, or emulsions in aqueous or non-aqueous vehicles. Other formulations can be administered intranasally, vaginally, rectally, or transdermally. The formulations can also be administered transmucosally. The preparation can be administered from once a day to four times a day.

Typically, pharmaceutical compositions are formulated to suit a particular route of administration. In some embodiments, pharmaceutical compositions are in the form of tablets, capsules (hard and soft gelatin capsules), sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations (solutions, emulsions, suspensions, or syrups), patches, inhalants, or suppositories. Therefore, pharmaceutical compositions typically contain pharmaceutically acceptable excipients.

For inclusion in the pharmaceutical compositions, pharmaceutically acceptable excipients are selected based on the mode of administration and may include inert and/or active components. In some embodiments, the pharmaceutically acceptable excipient is sterile, non-toxic, and/or biologically suitable for administration to a subject, i.e., buffered to an appropriate pH and isotonicity. In other embodiments, pharmaceutically acceptable excipients include diluents (such as inerts), carriers, adjuvants, and fillers.

Deuterated domperidone or the pharmaceutical composition comprising it may also contain and/or be administered with other active agents. In some embodiments, the additional active agent is useful for treating GERD. Thus, the additional active agent may include antacids, H-2 receptor blockers (such as cimetidine, famotidine, nizatidine, or ranitidine), proton pump inhibitors (such as lansoprazole, omeprazole, pantoprazole, rabeprazole, or dexlansoprazole), medications that strengthen the lower esophageal sphincter (such as baclofen), anti-nausea or anti-vomiting medications such as aprepitant, dolasetron, granisetron, ondansetron, palonosetron, prochlorperazine, promethazine, netupitant-palonosetron, rolapitant, lorazepam, metoclopramide, or dexamethasone, or combinations thereof.

In some embodiments, deuterated domperidone is administered orally, transdermally, parenterally, or a combination thereof. In other embodiments, deuterated domperidone is administered transdermally. In other embodiments, deuterated domperidone is administered parenterally. In still other embodiments, deuterated domperidone is administered orally.

FIG. 1 shows the decreased metabolism caused by deuteration of domperidone, where the area under the plasma level curve in rats of orally administered domperidone is greater for deuterated domperidone compounds 2 and 6 relative to non-deuterated domperidone. The table below shows the reduced metabolite formation in human hepatocytes for domperidone compounds 2 and 6 over a 60-minute time period relative to non-deuterated domperidone.

Another method to decrease domperidone metabolism is to administer the drug sublingually, so that the active agent is immediately available in the circulatory system and bypasses the digestive system, where metabolism occurs. A sublingual form of domperidone or a deuterated domperidone, formulated as a tablet, film, or other suitable formulation, can be administered at a lower dose but with comparable efficacy to an orally administered form. Domperidone's pharmacokinetics, particularly its t<1/2>, pKa, log P, and Kd, make it favorable for sublingual administration.

Another method for decreasing domperidone metabolism is to administer the active agent in particulate form, which provides greater surface area. For example, domperidone or a deuterated domperidone can be formulated as microparticles or nanoparticles. Using the biopharmaceutical classification system (BCS), Class II drugs are known to have high permeability and low solubility, such that their bioavailability is limited by their solvation rate. In this embodiment, the microparticle or nanoparticle or other formulation that provides greater surface area increases bioavailability by increasing the solvation rate and can be administered at a lower dose but with comparable efficacy to an orally administered form.

It will be appreciated that other formulations may achieve similar or equal results, for example, using a spray formulation, a powder, a thin film, etc., and using domperidone or a deuterated domperidone.

It will be appreciated that the embodiments may be used in combination. As an example, a microparticle or nanoparticle form of domperidone may be applied or incorporated into a thin film and administered sublingually. As another example, a deuterated form of domperidone may be formulated as a microparticle or nanoparticle, and in some embodiments may be administered sublingually, e.g., in or on a thin film, as a spray, etc. In these combination examples, the dose of domperidone may be further reduced due to its higher bioavailability and lower metabolism.

The following preparations and formulations may be used for deuterated or non-deuterated forms of domperidone.

Nanoparticles can be prepared by dry milling or wet milling. Examples of dry milling processes include those described in U.S. Patent Publication Nos. 2013/0209569, 2010/0092563, 2014/0287039, 2014/0200276, 2014/0194487, 2014/0255494, 2013/0243854, 2014/0248359, 2014/0256781, 2014/0302127, 2014/019395, 2014/0220121, 2012/0135048, 2014/0326812, 2009/0028948, and U.S. Patent Nos. 9,089,471; 9,095,496; 9,180,096; 9,173,854; 9,017,721; 8,679,544; 8,999,387; 8,734,847; 8,992,982; 9,180,096; 9,186,328; 8,735,450; and 8,808,751. An exemplary wet milling process is described in U.S. Patent No. 9,107,827. Any of these formulations, including, but not limited to, thin films, tablets, sprays, solutions, etc., include a sublingual dosage form.

Domperidone, in either deuterated or non-deuterated form, can be administered through the skin, i.e., transdermally. Absorption through the skin, also known as percutaneous administration, transdermal administration, or dermal administration, transports domperidone from the outer epidermal surface into the skin and into the systemic circulation. The epidermal surface is the primary route of absorption for transdermal administration, although small amounts of the agent may also be transferred via hair follicles or glands. From the initial epidermal surface, the agent passes through seven epidermal layers before entering the dermis, from where it enters the circulatory and/or lymphatic systems. The stratum corneum is the outermost or surface-exposed layer of skin and is the barrier that limits the entry of a foreign agent; therefore, the rate of passage through the stratum corneum determines overall absorption. The primary components of the stratum corneum are the lipophilic compounds cholesterol, cholesterol esters, and ceramides. Agents with greater lipid solubility penetrate the stratum corneum more rapidly and achieve systemic exposure, compared with agents with lower lipid solubility, but most all agents penetrate the stratum corneum to some extent. The solubility of domperidone is related to its pH; domperidone is a weak base, pKa 7.89, with limited solubility in water, having a lipid-to-water ratio of 3.90.

The health and integrity of the stratum corneum affect agent penetration. For example, agents such as strong acids that injure or alter the composition of the stratum corneum are rapidly absorbed. Skin damage due to burns, abrasions, wounds, and disease also affect absorption. Some solvents, for example, dimethyl sulfoxide (DMSO), increase the permeability of the stratum corneum by acting as carriers and are therefore used as penetration enhancers or facilitators. Some surfactants, for example, sodium lauryl sulfate, increase skin penetration of water-soluble agents, possibly by increasing the skin's permeability to water.

Transdermal administration can be achieved by topical administration, environmental exposure, and/or injection. Absorption through the skin depends on factors of the agent including, but not limited to, concentration, molecular weight, and lipophilic/hydrophilic nature or solubility, but also the duration of contact, the physical condition of the skin, the exposed surface, and the presence or absence of hair follicles on the exposed surface. For example, absorption of agents from various skin surfaces occurs according to the following schedule, from fastest to slowest: scrotum > forehead > axilla > scalp > back > abdomen > underside of palm/foot, due to the stratified, keratinized squamous cell layer of the stratum corneum, which functions to prevent water loss from the underlying tissues.

Dermal application of domperidone may allow for more localized therapy and may avoid or minimize first-pass hepatic metabolism. Thus, dermal administration may achieve higher systemic concentrations. Dermal administration formulations include patches, lotions, liniments, ointments, tinctures, creams, powders, sprays, gels, etc. Patches may be controlled-release and may allow for the release of domperidone for up to 7 days, in one embodiment. Patches may include a penetration enhancer, which may facilitate or, in some cases, be important for administration. In a transdermal patch, domperidone or a prodrug form of domperidone is present in the form of the free base and/or salt.

The amount of domperidone absorbed by transdermal application can be measured directly or indirectly using methods known in the art and as described below. Even with in vivo studies, interspecies differences can be significant. Furthermore, the different formulations described above may affect the administered concentrations. Direct concentration measurement can be performed using in vivo methods by applying domperidone directly to the skin and measuring domperidone in blood and urine at specified times, then graphing the results and measuring the area under the curve (AUC). Ex vivo methods can be used because the permeability of the stratum corneum is not significantly altered when the skin is gently removed. Chamber studies, using any formulation of domperidone (e.g. films, patches, lotions etc., see e.g. Basu, IRJP 3 (2012)134-45; Madishetti et al. Daru 18 (2010) 221-29; Khan et al. Bull. Pharm. Res. 2 (2012) 15-21) applied to one surface of an isolated skin sample and its concentration measured on the other surface of the same sample, are known, e.g. isolated perfused porcine flap (Riviere, Fundam Appl Toxicol 7 (1986) 444-53). In vitro methods include static and flow-through diffusion cells, examples of which are Franz cells and Bronaugh cells (Bronaugh and Stewart, J. Pharm. Sci, 74 (1985) 64-67), respectively. The static Franz cell apparatus has an upper donor chamber and a lower receiving chamber containing a fluid, with the upper and lower chambers separated by the skin sample as a membrane. The receiving fluid in the lower chamber is typically buffered saline with a known amount of protein, e.g., bovine serum albumin or a biological fluid, and is in contact with the skin membrane. In use, a known volume and concentration of domperidone in a vehicle is applied to the upper chamber and permeates through the skin membrane, diffusing or otherwise entering the receiving fluid in the lower chamber. Samples of this receiving fluid are taken, typically through a sampling port that also replaces the volume of removed fluid, and analyzed at regular intervals to determine the amount of domperidone that permeated the skin membrane. The continuous-flow Bronaugh cell apparatus is similar to the Franz cell apparatus, but uses a continuous-flow system in the lower chamber from which samples are obtained and analyzed continuously rather than at set time points.

Methods for transmucosal delivery of domperidone are described in U.S. Publication No. 2010/0255096. Mucoadhesive delivery technologies provide safe and effective delivery of an agent, such as domperidone. These mucoadhesive delivery technologies include all methods of diffusion in the oral mucosa: passive diffusion including transcellular (across cells) and paracellular (across lipid-rich domains around cells), carrier-mediated transport, and endocytosis/exocytosis for active cellular uptake and excretion via the endocytic pathway.

Mucous membranes, or mucosa, line body cavities that are externally exposed to the environment or are internal organs. The oral mucosa is the mucous membrane that lines the inside of the mouth and consists of stratified squamous epithelium (oral epithelium) and underlying connective tissue (lamina propria). It can be further divided into three main categories based on function and histology: masticatory mucosa of keratinized stratified squamous epithelium found on the dorsum of the tongue, hard palate, and attached gingiva; lining mucosa of non-keratinized squamous epithelium found almost everywhere in the oral cavity, including the buccal mucosa lining the cheeks, the labial mucosa which is the inner lining of the lips, and the alveolar mucosa which is the mucosa between the gums and the buccal/labial mucosa; and specialized mucosa in the taste bud regions on the lingual papillae on the dorsal surface of the tongue. Bioadhesive polymers adhere to any moist surface, so a mucoadhesive/bioadhesive formulation adheres to both keratinized and non-keratinized mucosa moistened with saliva.

Exemplary transdermal formulations are provided below; all percentages are weight/weight. While the following formulations list domperidone, one of ordinary skill in the art knows that domperidone can refer to both domperidone and deuterated domperidone.

Examples of sublingual dosage forms include sublingual tablets, biocompatible thin films, and sublingual sprays. For example, sublingual tablets could be prepared as rapidly disintegrating tablets (RDTs). RDTs are solid dosage forms containing a drug that disintegrates rapidly (< 30 seconds) when placed on or under the tongue, i.e., upon contact with saliva. The RDT formulation of domperidone or deuterated domperidone allows oral administration of domperidone without water or chewing. Commercially available RDT technologies include lyophilized tablets, compact tablets, molded tablets, spray-dried powders, thin films, and sugar floss systems (McLaughlin et al., Pharmaceutical Technology, September 2009 supplement).

In one embodiment, the domperidone or deuterated domperidone is formulated for topical application. In one embodiment, the domperidone or deuterated domperidone is formulated in and/or on a film, either directly or indirectly. For example, the deuterated domperidone may be formulated to be contained within the film matrix, or may be formulated as a layer of the film, or may be formulated in a carrier that is applied to the film. The carrier may be a suspension, foam, emulsion, etc. In one embodiment, the deuterated domperidone is formulated in a topically applied foam. In one embodiment, the deuterated domperidone is formulated in, on, or associated with a nanoparticle. In other embodiments, the deuterated domperidone is formulated as a solid tablet, or in a liquid, such as a syrup, suspension, solution, or emulsion, or as an injectable.

Thin film formulations include, but are not limited to, those disclosed in U.S. Patent Publication Nos. 2014/0271788, 2014/0272220, 2014/0271787, 2014/0163060, 2014/0070440, 2014/0017299, 2013/0333831, and 2013/0220526.

Nanoparticle formulations include any nanometer-sized structure including, but not limited to, quantum dots including graphene quantum dots, graphene oxide quantum dots, and zinc graphene oxide quantum dots, nanotubes including graphene nanotubes and/or carbon nanotubes, fullerenes, buckyballs, dendrimers, liposomes, aptamers, micelles, etc.

The formulations provide rapid patient compliance and optimal dosage delivery to treat the symptoms of gastroparesis. It will be appreciated that other gastric motility disorders can also be treated with the compositions and methods described.

In one embodiment, a solution or suspension of deuterated domperidone is placed in a blister pack and lyophilized to prepare a unit dose. A lyophilized suspension may include regular particles, micronized particles, or nanoparticles. Examples of lyophilized technology platforms include ZYDIS® (Catalent), LYOC™ (Cephalon), PHARMAFREEZE® (SPI Pharmaceuticals), and QUICKSOLV® (Janssen).

For a lyophilized RDT product for sublingual administration, domperidone or deuterated domperidone, as the active pharmaceutical ingredient (API), is dispersed in a matrix of a polymeric structure former, e.g., gelatin, and a saccharide, typically mannitol, dissolved in water. In the finished product, the glassy, amorphous structure of the polymeric component imparts strength and resilience while retaining some flexibility. The specific grade of gelatin and its associated dissolution characteristics ensure smooth and rapid melting in the mouth. The mannitol crystallizes during freezing, providing an elegant appearance and rigidity and ensuring the product is resistant to handling and transportation. Mannitol is readily soluble, thus also improving texture, flavor, and mouthfeel. Domperidone or deuterated domperidone can be dissolved in the matrix or dispersed to form a homogeneous suspension for dosing. Liquid dosing ensures good dose uniformity and allows for extremely low doses, for example, micrograms. Suspension doses up to 400 mg can be accepted, and domperidone or deuterated domperidone is typically micronized. Particle size is a factor because particles >50 µm can feel coarse. Solution products, due to the freezing point depression of the soluble API, can accept doses up to 60 mg. Both solution- and suspension-based products use domperidone or deuterated domperidone finely dispersed in the dry unit, which contributes to rapid dispersion and a smooth mouthfeel. Other excipients may be included, as described later. Domperidone or deuterated domperidone is dispensed in preformed blisters and rapidly cooled with liquid nitrogen for rapid freezing.

Freezing results in a network of ice crystals that sublimate during freeze-drying to produce a highly porous structure. The matrix components maintain the structure of the dry unit, but upon contact with moisture, the high porosity results in rapid water penetration. The matrix dissolves rapidly, resulting in rapid disintegration (< 10 seconds).

After freezing, domperidone or deuterated domperidone is lyophilized, metered, and dried in blisters that are sealed, providing physical and environmental protection. The product adheres lightly to the package, resulting in minimal movement of the product within the blister gaps to ensure its strength during transport. The product has a wafer-like structure, yet is minimally friable and strong enough to be removed from the package without breaking.

The wafer-like structure of lyophilized RDT formulations and their high porosity reflect the fact that water is typically the major component of the dosage formulation, so the dry product weight is significantly reduced and is often primarily determined by the dose of domperidone or deuterated domperidone. The recommended weight limit of 500 mg for RDT is likely to be reached for the highest dose of domperidone or deuterated domperidone in lyophilized formulations, which is offset by their rapid disintegration.

After administration and rapid dispersion on or under the tongue, the lyophilized formulation effectively reverts to the original solution or suspension of domperidone or deuterated domperidone. Thus, the lyophilized RDT tablet provides the convenience of a solid oral dosage form with the benefits of a solution/suspension product, suitability for buccal and sublingual absorption to enhance bioavailability directly into the systemic circulation and avoid first-pass metabolism to minimize undesirable metabolites, and physical and chemical stability with a shelf life comparable to conventional tablets, i.e., 2 to 5 years.

QUICKSOLV® begins with an aqueous dispersion of domperidone or deuterated domperidone and a matrix component, which is formed and frozen. Water is removed from the frozen matrix by lyophilization or immersion in alcohol (solvent extraction) to produce a dry unit. The formed product has uniform porosity and adequate strength for handling, with properties similar to those described above.

LYOC™ begins with an oil-in-water emulsion and is placed directly into blister cavities, followed by freeze-drying. To maintain homogeneity during freezing, polymers must be included to increase the viscosity of the matrix to a near-paste consistency and prevent settling. Increasing the viscosity of the matrix reduces the porosity of the product, thus increasing freeze-drying times and negatively impacting disintegration.

In one embodiment, the initial dose is a relatively low immediate release, followed by administration of an extended-release formulation. In one embodiment, 10 mg is the low immediate-release dose followed by 20 mg-30 mg of extended-release over 24 h.

Unless otherwise indicated, a formulation is a dosage form. A tablet is a non-limiting example of a dosage form. Dispersion and disintegration of the formulation are used synonymously. As used herein, the active agent, abbreviated "active," includes domperidone, domperidone derivatives, domperidone analogs, deuterated domperidone, etc.

The active ingredient includes all forms of the active ingredient domperidone, including deuterated forms of domperidone, and also includes, but is not limited to, intermediates, metabolites, enantiomers, polymorphs, crystal structures, hydrates, stereoisomers, salts, bases, complexes, carriers, analogs, derivatives, and conjugates. As used herein, extended release and sustained release are generally used interchangeably.

Both a bead and a pellet are any discrete component of a dosage form, for example, a capsule shell may be filled with a plurality of beads and/or a plurality of pellets.

Modified-release (MR) dosage forms include, but are not limited to, the following: An immediate-release formulation and a delayed-release formulation indicate the onset of release of the active agent relative to administration. An immediate-release formulation indicates that the release of the active agent from the formulation begins within a relatively shorter period of time after administration, for example, a few minutes or less. A delayed-release formulation indicates that the release of the active agent from the formulation does not begin within a relatively shorter period of time after administration, but is delayed and begins or is triggered after a relatively longer period of time after administration, for example, more than one hour. A rapid-release formulation and a slow-release formulation indicate the rate of release after onset. Once administration of the active agent begins, the active agent can be released relatively quickly or relatively slowly. A rapid-release formulation indicates that, after onset, a maximum or peak dose is reached in a relatively shorter period of time. A slow release formulation indicates that, after onset, a maximum or peak dose is reached over a relatively longer period of time. Once reached, the maximum dose can decrease at any rate, e.g., fast, slow, or constant. A sustained-release formulation and a continuous-release formulation indicate an ongoing release period and mean that the delivery of active ingredient continues or is maintained for an extended period of time after the initial onset, typically more than one hour, regardless of the shape of the dose-release profile. For example, the release of active ingredient is maintained between a peak and trough value of greater than zero for a relatively longer period of time. This release can be at a constant dose or at a dose that decreases over time.

A constant-release formulation indicates the dose being released. A constant release means that an active agent is delivered at a relatively constant dose over a moderate or extended period of time. This can be represented by a dose-release profile that is relatively flat or gently sloping after the initial onset, i.e., without distinct peaks or valleys. Therefore, a constant release is usually sustained or continuous, but a sustained or continuous release may not be constant.

A pulsed-release formulation indicates that an active agent is administered in one or more doses that fluctuate between a maximum dose and a minimum dose over a period of time. This can be represented by a dose-release profile that has one or more distinct peaks or valleys. However, two or more pulsed releases may produce an overlapping, overall, or compound release profile that appears to be or is effectively constant. When two or more pulsed releases occur, there may or may not be a non-release period between pulses. Typically, pulsed release results in the release of essentially all of an active agent within approximately 60 minutes or less.

An extended-release formulation provides a release of the active agent within a target dose range over a relatively longer period, or a plasma level of drug within a target dose range over a relatively longer period, without regard to the particular mechanism or character of release, e.g., sustained, pulsed, or constant.

A release profile for an orally administered drug indicates how and when a formulation releases or delivers the active agent to the stomach, intestines, etc. following administration. Several methods are known for evaluating drug release and producing release profiles, including in vitro tests that model the in vivo behavior of a formulation and USP dissolution tests for immediate-release and controlled-release solid dosage forms.

Drug release profiles are distinct from plasma profiles. A plasma profile indicates the dose or level of active agent in the bloodstream of a mammal, for example, a patient receiving a drug formulation. When an active agent is released from a formulation, for example, in the intestine, the amount of active agent present in the bloodstream over time can be determined.

A drug release profile can be designed to produce a desired or targeted plasma profile, and a plasma profile can mimic a release profile. For example, although a sustained release of active agent would be expected to produce a sustained dose in plasma, and a pulsed release would be expected to produce a pulsed (peak and trough) plasma profile, this is not necessarily the case. The half-life (t<1/2>) of the active agent in the bloodstream (its rate of decline) may be such that a sustained or continuous plasma profile could result in a pulsed delivery profile. Other factors may also play a role, such as bioabsorption, bioavailability, and first-pass effect. The plasma profile produced by a particular active agent release profile may also vary from patient to patient.

Bioavailability measures are known in the art and include area under the plasma concentration-time curve (AUC), maximum concentration (Cmax), and time to Cmax (Tmax).

The AUC measures the area under a plasma concentration-time curve, and represents the amount of drug absorbed after administration of a single dose of a drug (Remington: The Science and Practice of Pharmacy, Gennaro Ed. 2000, p. 999).

Cmax is the maximum plasma concentration achieved after oral administration of the drug (Remington, page 999). Oral administration of a drug results in one Cmax, but may result in more than one peak plasma concentration, for example after administration of a pulsed-dose formulation.

Tmax is the amount of time required to reach Cmax after oral administration of the drug, and is related to the rate of absorption of the active agent (Remington p. 999).

A "solubility-enhancing polymer" or "crystallization-inhibiting polymer" refers to a water-soluble polymer capable, at suitable concentrations, of forming a solid dispersion, as defined herein, of a weakly basic meclizine in the solubility-enhancing polymer, for example, by first dissolving both the drug and the polymer in the same solvent system and then removing the solvent under appropriate conditions. The weakly basic drug is substantially maintained as a molecular dispersion or in amorphous form during storage, transportation, and commercial distribution of the composition containing the solid dispersion of the solubility-enhancing polymer and the weakly basic drug.

A "controlled-release" coating encompasses coatings that delay the release, maintain the release, prevent the release, and/or otherwise prolong the release of a drug from a particle coated with a controlled-release coating. The term "controlled-release" encompasses "sustained release," "delayed release," and "pulsatile, timed release"; thus, a "controlled-release coating" encompasses a sustained-release coating, a pulsatile timed-release coating, or a "delay-time" coating.

An "enteric polymer" refers to a pH-sensitive polymer that is resistant to gastric juice (i.e., relatively insoluble at the low pH levels found in the stomach), and that dissolves at the higher pH levels found in the intestinal tract.

"Immediate release," in reference to a pharmaceutical composition that may be a dosage form or a component of a dosage form, refers to a pharmaceutical composition that releases greater than or equal to about 50% of the active, in another embodiment greater than about 75% of the active, in another embodiment greater than about 90% of the active, and in other embodiments greater than about 95% of the active within about one hour after administration of the dosage form. The term may also refer to pharmaceutical compositions in which a relatively rapid release of the active agent occurs after a lag time in which little or no release of the active agent occurs.

An immediate release (IR) bead or immediate release particle generally refers to a bead or particle containing an active that exhibits immediate release properties relative to the active.

A "sustained release (SR) bead" or "sustained release particle" generally refers to a bead or particle containing an SR coating disposed over a core containing active agent.

A "time-delay coating" or "pulsible programmed release" (TPR) coating refers to a controlled-release coating that combines water-insoluble and enteric polymers; a TPR coating alone provides an immediate pulse of active agent release after a predetermined delay time. A programmed sustained release (TSR) bead with a TPR coating disposed over a barrier coating (SR coating) provides a sustained active agent release profile after a predetermined delay time.

A "delayed-release (DR) bead" or "delayed-release particle" generally refers to a core containing an active agent. A DR coating refers to a controlled-release coating comprising an enteric polymer, optionally in combination with a plasticizer.

A "controlled release (CR) bead" or "controlled release particle" generally refers to a core containing active agent, having an inner SR coating optionally followed by an outer DR or TPR coating or an inner TPR coating followed by an outer DR coating.

"Lag time" refers to a period of time where less than about 10% of the active agent is released from a pharmaceutical composition after ingestion of the composition or a dosage form comprising the composition, or after exposure of the composition or dosage form comprising the composition to one or more simulated body fluid(s), for example evaluated with a USP apparatus using a two-stage dissolution medium (first 2 hours in 700 mL of 0.1 N HCl at 37°C followed by dissolution testing at pH 6.8 obtained by the addition of 200 mL of a pH modifier).

"Disposed upon," for example, in reference to a coating on a substrate, refers to the relative location of, for example, the coating with respect to the substrate, but does not require that the coating be in direct contact with the substrate. For example, a first coating "disposed upon" a substrate may be in direct contact with the substrate, or one or more intervening materials or coatings may be interposed between the first coating and the substrate. For example, an SR coating disposed upon an active agent-containing core may refer to an SR coating deposited directly onto the active agent-containing core or the acid crystal-containing core or acid, or may refer to an SR coating deposited over a protective seal coating deposited over the active agent-containing core.

A "sealing layer" or "protective sealing coating" refers to a protective membrane disposed over a core particle containing active agent or a functional polymer coating, which protects the particle from abrasion and wear during handling and/or minimizes static during processing.

An "orally disintegrating tablet" or "ODT" refers to a tablet that disintegrates rapidly in the oral cavity after administration without chewing. The disintegration rate may vary, but is faster than the disintegration rate of conventional solid dosage forms (e.g., tablets or capsules) that are intended to be taken immediately after administration, or faster than the disintegration rate of chewable solid dosage forms, when tested, e.g., by USP Test Method <701>.

The term "substantially disintegrates" refers to a level of disintegration equivalent to at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% disintegration. "Disintegration" is distinguished from "dissolution"; "disintegration" refers to the breaking down or loss of structural cohesion of, for example, the constituent particles that make up a tablet, while "dissolution" refers to the solubilization of a solid in a liquid, for example, the solubilization of a drug in solvents or gastric fluids.

A "water-insoluble polymer" is a polymer that is insoluble or very slightly soluble in aqueous media, regardless of pH, or over a wide pH range (e.g., pH 0 to pH 14). A polymer that swells but does not dissolve in aqueous media may be "water-insoluble."

A "water-soluble polymer" is a polymer that is soluble, that is, it dissolves in a significant amount, in aqueous media, regardless of pH.

An "enteric polymer" is a polymer that is soluble, i.e., dissolves to a significant extent, under intestinal conditions; that is, in aqueous media under neutral to alkaline conditions, and insoluble under acidic conditions (i.e., low pH).

A "reverse enteric polymer" or "gastrosoluble polymer" refers to a polymer that is soluble under acidic conditions and insoluble under neutral and alkaline conditions.

Unless otherwise indicated, the amount of the various coatings or layers described herein (the "coating weight") is expressed as the percentage increase in particle or bead weight provided by the dry coating, relative to the initial weight of the particles or beads prior to coating. Thus, a 10% coating weight refers to a dry coating that increases the weight of a particle by 10%.

Bioequivalence is the absence of a significantly different rate and extent of absorption from the active ingredient when administered at the same dose under similar conditions. Bioequivalence can be measured by pharmacokinetic parameters, e.g., AUC and Cmax.

One embodiment is an oral formulation containing a modified release (MR) formulation. In this embodiment, a single dosage form contains both an immediate release (IR) dosage form and an extended release (XR) dosage form. As used herein, an immediate release dosage form releases the active agent immediately upon administration. As used herein, an extended release dosage form encompasses delayed release, time-release, controlled release, or sustained release forms. As used herein, an extended release dosage form releases active agent at a predetermined rate over time to maintain a constant drug concentration for a specific period of time with minimal side effects. Extended release formulations can be achieved by a variety of formulations, as described below with illustrative, but non-limiting, examples, including polymer conjugates of the active agent and liposome formulations of the active agent.

The delivery system may comprise a core, seed, or matrix, which may or may not be loaded with active agent, and one or more coating layers comprising active agent and/or comprising a layer having release characteristics that controls the onset and release characteristics of the active agent. The core, seed, or matrix may be commercially prepared or obtained. By way of example only, there may be a core of sugar or microcrystalline cellulose, with a hydrophilic matrix made of, for example, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene oxide, polyvinyl alcohol, xanthan gum, carbomer, carrageenan, zooglan, etc.

The coating layers can provide immediate release, delayed pulsed release, or sustained release. Immediate release of the active agent from the immediate release layer can occur, for example, by using a very thin layer or coating that gastric fluids can rapidly penetrate, facilitating rapid leaching of the active agent; or by incorporating the active agent into a mixture that includes a carrier binder or other inert material that readily dissolves and releases the active agent into the gastric fluid; or by using a carrier binder or other inert material that rapidly disintegrates upon contact with the gastric fluid, rapidly dispersing both the material and the active agent in the gastric fluid as small particles. Such rapidly disintegrating and dispersing materials include, for example, lactose and microcrystalline cellulose. Hydroxypropyl methylcellulose is an example of a suspending agent and binder.

Enteric coatings for the delayed pulsed release component can be pH-dependent or pH-independent. Enteric coatings for the sustained release component are pH-dependent. A pH-dependent coating is activated to release the drug within a known pH range, which typically corresponds to the local pH of the environment where delayed release is desired. Exemplary pH-dependent coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethylcellulose, methacrylic acid/methacrylic acid methyl esters copolymer, such as, for example, materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100, or similar compounds used to make enteric coatings. Aqueous dispersions or redispersions of colloidal polymers can also be applied, e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Examples of commercially available pharmaceutical formulations that use an enteric system in the form of a coating or layer to prevent the active agent from dissolving in the stomach include CYMBALTA® (duloxetine HCl, Lilly Indianapolis IN), NEXIUM® (esomeprazole, AstraZeneca LP), ACIPHEX® (rabeprazole sodium, Eisai Inc. and Ortho-Mc-Neil-Janssen Pharmaceuticals, Inc.), ASACOL® HD (mesalamine, Procter & Gamble Pharmaceuticals, Inc.), LIALDA® (mesalamine, Shire US), PENTASA® (mesalamine, Shire US), ENTECORT® EC (budesonide capsules, AstraZeneca), LAMICTAL® XR (lamotrigine tablets, GlaxoSmithKline), Ka P iDEX® (dexlansoprazole, Takeda Pharmaceuticals North America, Inc.), CREON® (pancreatin capsules, Solvay S.A), ULTRASE® (pancrelipase capsules, Axcan Pharma US), PROTONIX® (pantoprazole, Pfizer) DEPAKOTE® (divalproex sodium, Abbott Laboratories), PRILOSEC® (omeprazole, AstraZeneca), PREV<a>C<i>D® (lanzoprazole, Novartis Consumer Health), ARTHOT<e>C® (diclofenac sodium, Pfizer); STAVZOR® (valproic acid, Noven Therapeutics), TRILIPIXI 4 (fenofibric acid delayed-release capsules, Abbott Laboratories), and VIDEX® EC (didanosine, Bristol-Myers Squibb).

An alcohol-resistant pharmaceutical composition uses an "alcohol protectant" to prevent or delay ethanol-induced "bleed-through" of the active agent from the dosage form that could cause too high a dose of domperidone or deuterated domperidone to be released into the patient, potentially resulting in a higher Cmax, potentially causing QT prolongation. With an alcohol-resistant composition, dose bleed-through is prevented, alleviating this safety concern. The alcohol protectant may be a single material, e.g., a polymer, or a combination of materials, e.g., a combination of polymers, in an excipient solution. The alcohol protectant is deposited in a layer or coating, or is in the form of a matrix in alternative embodiments. Alcohol protectant materials include, but are not limited to, organic-based cellulose acetate phthalate, ammonium methacrylate copolymers, methacrylate ester copolymers, methacrylic acid copolymers, natural and synthetic starches, poly(alkylene oxides), and natural and synthetic celluloses, including modified celluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxymethylcellulose (HMC), methylcellulose (MC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC), waxes such as insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes. In one embodiment, the alcohol protectant is an organic-based cellulose acetate phthalate Eastman C-A-P® or Cellacefate, NF (Eastman Chemical Company, Kingsport TN USA). The alcohol protectant may be present in the formulation in an amount sufficient to confer alcohol resistance at a given ethanol concentration, e.g., added in an amount of 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, and 500% by weight.

In one embodiment, the active agent composition comprises a plurality of CR and IR particles, wherein the CR particles each comprise a core coated with a layer of water-insoluble polymer, followed by a coating layer comprising an enteric polymer optionally in combination with a water-insoluble polymer, wherein the core comprises domperidone and a pharmaceutically acceptable polymeric binder, followed by a first coating layer comprising a water-insoluble polymer optionally in combination with a water-soluble polymer and an optional second coating of an enteric polymer optionally in combination with a water-insoluble polymer.

An embodiment has a plurality of CR and IR particles. The CR particle comprises a core coated with a water-insoluble polymer layer, followed by a coating layer comprising an enteric polymer optionally in combination with a water-insoluble polymer; the core comprising the active agent and a pharmaceutically acceptable organic acid (e.g., fumaric acid) separated from each other by at least one SR layer. Each of the IR particles comprises the active ingredient in combination with suitable excipients. In certain embodiments, the composition comprises the active agent and at least one solubility-enhancing organic acid, which is capable of creating an acidic pH microenvironment within the coated bead to solubilize the active agent prior to its release into a hostile pH environment of the intestinal tract where the drug is substantially insoluble.

In one embodiment, the CR particles comprise an inert core (e.g., a sugar sphere, cellulosic sphere, etc.) sequentially coated with a pharmaceutically acceptable organic acid (e.g., succinic acid) and a pharmaceutically acceptable binder (e.g., hydroxypropyl cellulose); an SR layer (e.g., comprising a pharmaceutically acceptable water-insoluble polymer, such as ethyl cellulose, optionally plasticized with a pharmaceutically acceptable plasticizer, such as triethyl citrate or polyethylene glycol); an active agent layer and a pharmaceutically acceptable binder (e.g., povidone); an optional seal layer (e.g., comprising a water-soluble polymer, such as hydroxypropyl methylcellulose); and an SR layer comprising a water-insoluble polymer, such as, ethylcellulose (EC-10), and an enteric polymer, such as, hypromellose phthalate, HP-55, and an optional pharmaceutically acceptable plasticizer such as triethyl citrate (TEC).

A pH-independent coating includes materials susceptible to enzymatic activation by azoreductases in intestinal bacteria (i.e., azopolymers) or materials susceptible to degradation by polysaccharidases in the colon (natural polysaccharides). Non-limiting examples of azopolymers include copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Non-limiting examples of natural polysaccharides include amylose, chitosan, chondroitin, dextran, and xylan.

An "enteric polymer" is a polymer having a polystyrene equivalent weight average molecular weight (MW) of about 50,000 to 150,000, and containing carboxyl groups that remain insoluble at pH below about pH 4 (gastric pH range), but which ionize, and thus cause the polymer to dissolve, at pH above about 5.0 (intestinal pH range). The enteric polymer may be film-forming, for example, cellulose acetate phthalate (C-A-P), cellulose acetate trimellitate (C-A-T), hydroxypropyl methylcellulose phthalate (HPMCP), methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinyl acetate phthalate (PVAP). The MW of HPMCP can be between approximately 80,000 and 110,000, or between 95,000 and 100,000. The MW for C-A-P can be between approximately 55,000 and 75,000, or between 68,000 and 80,000.

The sustained-release component may include sustained-release coatings, sustained-release matrices, and osmotic sustained-release systems. The sustained-release coatings may be prepared using a water-insoluble polymer, a combination of water-insoluble polymers, or a combination of water-insoluble and water-soluble polymers. Conventional sustained-release polymers are known to those skilled in the art and may be used for the sustained-release matrix.

Exemplary sustained release coatings include polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, fatty acids and esters thereof, alkyl alcohols, waxes, zein (corn prolamin), and aqueous polymer dispersions, such as, EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLICOAT® SR30D, and cellulose acetate latex.

The pellets or beads may be made from any pharmaceutically acceptable materials, based on compatibility with the active agent and the physicochemical properties of the pellets or beads.

Binders include cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, etc.

Disintegrating agents include corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®), etc.

Bulking agents include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

Surfactants include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, PLURONIC® line (BASF), etc.

Solubilizers include citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate, etc.

Stabilizers include antioxidants, buffers, acids, etc.

The following information illustrates exemplary but non-limiting manufacturing methods.

The core can be prepared by extrusion-spheronization, high shear granulation, solution layering or suspension.

In extrusion-spheronization, the active ingredient and other additives are granulated by adding a binder solution. The wet mass is passed through an extruder equipped with a pre-sized sieve. The extruded mixtures are spheronized in a marumerizer. The resulting pellets are dried and sieved.

In high-shear granulation, the active ingredient and other additives are dry-blended, then moistened by adding a binder solution in a high-shear granulator/mixer. After moistening, the granules are compressed by the combined mixing and milling actions. The resulting granules or pellets are then dried and screened.

In solution or suspension layering, a drug solution or dispersion with or without a binder is sprayed onto the initial seeds at a predetermined particle size in a fluid bed processor or other suitable equipment, thereby coating the active agent on the surface of the initial seeds. The active agent-laden pellets are then dried.

The core particles have a diameter ranging from about 50 microns to 1500 microns; preferably, 100 microns to 800 microns. The core particles can be coated in a fluidized bed apparatus with an alternating sequence of coating layers. The core can be coated directly with a layer or layers of the active agent, and/or the active agent can be incorporated into the core material. A protective or separating layer can be added on top of the active agent-containing layer and/or between the active agent layers. A protective or separating layer can be added over the surface of the active agent-loaded core, and then the enteric sustained-release or delayed-pulse layer can be coated thereon. Another layer of active agent can also be added to the enteric sustained-release or delayed-pulse layer to deliver an initial dose. A protective coating layer may be applied immediately outside an active agent-containing core or an active agent-coated core by conventional coating techniques used in the art, such as pan coating or fluid bed coating, using solutions of polymers in water or suitable organic solvents, or aqueous dispersions of polymers. Suitable materials for the protective layer include cellulose derivatives, such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, aqueous dispersions of ethylcellulose (AQUACOAT®, SURELEASE®), EUD<r>A<g>IT® RL 30D, OPADRY®, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, fatty acids and their esters, waxes, zein and aqueous dispersions of polymers, such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, and/or cellulose acetate latex, alone or in combination with hydrophilic polymers, such as hydroxyethylcellulose, hydroxypropylcellulose (KLUCEL®, Hercules Corp.), hydroxypropylmethylcellulose (METHOCEL®, Dow Chemical Corp.), polyvinylpyrrolidone, etc. Coating levels range from about 1% w/w to about 6% w/w, preferably about 2% w/w to about 4% w/w.

The sustained-release or delayed-release enteric coating layer is applied to the core, with or without a seal coating, by conventional coating techniques known in the art, for example, pan coating or fluid-bed coating, using solutions of polymers in water or suitable organic solvents, or using aqueous polymer dispersions. Suitable coating applicators are known in the art, for example, commercially available pH-sensitive polymers, such that the active agent is not released into the acidic environment of the stomach (pH < 4.5), but is released and becomes available when the pH-sensitive layer dissolves at a higher pH, after a certain delay time, or after the unit passes through the stomach.

Enteric polymers for the delayed pulsed release component and the sustained release component include, for example, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethylcellulose, methacrylic acid/methacrylic acid methyl esters copolymers, such as, for example, materials known under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous dispersions or redispersions of colloidal polymers can also be applied, for example, EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Delayed pulsed release and sustained release enteric polymers can be modified by mixing them with other known coating products that are not pH sensitive, for example, neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride commercially available as EUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without any functional groups, commercially available as EUDRAGIT® NE30D; and other pH-independent coating products.

The modifier component of the protective layer used on the sustained-release or delayed-release enteric coating may include a water penetration barrier layer (semipermeable polymer) that can be coated successively after the enteric coating to reduce the rate of water penetration through the enteric coating layer and thus increase the delay time for the release of the active agent. The coating is carried out as described above.

Optionally, an additional protective or colorant coating layer may be applied. OPADRY®, OPADRY II® (COLORCON®), and corresponding colored and colorless grades of COLORCON® can protect the pellets from becoming sticky and provide color to the product. In one embodiment, the protective or colorant coating ranges from 1% w/w to 6% w/w, preferably about 2% w/w to about 3% w/w. Talc may also be used.

Additional components can be incorporated into the coating formulation, for example, to facilitate and provide even faster release. Such components include, for example, plasticizers such as acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate, dibutyl sebacate, triacetin, polyethylene glycols, propylene glycol, etc.; lubricants such as talc, colloidal silica, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, etc.

The composition may be incorporated into hard gelatin capsules, either alone or with additional excipients. The composition may be incorporated into a tablet, for example, by incorporation into a tablet matrix which rapidly disperses the particles upon ingestion. To prevent particle destruction during the tableting process, a filler/binder, for example microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®), pregelatinized starches (STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®), present in the range of about 5% w/w to about 75% w/w, with a preferred range of about 25% w/w to about 50% w/w, is required.

Excipients typically include, but are not limited to, one or more inert fillers including microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, etc.; one or more materials that impart flowability to powders including fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate, etc.; one or more lubricants to ensure proper tablet formation including polyethylene glycol, leucine, glyceryl behenate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, etc. present in the range of about 0.1% w/w to about 10% w/w, with a preferred range of about 0.3% w/w to about 3.0% w/w.

Disintegrants are added to disperse the beads once the tablet is swallowed. Disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), cross-linked polyvinylpolypyrrolidone (PL<a>S<d>ONE-XL®), etc., present in the range of about 3% w/w to about 15% w/w, with a preferred range of about 5% w/w to about 10% w/w.

In one embodiment, tablets are formed from particles that are introduced into a mixer with AVICEL®, disintegrants, and lubricant. These particles are mixed for a defined time (minutes) to achieve a homogeneous mixture. The mixture is then placed in the hopper of a tablet press, where the tablets are compressed. The compression force used is adequate to form a tablet but not sufficient to rupture the beads or coatings.

A tablet can be constructed in three layers, where the immediate-release component is dry-blended, and the delayed-pulsed and sustained-release components are wet-granulated. The tablet is then formed into a single-layer or three-layer tablet. Upon dissolution of the layers, each component is released and acts as formulated: for example, immediate-release particles provide immediate release, delayed-pulsed particles provide delayed pulsed release, and sustained-release particles provide sustained release after a delay time.

One embodiment of the invention is an oral formulation of deuterated domperidone containing, in a single dosage form, both an immediate-release form and an extended-release form.

A dosage form of deuterated domperidone combining a 10 mg immediate release formulation, ranging from 5 mg to 20 mg, and a 20 mg extended release formulation, ranging from 10 mg to 80 mg, provides for delivery of the agent to the patient continuously over a period of approximately 12 h. Such a dosage formulation provides therapy for 12 hours with a single dose to the patient, providing convenience for the patient and extended therapy, e.g., a patient may beneficially experience a full night's sleep, a full day of work, a full day of leisure, etc. without symptoms.

In embodiments, the formulation of the invention contains an immediate release (IR) portion or component of the composition, and an extended release (XR) portion or component, or combinations thereof. The immediate release portion delivers 100% of the immediate release dose in less than about one hour, and the extended release portion delivers the extended release dose over a 12-hour period.

A typical dissolution profile, also referred to as a release profile, of domperidone is shown in FIG. 2. The percentage of drug release approaches 100% in less than or equal to one hour for the immediate release portion of the delivery system and approximately 100% in or equal to 12 hours for the extended release portion of the delivery system. FIG. 3 is a schematic of a simulated plasma concentration of domperidone, where the plasma drug concentration of the immediate release portion peaks at approximately twice the concentration at the same time that the drug in the extended release portion reaches a plateau, approximately half that of the immediate release portion.

In one embodiment, the active ingredient can be administered rectally. Rectal administration of the active ingredient can be 10 mg-20 mg three times a day. Rectal administration can be via a suppository formulation. In one embodiment, the formulation is administered rectally, for example via a suppository.

The composition may take a variety of forms or delivery systems. The following formulations may be used; these are exemplary and not limiting. Oral formulations include a tablet, capsule, sachet, softgel, liquid, gel, strip, film, powder, granules, gel, pulsatile release, core-coated, delayed-release form, banded drug form, sustained-release form, tablet-capsule, granulation-coated tablet, layered tablet, etc., including combinations thereof, for example, a tablet-capsule, granulation-coated tablet, layered tablet, etc., with an active agent and at least one pharmaceutically acceptable excipient.

A tablet formulation is known to one of skill in the art. The tablet may be of any shape or size convenient for oral administration, e.g., circular, elliptical, etc. In one embodiment, the tablet may be for immediate release (IR), extended release (XR), or combinations thereof. The tablet may be a bilayer tablet containing IR and XR layers adjacent to each other (FIG.

4); a three-layer tablet containing both IR and XR layers separated by a pharmaceutically acceptable buffer layer (FIG. 5); or an XR tablet containing the active agent in the matrix layer and coated with an IR layer of active agent (FIG. 6).

The composition may also be provided in other dosage forms, for example, a capsule containing an IR tablet, a filler, and an XR tablet within an osmotic drug delivery system for controlled delivery of the composition over a 12-hour duration (FIG. 7); a capsule containing IR beads and XR beads mixed in appropriate proportions (FIG. 8); a capsule containing IR mini-tablets mixed with XR mini-tablets (FIG. 9); a capsule containing IR granules and XR granules that are coated with extended-release polymers (FIG. 10); a capsule containing XR beads that are coated with an IR layer (FIG. 11), etc. Other dosage forms of the active agent may be a compact tablet containing IR granules and coated XR beads that are embedded within the tablet (FIG. 12); a compact tablet containing an XR tablet embedded within the IR tablet (FIG. 13); or an XR tablet suspended in an immediate-release liquid drug solution within a capsule (FIG. 14).

Another form of administration is a sachet. A sachet may contain a mixture of IR and XR granules or beads (FIG. 15), or it may contain a mixture of effervescent IR granules and coated XR granules (FIG.

16).

Other immediate, extended, or sustained, modified, and delayed pulsed release systems are described in each of the following references: U.S. Publication Nos. 2005/0095295, 2005/0106247, and 2007/0264323; and in U.S. Patent Nos. 6,126,969 and 8,211,465. As an example, U.S. Publication No. 2005/0106247 describes a drug (cyclobenzaprine hydrochloride) in extended release particles such as beads, pellets, granules, etc. having an extended release coating comprising a water-insoluble polymer and/or a water-soluble polymer, some of the particles being contained in a gelatin capsule. As another example, U.S. Publication No. 2007/0264323 describes delivery systems for a drug (ADDERALL®), such as beads within capsules, tablets, or sachets including coating layers, delayed pulsed release components, immediate release formulations, intermediate release formulations, sustained release formulations, and controlled release capsules. U.S. Patent No. 6,126,969 describes delivery systems for a drug (acetaminophen), such as a combination of coated and uncoated drug particles for an immediate release/sustained release dosage form. U.S. Patent No. 8,211,465 describes dosage forms for an initial release of a drug (NSAID, such as ibuprofen) and a second sustained release of the same drug. An osmotic delivery system is described in Patra et al. Osmotic Drug Delivery Systems: Basis and Design Approaches, Recent Patents on Drug Delivery and Formulation, 7 (2013) 1-12.

The active ingredient core of the dosage form may be an inert particle or an acidic or alkaline buffer crystal, which is coated with a film-forming formulation containing the drug. In one embodiment, a water-soluble film-forming composition forms a water-soluble/dispersible particle. Alternatively, the active ingredient may be prepared by granulation and milling and/or by extrusion and spheronization of a polymeric composition containing the active ingredient. The amount of active ingredient substance in the core depends on the required dosage and typically ranges from about 5% by weight to 60% by weight. The polymeric coating on the active ingredient core will typically be about 4% to 20% based on the weight of the coated particle, depending on the type of release profile required and/or the coating polymers and solvents selected. Those skilled in the art will be able to select an appropriate amount of active ingredient to coat or incorporate into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. that alters the microenvironment of the active to facilitate its release.

The drug-containing particle can be coated with an extended-release (XR) coating comprising a water-insoluble polymer or a combination of a water-insoluble polymer and a water-soluble polymer to provide XR beads. In some embodiments, the water-insoluble polymer and the water-soluble polymer can be present in a weight ratio of 100:0 to 65:35, or about 95:5 to 70:30, or about 85:15 to 75:25. The extended-release coating is applied in the amount necessary to provide the desired release profile. In some embodiments, the extended-release coating is about 1% to 15% by weight of the coated beads, or about 7% to 12% by weight of the coated beads.

The modified release dosage form, which includes a mixture of two populations of beads, can be prepared as follows. A drug-containing core is prepared by coating an inert particle, such as a nonpareil seed, an acidic buffer crystal, or an alkaline buffer crystal with an active agent and a polymeric binder, or by granulation and milling, or by extrusion/spheronization to form an IR bead. The IR bead is coated with a plasticized water-insoluble polymer alone, such as ethylcellulose, or in combination with a water-soluble polymer, such as hydroxypropylmethylcellulose, to form an XR bead. Hard gelatin capsules with XR beads, alone or in combination with IR beads, are filled in the desired ratio to produce modified release (MR) capsules that provide the desired release profile.

IR beads using the following dissolution procedure have been reported to release at least about 70%, more specifically at least about 90%, of the active agent within 30 minutes.

A USP 2 apparatus (paddles at 50 rpm) is used with the following dissolution medium: 900 mL of 0.1 N HCl (or suitable dissolution medium) at 37 °C, with active agent release determined by HPLC.

An aqueous or pharmaceutically acceptable solvent can be used to prepare core particles containing active agent. The type of film-forming binder used to bind the drug to the inert sugar sphere is not critical, but water-soluble, alcohol-soluble, or acetone/water-soluble binders are usually used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polysaccharides such as dextran, corn starch, can be used in concentrations of about 0.5% by weight to about 5% by weight, with other concentrations also being used. The active agent can be present in this coating formulation as a solution or can be dispersed in a solids content of up to about 35% by weight, depending on the viscosity of the coating formulation.

The active agent, optionally a binder such as PVP, a dissolution rate controlling polymer if used, and optionally other pharmaceutically acceptable excipients are mixed in a planetary mixer or a high shear granulator, such as, FIELDER® and granulated by adding/spraying a granulating fluid, such as, water or alcohol. The wet mass can be extruded and spheronized to produce spherical particles (beads) using an extruder/marumerizer. In these embodiments, the active loading can be as high as 90% by weight with respect to the total weight of the extruded/spheronized core.

Illustrative, but not limited to, examples of water-insoluble polymers useful in XR coating include ethylcellulose powder or an aqueous dispersion (e.g., AQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate (KOLLICOAT® SR 30D, BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as, EUD<r>A<g>IT® NE, RS and RS30D, RL or RL30D, etc. Illustrative, but not limited to, water-soluble polymers include low molecular weight hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and/or polyethylene glycol (PEG) of molecular weight >3000. The extended release coating is typically applied at a thickness ranging from about 1% by weight to 15% by weight depending on the solubility of the active agent in water and the latex suspension or solvent-based coating formulation used.

The coating compositions used to form the membranes are usually plasticized. Illustrative, but not limited to, plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethylene glycol, polypropylene glycol, castor oil, dibutyl sebacate, and/or acetylated monoglycerides, etc. The plasticizer may comprise from about 3% by weight to about 30% by weight, more typically from about 10% by weight to about 25% by weight based on the polymer. The type of plasticizer and its content depend on the polymer(s) and the nature of the coating system (e.g., water- or solvent-based, solution- or dispersion-based, and the total solids).

The particle can be primed by applying a thin film of hydroxypropyl methylcellulose (HPMC) (OPADRY® Clear) before applying a time-release membrane coating to separate the different membrane layers. HPMC is typically used, but other primers, such as hydroxypropyl cellulose (HPC), can also be used.

Membrane coatings can be applied to the core using any coating technique used in the pharmaceutical industry. In one embodiment, fluidized bed coating is used.

Multidose forms may be used, i.e., products in the form of multiparticulate dosage forms (globules, beads, granules, mini-tablets, etc.) or other forms suitable for oral administration. As used herein, these terms are used interchangeably to refer to multiparticulate dosage forms.

An extended-release dosage form including a mixture of two or more bead populations may be prepared as follows. An inert particle, such as a non-pareil seed, an acidic buffer crystal, or an alkaline buffer crystal, is coated with an active agent and a polymeric binder to form an active agent particle, i.e., an immediate-release (IR) bead, which may be in unit dosage form to act as a bolus dose. The active particle is coated with a solution or suspension of a water-insoluble polymer or a mixture of water-soluble and insoluble polymers to form an extended-release, i.e., extended-release (XR), coated active agent particle. XR beads in a hard gelatin capsule alone, and optionally in combination with IR beads in a ratio ranging from 95:5 to 70:30 (ER beads:IR beads), are filled to produce a modified release (MR) capsule having a targeted active agent release profile.

In one embodiment, the dosage form has an immediate-release portion of active agent dispersed in an oily or lipid system, and another portion formulated in a waxy matrix or active particles coated with hydrophobic carriers. At least 15%-50% of the active agent is an immediate-release portion and is in a dosage form suitable for immediate release. The remainder of the tablet capsule, by weight, may include a sustained-release formulation of active agent or a portion of the sustained-release formulation of active agent.

The active agent of domperidone or deuterated domperidone can be formulated in a lipid-based delivery system. Encapsulating or solubilizing the active agent in lipid excipients can lead to greater solubilization and absorption, resulting in greater bioavailability.

Lipid excipients are commercially available. Because lipids affect absorption, it is necessary to understand the characteristics of lipid excipients. Factors determining the choice of excipients for lipid-based formulations include miscibility, solvent capacity, self-dispersibility and ability to promote self-dispersion of the formulation, digestibility and fate of digested products, irritant effect, toxicity, purity, chemical stability, capsule compatibility, melting point, cost, etc.

Dietary oils composed of medium- and long-chain triglycerides, along with various solvents and surfactants, are frequently used to prepare lipid-based formulations. Many lipids are amphiphilic, meaning they have a lipophilic (fatty acid) portion and a hydrophilic portion. The melting point increases as the fatty acid chain length increases, but the melting point decreases with increasing fatty acid unsaturation, which also increases susceptibility to oxidation. Solubilizing agents used in lipid-based formulations are provided in the following table:

Triglyceride vegetable oils are the most common lipid excipients. They are completely digested and absorbed, eliminating safety concerns. Triglycerides are long-chain triglycerides (LCTs), medium-chain triglycerides (MCTs), and short-chain triglycerides (SCTs). Their solvent capacity for an active agent is primarily due to the effective concentration of ester groups. MCTs have a higher solvent capacity than LCTs and are less prone to oxidation. Oils from different plant sources have different proportions of each fatty acid. The fatty acid composition of various lipid excipients is shown below.

Composition of fatty acids found in lipid-based excipients

D-α-Tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) is derived from plant tocopherols. It is water-soluble and acts as an absorption enhancer for poorly water-soluble drugs. Pure triglycerides are present in refined vegetable oils.

Mixed glycerides are obtained by partial hydrolysis of vegetable oils. The starting material, the triglycerides, and the degree of hydrolysis determine the chemical composition of the mixed glycerides produced. Medium-chain mixed glycerides are not susceptible to oxidation, have greater solvent capacity, and promote emulsification. These polar oil excipients also improve the solvent capacity and dispersibility of the formulation. Examples of polar oils include sorbitan trioleate (SPAN® 85) and oleic acid.

Cosolvents, for example, ethanol, glycerol, propylene glycol, polyethylene glycols (PEG)-400, etc., increase the solvent capacity of the formulation for the active ingredients and aid in the dispersion of systems containing a high proportion of water-soluble surfactants. Practical limitations associated with cosolvents include precipitation of the solubilized active ingredient from the solvent due to loss of solvent capacity upon dilution, the immiscibility of some cosolvents with oils, and the incompatibilities of low molecular weight solvents with capsule shells.

Water-insoluble surfactants are lipid excipients with an intermediate hydrophilic-lipophilic balance (HLB 8-12) that adsorb at oil-water interfaces. Depending on the degree of ethoxylation, they have a finite solubility in water. They can form emulsions if subjected to shear and can be designated as "dispersible" in water. They can form micelles, but cannot self-emulsify due to their insufficiently hydrophilic nature. Oleate esters such as polyoxyethylene (20) sorbitan trioleate (TWEEN®-85) and polyoxyethylene (20) glyceryl trioleate (TAGOT®-TO) are examples of water-insoluble surfactants with a HLB of 11-11.5. However, a mixture of TWEEN®-80 and SpA n®-80 with an average HLB of 11 is not functionally similar to TWEEN®-85. A mixture of TWEEN®-80 and SPAN®-80 has both water-soluble and water-insoluble molecules, but TWEEN®-85 predominantly has water-insoluble molecules.

Water-soluble surfactants are the most common surfactants for formulating self-emulsifying drug delivery systems. Materials with HLB > 12 can form micellar solutions at low concentrations when dissolved in pure water above their critical micelle concentration (CMC). Water-soluble surfactants are synthesized by PEG with hydrolyzed vegetable oils, or alternatively, alcohols can be reacted with ethylene oxide to produce alkyl ether ethoxylate, a commonly used surfactant (e.g., cetostearyl alcohol ethoxylate or CETOMACROGOL™). A reaction of sorbitan esters with ethylene oxide produces polysorbates, predominantly ether ethoxylates. CREMOPHOR® RH40 and RH60 (ethoxylated hydrogenated castor oil) are examples of this type, obtained from the hydrogenation of materials derived from vegetable oils. CREMOPHOR® EL (ethoxylated castor oil), which is not hydrogenated, is also widely used. CREMOPHOR® enhances absorption by inhibiting efflux pumps; although the mechanism of inhibition is undetermined, it may be a nonspecific conformational change due to penetration of surfactant molecules into the membrane, adsorption on the surface of efflux pumps, or interaction of molecules with the intracellular domains of the efflux pump.

Additives can be added to protect the formulation from oxidation. Examples include lipid-soluble antioxidants such as α-tocopherol, β-carotene, propyl gallate, butylated hydroxytoluene (bHt), butylated hydroxyanisole (BHA), etc.

Lipid behavior during formulation is evaluated because lipid excipients have different chemical compositions, leading to wide melting ranges. Lipid thermal properties, e.g., crystallization temperature, melting point, glass transition temperature, and determination of the solid fat content of the excipient versus temperature, are evaluated using differential scanning calorimetry (DSC). Lipid organization during heating or cooling is assessed by hot stage microscopy. The crystallinity of a lipid excipient is confirmed by X-ray diffraction (XRD).

High-performance liquid chromatography (HPLC) and gas chromatography (GC) can determine the exact composition of the distribution of ethers, esters, and fatty acids. Other chemical indices include the molecular weight of fatty acids determined from their saponification value; the saturation of hydrocarbon chains determined by an iodine-based assay; oxidative changes determined by measuring peroxides; free fatty acids measured from acid content; and free hydroxyl groups determined by measuring hydroxyl group content.

The FDA-required dissolution testing does not correlate with the in vivo behavior of lipid-based formulations. Lipids in the gastrointestinal tract undergo digestion processes in the presence of lipases (gastric and pancreatic), which also affect the emulsification and dispersion properties of lipid excipients, leading to altered solubilization capacity in vivo. Therefore, the digestibility of lipid excipients should be considered when selecting lipid-based formulations. Dissolution testing in biorelevant media can assess such effects and predict in vivo behavior. The efficacy of self-emulsifying formulations can be determined by dispersion testing (emulsification capacity and particle size). Photon correlation spectroscopy (PCS) or laser light diffraction can be used to measure particle size, and visual observation can help predict emulsification capacity.

Lipid-based excipients enhance oral drug absorption by affecting several physiological processes, e.g., by stimulating bile flow and pancreatic juice secretion, prolonging gastric emptying, increasing membrane fluidity, opening tight junctions, promoting lymphatic transport of drugs thereby preventing first-pass metabolism, and inhibiting efflux transporters. Several in vitro models are available to evaluate these effects, including intestinal microsomes, Caco-2 cells, everted intestinal sac using a chamber, and in situ perfusion assays.

Liposomes can be used; these spherical bilayer structures resemble the cell membrane in their arrangement and are primarily amphiphilic phospholipids (hydrophilic head and hydrophobic fatty acid tail). When hydrated, these phospholipids form spherical bilayer structures, oriented with their hydrophobic tails toward the interior of the structure and the hydrophilic heads toward the exterior. Hydrophilic substances can be embedded in the aqueous internal spaces of the globules, while hydrophobic active ingredients can be embedded within the inner fatty acid layers.

Solid lipid nanoparticles (SLNs) can be used. SLNs can enhance bioavailability along with controlled and site-specific drug delivery, as well as potential vehicles for oral intestinal lymphatic delivery. SLNs are typically spherical particles ranging from 10 nm to 1000 nm with a solid lipid core matrix (stabilized by surfactants) that can solubilize lipophilic molecules. Lipids commonly used include monoglycerides such as glycerol monostearate, diglycerides such as glycerol behenate, triglycerides such as tristearin, fatty acids such as stearic acid, steroids such as cholesterol, and waxes such as cetyl palmitate. Oral bioavailability of a drug was improved by formulating an N-carboxymethylchitosan polymer coating drug-loaded SLNs using a monoglyceride lipid and soy lecithin and poloxamer 188 surfactant (Venishetty et al.).

In spray coagulation, also known as spray cooling, molten lipid is sprayed into a cooling chamber and, upon contact with air, coagulates into spherical solid particles. The solid particles are collected from the bottom of the chamber and filled into hard gelatin capsules or compressed into tablets. Ultrasonic atomizers generate solid particles in the spray cooling process. Parameters to be considered include the melting point of the excipient, the viscosity of the formulation, and the temperature of the cooling air within the chamber to allow for instant solidification of the droplets. Drug granules have been reported to be prepared by melt granulation using PEG 4000 or Poloxamer 188 as the meltable binder and lactose monohydrate as the filler. Microparticles with a narrow size distribution have been reported when polyoxystearoyl glycerides (GELUCIRE® 50/13) were used as an excipient and significantly increased solubility of poorly water-soluble drugs (Cavallari et al.).

Melt granulation, also known as pelleting, transforms a powder mixture of active agent into granules or pellets. A meltable binder (melt) is sprayed onto the powder mixture under high-shear mixing ("pumping" technique), or the meltable binder is mixed with the powder mixture and melts due to particle friction (solid/semi-solid) during high-shear mixing. The molten binder forms liquid bridges between powder particles and forms small granules that transform into spheronized pellets under controlled conditions. Depending on powder fineness, 15%–25% of the lipid-based binder can be used. Process parameters that must be considered are binder particle size, mixing time, impeller speed, and the viscosity of the melted binder. The dissolution rate of a drug was improved by formulating melt agglomerates containing solid drug dispersions (Seo et al.). Lactose monohydrate was melt agglomerated with a meltable binder, e.g., PEG 3000 from GELUCIRE® 50/13, in a high-shear mixer.

Polyoxyglycerides, partial glycerides or polysorbates and lecithins are exemplary lipid excipients used in the melt granulation technique to form self-microemulsifying systems.

In some embodiments, the sustained release matrix tablets can be formulated using hydrophobic carriers or meltable binders such as stearic acid, carnauba wax, and beeswax, by melt granulation techniques, rendering the carriers hydrophobic for sustained delivery.

In one embodiment, a pulsatile release form is used. The pulsatile release form includes an active agent core having one or more coatings, referred to as a "coated core" formulation. The coated core can also be used in combination with an amount of the active agent suitable for immediate release.

In one embodiment, an amount of active agent formulated for immediate release in combination with at least a second amount of active agent, formulated such that the second amount has a delay before onset and the release of the second portion is or can be prolonged over time, is referred to as a "delayed extended-release" formulation. Each of these pulsatile-release dosage formulations is described in more detail, with all percentages by weight unless otherwise indicated.

The "coated core" formulation is an active agent core of the dosage form that includes an inert particle such as a commercially available nonpareil sugar sphere. The amount of active agent in the core varies depending on the desired dose to be administered. In one embodiment, the core contains from about 5% active to about 90% active. In one embodiment, the core contains from about 5% active to about 60% active. The amount of active is based on the total weight of the core. Those skilled in the art will be able to select an appropriate amount of active agent to coat or incorporate into the core to achieve the desired dosage form. Typically, the coated core may include about 80 mg, 160 mg, up to about 480 mg of active agent. An aqueous or pharmaceutically acceptable solvent medium may be used to coat the core particles. Any type of pharmaceutically acceptable inert binder can be used to bind the active agent to the inert particle. Water-soluble binders can be used. Alcohol-soluble binders can be used. Binders such as polyvinylpyrrolidone (PVP), carboxyalkylcelluloses, polyethylene oxide, polysaccharides, such as dextran, corn starch, hydroxypropyl methylcellulose (HPMC (formerly) or hypromellose (now)), hydroxypropyl cellulose, etc. can be used by dispersing them in water at a concentration of about 0.5% by weight to 5% by weight. The active agent in this coating formulation can be in the form of a solution or in the form of a suspension. The concentration of active agent can vary from about 0.1% by weight to about 20% by weight, depending on the viscosity of the coating formulation.

In one embodiment, the active core is prepared by granulation or by extrusion and spheronization. The active agent, a binder such as PVP, an optional dissolution rate controlling polymer, such as high viscosity HPMC (hypromellose), and optionally other pharmaceutically acceptable excipients are mixed in a high shear granulator (e.g., FIELDER® granulator) or a fluid bed granulator (e.g., GLATT® GPCG granulator), granulated to form agglomerates by adding/spraying a granulating fluid, such as water or alcohol, and dried. The wet mass is extruded and spheronized to produce spherical particles (beads) using an extruder. In these embodiments, the drug loading may be 90% by weight based on the total weight of the extruded or granulated core.

In one embodiment, one membrane coating layer on the active-containing particle includes a plasticized enteric polymer, and the other layer includes a blend of a water-insoluble polymer and a plasticized enteric/water-dispersible polymer. The water-insoluble polymer and water-dispersible polymer are present in a weight ratio of about 10:1 to 1:1, or about 4:1 to 1:1. The total weight of the coatings is about 15% by weight to 80% by weight, or about 20% by weight to about 60% by weight based on the total weight of the multiparticulate dosage form.

An acid-containing intermediate membrane is optional. If included, the acid-containing intermediate membrane may include an organic acid, e.g., fumaric acid, citric acid, succinic acid, tartaric acid, malic acid, maleic acid, etc.; and a binder, e.g., PVP. Typically, water-soluble polymers or alcohol-soluble polymers are used. The weight of this acid-containing membrane is about 5% to about 20% based on the total weight of the coated beads. The acid in the acid-containing membrane retards the dissolution of the enteric polymer in the inner layer, thereby increasing the lag time and decreasing the release rate of the active agent from the coated bead. The composition of the outer layer of the polymeric membrane and the individual weights of the inner, middle, and outer membrane layers are further optimized to achieve pulsatile release profiles for the active based on predicted in vitro/in vivo correlations. Thus, the pulsatile release dosage formulation is optimized to release an amount of active agent after a predetermined period of time and/or at a particular point in the digestive tract of the individual to whom the formulation is being administered.

Examples of enteric polymers include, but are not limited to, the following compounds or composition, alone or in combination: cellulose esters and their derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methacrylate copolymers, and shellac. These polymers can be used as a dry powder or as an aqueous dispersion. Available are EUDRAGIT® L100, S100, L30D methacrylic acid copolymers (Rohm Pharma), CELLACEFATE® cellulose acetate phthalate (Eastman Chemical Co.), AQUATERIC® cellulose acetate phthalate aqueous dispersion (FMC Corp.), and AQOAT® hydroxypropyl methylcellulose acetate succinate aqueous dispersion (Shin Etsu K.K.).

Examples of water-insoluble polymers include, but are not limited to, the following compounds or compositions, alone or in combination: cellulose derivatives (e.g., ethylcellulose), polyvinyl acetate (KOLLICOAT® SR 30D, BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as, EUDRAGIT® NE, RS or RS30D, RL or RL30D, etc.

Membrane coatings can be applied to the core using any pharmaceutical coating method known in the art. For example, a fluidized bed coating can be used.

A pulsatile release dosage formulation can be prepared by (i) coating an inert particle, for example, a nonpareil seed (sugar sphere), with the active agent and the polymeric binder, or by preparing the active agent-containing particle by granulation and/or extrusion/spheronization to form an active agent particle; (ii) coating the active agent particle with a plasticized enteric coating, forming the plasticized enteric-coated active agent particle; and (iii) coating the plasticized enteric-coated active agent particle with a mixture of a water-insoluble polymer and an enteric polymer. The release characteristics can be modulated by interchanging parts (ii) and (iii). An organic acid, as described above, can be added to the membrane between parts (ii) and (iii) to further modulate the lag time and release profile of active agent from the particle.

In one embodiment, the formulation may use a single particle form to provide a time-controlled pulsatile release of the active agent several hours after oral administration, or to target specific absorption sites. In one embodiment, dosage forms incorporating the multi-layered active-containing particles are combined in a compounded dosage formulation with an immediate-release amount of active, for example, in a gelatin capsule, either hard gelatin or soft gelatin. This embodiment provides a compounded dosage form having both an immediate-release portion and a time-controlled pulsatile release portion of the active agent.

The optional immediate release portion and the active of the coated core may each include about 10 mg, 20 mg, etc. of active, a coated core dosage form of the present invention may contain about 10 to 80 mg of active.

In one embodiment, a delayed extended release form is used.

In one embodiment, a dosage form can provide at least one bimodal blood profile of active agent, for example the profile shown in FIG. 2. In this embodiment, the dosage form contains at least a first amount of active agent for immediate release and a second amount of active agent for delayed extended release. For example, a first portion of active agent is released immediately during the first hour after administration of the dosage form of the invention. There is a period of time elapsed where substantially no active agent is released and/or is able to enter the circulation, and/or is bioavailable from a second portion of the administered active agent. Then, after another time elapsed, for example, a few hours, additional active agent is released and the release of this second portion occurs over an extended period of time, for example up to 12 hours after the initial administration or even longer. This release of the second portion typically occurs after a delay period during which no active agent is released, so such dosage forms that may exhibit a delay before the onset of release of a quantity of active agent are referred to as "delayed extended-release" dosage forms. Such a dosage form can be administered alone or in combination with other dosage forms.

It is desirable that the blood level of the active agent increases, with the blood concentration corresponding to the amount of active agent that is bioavailable after immediate release within the first hour after administration. Over time, the blood levels of the active agent decrease to levels below desirable or therapeutic levels. The second portion of the active agent may enter the circulation after the immediate-release portion of the active agent has been released. In some embodiments, after the blood levels of the active agent begin to decrease, the formulation desirably increases and/or maintains the blood levels at or above the desired concentration without the need to administer a second dose of the active agent.

The following example illustrates one embodiment. The first immediate-release portion of the active agent has an initial pharmacokinetic profile. Fillers, excipients, etc., may represent the final weight percentage.

Formulations for delayed, sustained, or extended release are as follows. Each sustained-release composition includes an amount of active agent formulated to release the active agent over a period of 4 to 12 hours, typically 6 to 12 hours.

Polyols, such as mannitol, coagulants, such as POLYOX®, and lubricants, such as stearic acid, are added to produce a granulation that can provide a delayed- and extended-release active agent formulation. Coated tablets, lozenges, or other dosage forms of the delayed-release formulation are prepared using methods known in the art, including encapsulation methods. Such dosage forms, without more, typically exhibit "sustained-release" blood profiles, that is, the dosage forms typically release the active agent immediately after ingestion and continue to release the active agent over time. These compositions can also be formulated in a dosage form and can exhibit extended-release profiles, releasing active agent over a period of a few hours to 12 hours after ingestion.

In one embodiment, the dosage forms formed from the compositions may optionally be coated with a base to seal the tablets for further processing. Sealants include, for example, HPMC, (poly)ethylene glycol (PEG), etc.

In one embodiment, a dosage form has one or more bands of one or more polymeric materials, as described and shown below in FIG. 17. One or more circumferential or other bands of polymeric material are used, e.g., a relatively insoluble polymeric material that only minimally or not at all erodes or degrades during the dispensing period. Typical insoluble polymers include the water-insoluble polymers described above. The number of bands, the position or spacing between bands, and the thickness of the bands can control the rate of active agent release. For example, there may be a 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, or 3.0 mm space between bands if multiple bands are used. For example, each band may be 0.5 mm, 1.0 mm, 1.5 mm, or 2.0 mm wide and have a thickness of about 0.1 microns to 100 microns, or 0.1 microns to 50 microns, or 0.1 microns to 20 microns. As shown in FIG. 17, in one embodiment, a caplet has two circumferential polymeric bands, each band 20 and 30 having a width of about 1 mm and a separation 40 of about 2 mm. The banded formulation slows the release of the active agent and prolongs the period of time over which the active agent can be released and/or enter the circulation, i.e., become bioavailable. In some embodiments, the band(s) delay the onset of active release such that there is a lag time, also referred to as delayed onset or delayed release, during which no active is released. A delayed onset may be 0 hours to 4 hours, or it may be 0 hours to 3 hours, or it may be 0.5 hours to 4 hours, or it may be 1 hour to 2 hours after administration.

The enteric coating may also include other excipients or fillers, for example, talc, lactose, dicalcium phosphate, lubricants, such as magnesium stearate, etc.

The banded dosage form may be enteric coated at a level of about 2 µg/cm2 to 10 µg/cm2, typically about 7 µg/cm2. The enteric coating delays the onset of active agent so that there is a time during which no active agent is released after administration of the dosage form. Typically, after enteric coating, the delay in onset of active agent from a coated banded dosage form (e.g., an enteric-coated banded tablet) may be from 0.5 hours to 4 hours, typically from 1 hour to 2 hours.

In one embodiment, an immediate-release dose of the active ingredient described above is combined with an enteric-coated banded caplet using methods known in the art to produce a single compounded dosage form, for example, in a single gelatin capsule. The formulation can be tailored to provide a specific desired blood profile.

In some embodiments, the compositions include at least one immediate-release formulation and one sustained-release formulation, described further below. Sustained-release formulations typically do not have a delayed onset of active agent. The sustained-release formulation typically does not have a significant period of time during which the drug becomes bioavailable from the dosage form after administration.

In one embodiment, a tablet capsule is a capsule containing a first active portion in tablet form that is formulated for immediate release upon ingestion or administration, and at least a second active portion that is in a tablet form formulated for sustained release, i.e., the second portion continues to release an amount of active for up to 6-12 hours after ingestion. At least 15%-50% of the active agent is an immediate release formulation and is in a tablet form suitable for immediate release. The remainder of the tablet capsule, by weight, may include a sustained release formulation of active agent or a portion of the sustained release formulation of active agent. The tablet containing an immediate release formulation of active agent and the tablet containing a sustained release formulation of active agent may be combined into a single dosage form, e.g., a gelatin capsule, using methods known in the art.

In one embodiment, a granulation caplet is a capsule or caplet containing a first portion of an active agent granulate formulated for immediate release, and at least a second portion of active agent in tablet form formulated for sustained release. At least 15%-50% of the active agent is an immediate release formulation and may be in the form of granules rather than a tablet. In one embodiment, at least about 80% of the granulation capsule includes an immediate release active composition in granular form, typically contained in a separate caplet. The remainder of the granulation caplet, by weight, may include a sustained release active formulation, or the granulation caplet may include a portion of the sustained release active formulation. The coated tablet containing an immediate release active formulation and the coated tablet containing a sustained release active formulation may be combined into a single dosage form, e.g., a gelatin capsule, using methods known in the art.

In one embodiment, a layered tablet contains a tablet having two or more layers with the active formulated for immediate release, and a layer of active formulated for sustained release. The layered tablet contains an amount of active agent for immediate release upon ingestion, and at least a second portion of active agent that can immediately provide an amount of active agent for up to 6 hours-12 hours after ingestion of the layered tablet. At least 15%-50% of the active is an immediate release formulation. In one embodiment, at least about 80% of the layered tablet includes an active composition for immediate release. The remainder of the layered tablet, by weight, may include a sustained release formulation of active, or may include a portion of the sustained release formulation of active. The formulations may be compounded in a conventional manner, for example, in a tablet press, such that after processing the final tablet dosage form has two or more layers, at least a first layer containing the immediate release formulation of active agent and a second layer containing the sustained release formulation of active agent.

In one embodiment, the active is at least 20% to 30%, 30% to 60%, or 70% by weight of the sustained release composition, with the remaining weight consisting of excipients in the composition, e.g., fillers, lubricants, polymers, etc. The polymer may be present from 5% to 20% by weight of the sustained release composition in one embodiment, and from 7% to 10% by weight of the sustained release composition in one embodiment, and from 10% to 16.5% by weight of the sustained release composition in one embodiment. In one embodiment, the polymer is a cellulosic polymer, e.g., Methocel K4M, and is present at about 10% by weight. The sustained release formulation may be prepared by direct compression or wet granulation.

The formulation can be compressed into tablets or incorporated directly into food. Such compositions should contain at least 0.1% of the active compound. The percentage of the compositions and preparations can vary, for example, from 2% to approximately 60% of the unit weight.

Excipients include, but are not limited to, one or more of a pharmaceutically acceptable inert diluent; an assimilable edible carrier; a disintegrant to facilitate disintegration, for example, modified cellulose derivatives, modified starch derivatives, etc., it being appreciated that one of skill in the art will appreciate that other ingredients, including binders and lubricants, may also affect the dissolution profile of the dosage form; a hard or soft shell gelatin capsule; dicalcium phosphate; a binder such as gum tragacanth, acacia, corn starch, or gelatin; a disintegrating agent, such as corn starch, potato starch, alginic acid, etc.; a lubricant, such as magnesium stearate; a sweetening agent, such as sucrose, lactose, or saccharin; a flavoring agent, such as peppermint, oil of wintergreen, cherry flavoring; one or more surfactants, such as ionic, non-ionic and/or bile salt surfactants, with anionic surfactants including sodium alkyl sulfate (sodium lauryl sulfate) and sulfosuccinate derivatives such as docusate sodium, non-ionic surfactants including polyoxyethylene sorbitan fatty acid esters (polysorbates), such as TWEEN® 20, TWEEN® 80, TWEEN® 40, SPAN® 20, fatty acid esters of polyethylene glycols such as GELUCIRE® 44/14, GELUCIRE® 50/13, saturated polyglycolyzed monoglycerides (including mono, di or tri) medium chain (6-10 carbon) glycerides, such as glyceryl monocaprylate (IMWITOR® 308), glyceryl monocaproate (CAPMUL® MCM C-8), glyceryl caprylate/caprate (CAPMUL® MCM), polyoxyethylene glyceryl caprylate, and polyoxyethylene glyceryl caproate (LABRASOL®), medium chain fatty acid esters, such as, glyceryl tricaprate and glyceryl tricaprate (MIGLYOL® 612), block polymers of ethylene oxide and propylene oxide, polyoxyethylene-polyoxypropylene block copolymers, such as, Poloxamer 188 (PLURONIC® F-68), Poloxamer 237 (PLURONIC® F-87), Poloxamer 338 (PLURONIC® F-108), Poloxamer 407 (PLURONIC® F-127), Poloxamer 124 (PLURONIC® L-44), polyoxystearate-polyethoxylated stearic acid (40) (MYRJ® 52), ethoxylated castor oil - hydrogenated polyethoxylated (60) castor oil (CREMOPHOR® EL), ethoxylated hydrostearic acid polyethylene glycol 660 hydroxystearate (SOLUTOL® HS 15), polyoxyethylene (12-18 carbon) alkyl ethers, such as, polyoxylated 20 cetostearyl ether (ATLAS® G-3713), polyoxylated 10 oleyl ether (BRIJ® 96, BRIJ® 97, Oleth 10), polyethylene glycol ether (TRITON™ X-100, TRITON™ X-114, TRITON™ X-405, TRITON™ N-101) and lecithins, such as, phospholipids (dimyristoyl DL-alpha-phosphatidylcholine), bile salt surfactants including deoxycholic acid, sodium deoxycholate, cholic acid, sodium taurocholate; etc. A capsule dosage form may also contain a liquid carrier. Other materials may be present as coatings or to otherwise modify the physical form of the dosage form, e.g., tablets, pills, or capsules may be coated with shellac and/or sugar. A syrup or elixir may contain the active agent, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring agent.

In some embodiments, other active ingredients may be included in the formulation.

In one embodiment, the dosage forms are a liquid-filled soft gelatin capsule containing excipients such as lipids, surfactants, and solvents. The capsules may contain immediate-release, delayed-release, sustained-release, or controlled-release formulations.

The formulation may contain excipients such as one or more fatty acids. The method involves dissolving, melting or suspending a poorly water-soluble active agent in one or more fatty acids, conjugated fatty acids, (semi)solid surfactants with a high HLB value and/or hydrophilic polymers. Suitable fatty acids include C<10>-C<18> fatty acids, preferably C<16>-C<18> fatty acids. Suitable conjugated fatty acids include C<10>-C<18> fatty acids, preferably C<16>-C<18> fatty acids, conjugated with glycerol (e.g. monoglycerides), monosaccharides and/or polyethylene glycol (PEG). Suitable hydrophilic polymers include poloxamers and poloxamines.

Suitable fatty acids include C<10>-C<18> fatty acids, more preferably C<16>-C<18> fatty acids. Exemplary fatty acids include, but are not limited to, dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid, tritriacontanoic (ceromelissic) acid, tetratriacontanoic (gedic) acid, and pentatriacontanoic (ceroplastic) acid. Fatty acids can be saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids or combinations thereof.

Oils, for example, vegetable oils such as soybean oil, can be used alone or in combination with the coating materials listed above. Soybean oil contains 14.4% saturated fatty acids, 23.3% monounsaturated fatty acids, such as oleic acid, and 57.9% polyunsaturated fatty acids, such as linoleic acid and alpha-linolenic acid.

In one embodiment, the fatty acid is covalently coupled to glycerol, a monosaccharide, such as sorbitol or sorbitan, a polyalkylene oxide, such as polyethylene glycol and polypropylene glycol, or combinations thereof. These materials are referred to as conjugated fatty acids. Suitable conjugated fatty acids include, but are not limited to, polyethylene glycol esters of fatty acids, such as those commercially available under the tradename GELUCIRE®, sorbitan esters of fatty acids, such as sorbitan monostearate, glycerol fatty acid esters of the above-listed fatty acids, such as glycerol behenate and glyceryl monostearate, and combinations thereof.

The concentration range of the fatty acid is from about 1% to about 20% by weight of the composition, preferably from about 5% to about 15% by weight of the composition (microparticles and carrier).

The water-insoluble active agent can be coated with one or more surfactants, alone or in combination with one or more fatty acids or conjugated fatty acids and/or one or more hydrophilic polymers. In one embodiment, the surfactant has an HLB value greater than about 10, greater than about 12, greater than about 14, or greater than about 16 (on a scale of 1-18). Surfactants having the desired HLB are known in the art. The surfactant can be anionic, cationic, or nonionic. In one embodiment, the surfactant is a nonionic surfactant.

Examples of such surfactants include, but are not limited to, polysorbate 20, 40 and 80 (marketed under the name TWEEN®), polyoxyethylene monostearate, certain sugar esters such as sucrose monolaurate, ethoxylated nonylphenols, alpha olefin sulfonates, ethoxylated tallow amines, ethylene oxide/propylene oxide block copolymers, ethoxylated soybean amines, fatty acids and alcohols, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers and polyoxyethylene stearates.

In one embodiment, the surfactant is a high HLB surfactant containing a fatty acid chain. Suitable surfactants include, but are not limited to, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers, and polyoxyethylene stearates.

Polyoxyethylene castor oil derivatives primarily contain ricinoleyl glycerol ethoxylated with 30 to 50 molecules of ethylene oxide. Polysorbates or polyoxyethylene sorbitan fatty acid esters are a series of partial fatty acid esters of sorbitol and its anhydrides copolymerized with approximately 20, 5, or 4 moles of ethylene oxide per mole of sorbitol and its anhydrides. The resulting product is a mixture of molecules with a wide range of molecular weights. Polyoxyethylene alkyl ethers are a series of polyoxyethylene glycol ethers of linear fatty alcohols (n-alcohols), such as lauryl, myristyl, cetyl, and stearyl alcohol. Polyoxyethylene stearates are produced by polyethoxylation of stearic acid.

Without wishing to be bound by any theory, it is believed that the hydrophilic portion of the surfactant improves the compatibility of the active agent with aqueous dissolution media in vitro or in vivo, and that the fatty acid side chain enhances absorption through fatty acid oxidation. During fatty acid oxidation, intracellular Ca2+ is consumed, resulting in the widening of gap junctions, allowing passage of the active agent between cells. Furthermore, such coated particles may be more stable than the drug alone, for example, by preventing oxidation of the active agent.

The concentration of the surfactant is from about 1% to about 50%, preferably from about 5% to about 15% by weight of the composition (microparticles and carrier).

Suitable hydrophilic polymers include, but are not limited to, poloxamers, poloxamines, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidone, polyvinyl alcohol, cellulosic materials, such as, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, carboxymethylcellulose, and polypeptides.

The concentration of the hydrophilic polymer is from about 1 to about 50% by weight of the composition, more preferably from about 5% to about 15% by weight of the composition. If the hydrophilic polymer is a polyethylene glycol, the concentration is from about 1% to about 80% by weight of the composition, from about 30% to about 60%, from about 35% to about 60%, or from about 40% to about 60% by weight of the composition (microparticles and carrier).

In one embodiment, the microparticles are formed by adding a mixture of the drug and the coating material(s) to a pharmaceutically acceptable carrier. In one embodiment, the carrier is a hydrophilic or lipophilic carrier. The resulting particles are suspended in the carrier. The carrier may consist of a single component or a mixture of components. The carrier may include solvents, surfactants, or other excipients. The carrier materials may alter or modify the rate of drug release from the microparticles and/or the rate of drug dissolution. The compositions may exhibit a biphasic release profile due to the controlled-release properties of the microparticles and the controlled-release properties of the carrier. Varying the qualitative and quantitative composition of the carrier materials may allow the release profile of the active agent to be modulated. The carrier may contain one or more rate-controlling excipients that regulate the release of the active agent. Exemplary rate controlling excipients include, but are not limited to, glyceryl behenate, GELUCIRE®, CREMOPHOR®, hydrogenated vegetable oil, beeswax, cellulosic polymers, such as hypromellose, alginates, CARBOPOL® and combinations thereof.

In one embodiment, the carrier is a hydrophilic carrier containing a surfactant having an HLB value greater than about 10, greater than about 12, greater than about 14, or greater than about 16, and/or is water-soluble. Exemplary hydrophilic carriers include, but are not limited to, polyethylene glycols, polyoxyethylene 32 lauric glycerides (available from Abitech under the tradename ACCONON® M-44), polyoxyethylene 8 caprylic/capric glycerides (available from Abitech under the tradename ACCONON® MC-8), and glycofurol. The hydrophilic carrier may further contain one or more miscible solvents, such as glycerin, ethanol, glycofurol, and caprylocaproyl macrogol-8 (available from Gattefosse S.A., Saint Priest, France under the tradename LABRASOL®).

In one embodiment, the hydrophilic vehicle is water or an alcohol. In another embodiment, the vehicle is a mixture of hydrophilic vehicles containing polyethylene glycol and, optionally, one or more surfactants and/or water. In a particular embodiment, the hydrophilic vehicle is a mixture of PEG 400 (e.g., 57% by weight of the composition), water (e.g., 8% by weight of the composition), and TWEEN® 20 (e.g., 10% by weight of the composition). The hydrophilic vehicle may also contain CREMOPHOR® RH 40. The concentration of the hydrophilic vehicle is generally from about 50% to about 85% by weight of the composition (microparticles and vehicle), preferably from about 70% to about 80% by weight of the composition.

In another embodiment, the carrier is a lipophilic carrier. In a preferred embodiment, the lipophilic carrier has an HLB value of less than about 10 and/or is oil-soluble. Exemplary lipophilic oily vehicles include, but are not limited to, vegetable oils, mono-, di- and medium chain triglycerides, glyceryl stearates (available from Sasol under the trade name IMWITOR®), polyoxyethylated oleic glycerides (available from Gattefosse, SA., Saint Priest, France, under the trade name LABRAFIL®), mineral oil, mono- and diglyceride emulsifiers, such as, glyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate, propylene glycol monocaprylate and propylene glycol monolaurate (available from Abitec Corp., Columbus, Ohio, under the trade name CAPMUL®), and dimethylpolysiloxanes, such as, simethicone.

The concentration of the lipophilic carrier is generally from about 10% to about 50% by weight of the composition (microparticles and carrier), preferably from about 5% to about 35% by weight of the composition.

The disclosed compositions may contain one or more pharmaceutically acceptable excipients that are considered safe and effective and that can be administered to an individual without causing undesirable biological side effects or unwanted interactions. Exemplary additives include, but are not limited to, solvents, suspending agents, dispersants, buffers, pH modifying agents, isotonicity modifying agents, preservatives, antimicrobial agents, and combinations thereof. Suitable additives for inclusion in the compositions disclosed herein include, but are not limited to, antioxidants (e.g., alpha tocopherols, such as vitamin E acetate, ascorbic acid, butylated hydroxyanisole, and butylated hydroxytoluene); polar solvents (e.g., water, propylene glycol, and glycerin); hydrophobic solvents (e.g., corn oil, castor oil, soybean oil, olive oil, fish oil, peanut oil, peppermint oil, safflower oil, sesame oil, medium-chain triglycerides, caprylic triglycerides, capric triglycerides derived from coconut oil or palm kernel oil); and viscosity-increasing agents (e.g., gelatin, glycerin, carrageenan, colloidal silicon dioxide, hydrogenated vegetable oil; povidone; and propylene glycol alginate).

The microparticle compositions described herein are generally formulated for oral or parenteral administration. Suitable oral dosage forms include capsules, such as hard or soft capsules, gelatin or non-gelatin, or oral suspensions or syrups (e.g., FIG. 21). Suitable parenteral formulations include suspensions.

In one embodiment, the microparticle compositions (microparticles suspended in a hydrophilic or lipophilic carrier) are encapsulated in a capsule, such as a hard or soft capsule. The capsules can be prepared from natural and/or synthetic film-forming polymers. Suitable natural film-forming materials include, but are not limited to, gelatin. Non-gelatin capsules include, but are not limited to, capsules made from carrageenan, shellac, alginates, pectin, and zeins. Suitable synthetic film-forming polymers include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and acrylates such as poly(meth)acrylate.

The compositions may also be encapsulated in an enteric capsule, wherein the capsule is coated with an enteric coating or the capsule shell contains an enteric polymer as described in WO 2004/030658 to Banner Pharmacaps, Inc.

Hard-shell capsules are typically prepared by forming two capsule halves, filling one half with the fill solution, and then sealing the capsule halves to form the finished capsule. Soft gelatin capsules are typically prepared by a rotary die encapsulation process. Such processes are known in the art.

The capsule shell may contain one or more additives. Suitable shell additives include plasticizers, opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids, and combinations thereof.

Plasticizers are chemical agents added to gelatin to make the material softer and more flexible. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions (mixtures of sorbitol and sorbitan), and other polyhydric alcohols such as propylene glycol and maltitol, or combinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulated active agents are photosensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

Colorants can be used for marketing and product identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of properly stored, dry softgels, the greatest risk of microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid, such as methyl, ethyl, propyl, butyl, and heptyl esters (collectively known as "parabens"), or combinations thereof.

Flavorings can be used to mask unpleasant odors and flavors in filler formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes, which can crosslink gelatin. As a result, buffering salts and acids can be used, along with flavorings containing aldehydes, to inhibit gelatin crosslinking.

Medium-chain triglycerides may also be used. As used herein, "medium-chain triglycerides" means C<6-12> ester chains formed by the esterification of glycerol with three fatty acids. There are several sources of medium-chain triglycerides, for example, coconut oil, palm kernel oils, etc. Fractionated coconut oils are the most commonly used sources for medium-chain triglycerides. Examples of commercially available medium-chain triglycerides may include MIGLYOL® 810, 812 or 881 produced by Sasol Germany GmbH, c A pTEX® 300, 355 or 810D produced by Abitec Corporation, NEOBEE® M5 by Stepan Company, CRODAMOL® GTC/C produced by Croda Inc, and LABRAFAC® Lipophile WL 1349 produced by Gattesfosse Group. In an exemplary embodiment, the medium chain triglyceride may comprise CApTEX® 355, which is a caprylic (C8)/capric (C10) acid triglyceride.

Various amounts of the medium chain triglycerides may be included in the pharmaceutical formulation. In one or more embodiments, the pharmaceutical formulation may comprise from about 50% to about 95% by weight of medium chain triglycerides, or from about 85% to about 95% by weight of medium chain triglycerides. Furthermore, in embodiments, the pharmaceutical formulation may include from about 100 mg to about 300 mg, or from about 200 mg to 300 mg of the medium chain triglycerides by weight, or from about 225 mg to 275 mg of the medium chain triglycerides by weight, or about 250 mg by weight of the medium chain triglycerides.

Similar to medium-chain triglycerides, “medium-chain monoglycerides” and “medium-chain diglycerides” are C<6-12> ester chains formed by the esterification of glycerol with one or two fatty acids, respectively. Examples of commercially available medium-chain mono/diglycerides may include the CAPm Ul® products produced by Abitec. The use of medium-chain mono/diglyceride compounds that also include medium-chain triglycerides is also contemplated, for example, the commercially available IMWITOR® compositions produced by Sasol.

In embodiments, the medium chain mono/diglycerides may comprise CAPMUL® MCM, including caprylic (C8)/capric (C10) acid medium chain mono/diglycerides. While all grades of the CAPMUL® MCM product line are suitable for use in the present invention, for example the National Formulary (NF) grade or CAPMUL® MCM EP, it may be desirable to use the EP grade since it includes 3% glycerol, while the NF grade includes 7% glycerol.

According to one or more embodiments, the pharmaceutical formulation may comprise from about 5% to about 25% by weight of medium chain mono/diglycerides, or from about 5% to about 15% by weight of medium chain mono/diglycerides. Furthermore, in exemplary embodiments, the pharmaceutical formulation may include about 20 mg to about 50 mg of medium chain mono/diglycerides by weight, or about 25 mg to about 30 mg of medium chain mono/diglycerides by weight, or about 25 mg of medium chain mono/diglycerides by weight.

Without intending to be bound by any theory, the mixture of medium chain triglycerides and medium chain mono/diglycerides is important for the bioavailability of the active agent ingredient within the liquid-filled hard gel capsule formulation. While a soft gel capsule may include only medium chain mono/diglycerides, a hard gelatin capsule with only medium chain mono/diglycerides may not provide the required physical stability of the finished dosage forms. However, a mixture of medium chain triglycerides and medium chain mono/diglycerides within a hard gelatin capsule can achieve the desired product stability, solubility, and bioavailability of the active agent pharmaceutical ingredient. Accordingly, in accordance with the invention, the weight ratio of medium chain triglycerides to medium chain mono/diglycerides facilitates the solubility and stability of the active agent pharmaceutical ingredient (e.g., dutasteride) within the non-emulsified mixture before and after the mixture is added to the capsule. Medium chain triglycerides and medium chain mono/diglycerides may be present in a weight ratio of about 10:1 to about 5:1, or about 10:1 to about 7:1.

In addition to the above components, other excipients known to one skilled in the art may be used, for example, excipients in the oral composition may be diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners.

Diluents may include liquid diluents, such as, any long chain triglycerides (peanut oil, almond oil, peanut oil, palm oil, palm kernel oil, blackcurrant seed oil, rice bran oil, soybean oil, canola oil, corn oil, coconut oil, cottonseed oil, castor oil, olive oil, Linn (Neem) oils, sesame oil, evening primrose oil, vegetable oil, LIPEX 108 (Abitec), wheat germ oil, fish oil, rapeseed oil, sunflower oil, and safola oil). In alternative embodiments, it is contemplated that other diluents may be used, for example, diluents selected from calcium aluminum silicates (SIPERNAT® 106PQ), calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, silicified cellulose microcrystalline, powdered cellulose, dextrates, dextrose, fructose, lactitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol, silicon dioxide, HPMC and combinations thereof.

The formulation includes the route of administration, the type of preparation, non-active ingredients, release of the active agent, stability, scale-up, new processes for preparing the active agent, new processes for the formulation.

In vivo performance evaluation includes pharmacokinetic data such as pK/pD, such as Tmax, Cmax, plasma concentration curve, efficacy, side effects, etc.

Other release profiles include, but are not limited to, controlled, enteric, sustained, rapid, multiphasic, etc. The invention encompasses other known and to be determined uses of the inventive formulations of domperidone and deuterated domperidone.

Chang and Robinson, Chapter 4: Sustained Drug Release from Tablets and Particles Through Coating, Pharmaceutical Dosage Forms: Tablets, Vol. 3, Eds. Lieberman, Lachman, and Schwartz, Marcel Dekker, Inc., 1991.

Campbell and Sackett, Chapter 3: Film coating, Pharmaceutical Unit Operations: Coating, edited by Avis, Shukla, and Chang, Interpharm Press, Inc., 1999.

Youssef et al., Identification of Domperidone Metabolites in Plasma and Urine of Gastroparesis Patients with LC-ESI-MS/MS, Xenobiotica 43 (2013) 1073-1083.

Michaud et al., An Improved HPLC Assay with Fluorescence Detection for the Determination of Domperidone and Three Major Metabolites for Application to in vitro Drug Metabolism Studies, J. Chromatogr. B, 852 (2007) 611-616.

The disclosed compositions include a therapeutic amount of domperidone or deuterated domperidone or a pharmaceutically acceptable salt thereof and at least one excipient. The excipient may, for example, facilitate administration of the active agent. As described above, other active agents may be included, for example, analgesic agents, anesthetic agents, antioxidants, antimicrobial agents, antifungal agents, vitamins, etc.

One or more analgesic agents may be included in the pharmaceutical compositions to provide relief from pain that may result from gastroparesis. Examples of analgesics include, but are not limited to, simple analgesics, such as acetaminophen or aspirin; nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac sodium, or naproxen sodium; and/or opioids, such as codeine, dihydrocodeine, codeine phosphate, fentanyl, methadone, tramadol hydrochloride, dextropropoxyphene hydrochloride, morphine, oxycodone, buprenorphine, or pethidine hydrochloride.

One or more anesthetic agents may be included in the pharmaceutical compositions to induce temporary and reversible absence of the sensation of pain caused by gastroparesis. Examples of anesthetics include, but are not limited to, one or more of lidocaine, benzocaine, bupivacaine, articaine, cocaine, etidocaine, flecamide, mepivacaine, pramoxine, prilocalne, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, tetracaine, dyclonine, dibucaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rhodocaine and pharmaceutically acceptable derivatives thereof.

One or more antioxidants may be included in the pharmaceutical compositions. Examples of antioxidants include, but are not limited to, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, diethylenetriaminepentaacetic acid (DTPA), edetates (EDTA), monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, triglycolamate, vitamin E or a derivative thereof, and propyl gallate.

In one embodiment, deuterated domperidone, and optionally any other agent, is incorporated into or onto particles, including nanoparticles. The deuterated domperidone particles can be suspended or dispersed in an aqueous medium. The particle size can range from microparticles (|µm) to nanoparticles (nm).

A human or other mammal suffering from gastrointestinal motility disorders may be treated by periodic administration of the disclosed inventive pharmaceutical compositions one or more times daily. The pharmaceutical agents, including deuterated domperidone and any adjunctive therapeutic agents, are present in the composition in an amount that constitutes a therapeutically effective dose. A therapeutically effective dose is an amount of the pharmaceutical agent that, upon treatment, produces a degree of symptom reduction relative to the pre-dose symptom state.

Pharmaceutical compositions can be administered one to four times a day.

In one embodiment, the deuterated domperidone is administered in the range between about 0.1 mg and about 120 mg, or in the range between 0.01% and 12.0% w/w, or in the range between about 0.0014 mg/kg and about 1.71 mg/kg. In other embodiments, the domperidone or deuterated domperidone is administered in a range between about 0.5 mg and about 100 mg, or in a range between about 0.05% and about 10.0%, or in a range between about 0.007 mg/kg and about 1.43 mg/kg. In one embodiment, the deuterated domperidone is administered in a range between about 1 mg and about 60 mg, or between about 0.1% and about 6.0%, or between about 0.014 mg/kg and about 0.86 mg/kg. In one embodiment, the deuterated domperidone is administered in a range between about 2.0 mg and about 30 mg, or between about 0.2% and about 3.0%, or between about 0.028 mg/kg and about 0.43 mg/kg. In one embodiment, the deuterated domperidone is administered in a range between about 0.5 mg and about 120 mg, or between about 0.05% and about 12.0%, or between about 0.007 mg/kg and about 1.71 mg/kg. In one embodiment, the deuterated domperidone is administered in a range between about 2.0 mg and about 40 mg, or between about 0.2% and about 4.0%, or between about 0.028 mg/kg and about 0.57 mg/kg. All % designations are w/w.

The formulations may also include excipients. Exemplary excipients include, but are not limited to, binders, fillers, solvents, lubricants, antioxidants, buffering agents, salts, surfactants, vitamins, pigments, flavorings, disintegrating agents, and/or plasticizers.

Solid excipients may be added to the pharmaceutical composition and then ground and formed into tablets. Exemplary solid excipients include, but are not limited to, sugars, including lactose, sucrose, sucralose, mannitol, or sorbitol; cellulose-based materials, such as corn starch, wheat starch, rice starch, potato starch, tragacanth gum, gelatin, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and/or sodium carboxymethylcellulose. Excipients to facilitate tablet disintegration upon ingestion include, but are not limited to, agar, alginic acid and/or salts thereof, mannitol, microcrystalline cellulose, corn starch, citrus pulp, sodium lauryl sulfate, bentonite, sodium starch glycolate, calcium carboxymethylcellulose, clays, aligns, gums, wood cellulose, natural sponge powder, and/or cation exchange resins.

The composition may include other excipients and additives to modify one or more characteristics of the composition, such as coating ability, viscosity, palatability, etc. Excipients to improve palatability may include, but are not limited to, sugars, such as lactose, sucrose, sucralose, dextrose, mannitol or sorbitol; natural sweeteners, such as honey; cellulose-based additives, such as corn starch, wheat starch, rice starch; other sweeteners, such as alitame, aspartame, cyclamic acid and salts thereof, dihydrochalcones, glycyrrhizinates, monellin, sodium saccharin, thaumatin or acesulfame potassium; and/or other sweeteners or flavorings.

Optional viscosity-modifying excipients can be added to a liquid formulation of the composition to alter the composition's flow characteristics. The flow characteristics can be modified to accommodate a specific application device or mechanism for applying the composition to a treatment site. Exemplary viscosity modifying excipients include, but are not limited to, glycerin, a carbomer homopolymer, a carbomer copolymer, acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus, bentonite, carbomer, carrageenan, ceratonia, chondrus, dextrose, furcellaran, gelatin, gum Ghatti, guar gum, sterculia gum, tragacanth gum, xanthan gum, hectorite, lactose, maltodextrin, mannitol, sucrose, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, polyethylene glycols, cellulose, ethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygelin, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose (CMC) (including its salts), silicon dioxide, polyvinylpyrrolidone (PVP) and/or SPLENDA®.

The pharmaceutical compositions may also include one or more binders, fillers, solvents, lubricants, antioxidants, buffering agents, salts, surfactants, vitamins, pigments, flavorings, disintegrating agents and/or plasticizers. Exemplary binders include, but are not limited to, any of the previously described starches, such as, corn starch, wheat starch, rice starch and/or potato starch, cellulosic derivatives, such as, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc., POLYOX™ polyethylene oxide polymers of any molecular weight or grade, irradiated or not, polyvinylpyrrolidone (PVP), AVICEL® microcrystalline cellulose powder, etc. Exemplary fillers include, but are not limited to, any of the previously described sugars and starches, cellulose, calcium salts, diatomaceous earth, and/or titanium dioxide. Exemplary buffers include, but are not limited to, acetate buffers, citrate buffers, and/or phosphate buffers.

Surfactants added to the pharmaceutical composition may be anionic, cationic, nonionic, or zwitterionic. Exemplary surfactants include, but are not limited to, sodium alkyl sulfates (e.g., sodium dodecyl sulfate (SDS)), cationic quaternary ammonium and pyridinium surfactants, polysorbates, sorbitan esters, bile acids, bile acid salts, nonoxynol or polyoxyethylene glycol fatty acid esters, and/or poloxamers. Exemplary lubricants include, but are not limited to, talc, hydrogenated fatty oils, magnesium stearate, calcium stearate, and/or stearic acid. Flavorings may include natural or synthetic flavorings. Plasticizers include, but are not limited to, glycerol and sorbitol.

Pharmaceutical compositions for the treatment of gastrointestinal motility disorders with deuterated domperidone can be formulated for topical oral administration to mucosal surfaces. Mucoadhesive delivery technologies provide safe and effective delivery of deuterated domperidone across the oral mucosa. These mucoadhesive delivery technologies include all methods of diffusion in the oral mucosa: (i) passive diffusion, including transcellular (through cells) and paracellular (where the material passes through lipid-rich domains around cells), (ii) vehicle-mediated transport, and (iii) endocytosis/exocytosis where the material is actively taken up and excreted by cells via the endocytic pathway. Bioadhesion, also known as mucoadhesion, defines the ability of a biological or synthetic material to adhere or "stick" to a mucous membrane, resulting in adhesion of the material to the tissue for an extended time. This capability provides application in drug delivery and improved drug bioavailability, resulting from the increased time the bioadhesive dosage form remains in contact with absorbent tissues compared to a standard dosage form. For a material to be bioadhesive, it must interact with mucus. Mucus is a layer of highly hydrated, viscous, anionic hydrogel that protects the mucosa. Mucin is composed of flexible glycoprotein chains.

In this embodiment, the pharmaceutical composition includes a therapeutic amount of deuterated domperidone and any other optional active agents, if present, and at least one excipient, which may include a mucoadhesive or bioadhesive to increase the duration of contact between the pharmaceutically active agent and the oral mucosa and to increase mucosal absorption of the active agent. The absorptive surface is the tissue surface beneath the oral mucosa to which the pharmaceutically active agent is intended to be applied. The pharmaceutical compositions may be applied in the form of ointments, creams, lotions, gels, powders, or pastes, and may be applied to treatment sites with or without occlusion by films or tapes, or by specific adhesive bandages. The compositions may also include a carrier to facilitate delivery of the composition to the oral mucosa.

Exemplary mucoadhesive or bioadhesive excipients include, but are not limited to, polymers that are natural, synthetic, or biological; lipids, phospholipids, etc. Examples of natural and/or synthetic polymers include cellulosic derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, microcrystalline hydroxyethylmethylcellulose, etc.; natural gums, such as guar gum, xanthan gum, locust bean gum, karaya gum, vee gum, etc.; polyacrylates such as CARBOPOL® polymers, polycarbophil, etc.; alginates, thiol-containing polymers, polyoxyethylenes, polyethylene glycols (PEG) with molecular weights preferably between 1000 and 40,000 Da whether linear or branched, dextrans with molecular weights preferably between 1000 and 40,000 Da from any source, block copolymers, for example, combinations of lactic acid and glycolic acid, such as PLA, PGA, PLGA of various viscosities, molecular weights and ratios of lactic to glycolic acid; polyethylene glycol-polypropylene glycol block copolymers of any number and combination of repeating units such as PLURONIC® block copolymers, TETRONIC® block copolymers or GENAPOL® block copolymers, combination of the above copolymers whether physically or chemically linked units, for example, blends of PEG-PLA or PEG-PLGA copolymers. The bioadhesive material may be selected from polyethylene glycols, polyoxyethylenes, polyacrylic acid polymers, such as, CARBOPOL® polymers (such as, CARBOPOL® 71G, 934P, 971P 974P) and polycarbophils (such as, NOVEON® AA-1, CA-1 and CA2 polycarbophils), cellulose and its derivatives, polyethylene glycol, CARBOPOL® polymers and/or a cellulosic derivative or a combination; a soluble polyvinylpyrrolidone (PVP) polymer, a carbomer homopolymer, a carbomer copolymer, one or more maltodextrins, alginate, a crosslinked alginate gum gel, a water-swellable but water-insoluble fibrous crosslinked carboxyfunctional polymer, a hydrophilic polysaccharide gum, thiomers, e.g., thiolated chitosan, thiolated polycarbophil, thiolated alginate, thiolated cellulose derivatives, thiolated carboxymethylcellulose, thiolated polyacrylic acid or thiolated polyacrylates; lectin, hydroxypropyl methylcellulose (HPMC), cellulose derivatives, HPMA copolymers, a water-dispersible polycarboxylated vinyl polymer, cationic polymers, nonionic polymers or anionic polymers. Cationic polymers include, but are not limited to, chitosan (Wella "low viscosity"), chitosan (Wella "high viscosity"), chitosan (Dr. Knapczyk), daiquitosan H, daiquitosan VH, Sea Cure 240, Sea Cure 210+, chitosan (Sigma), polycarbophil/diachitosan VH blend, DEAE-dextran, and aminodextran. Non-ionic polymers include, but are not limited to, scleroglucan, HE starch, and HPC. Anionic polymers include, but are not limited to, low, medium, or high viscosity carboxymethylcellulose (CMC), pectin, xanthan gum, and/or polycarbophil. In one embodiment, the mucoadhesive agent is a CARBOPOL® polymer and/or a cellulosic derivative.

Chitosan, due to its mucoadhesive character (Lehr et al. 1992) and favorable toxicological properties, is an enhancer of absorption across intestinal epithelia. Chitosan glutamate reduced the transepithelial electrical resistance (TEER) in vitro of a cultured intestinal epithelial cell line (Caco-2) (Borchard et al., 1996) and significantly increased the transport of hydrophilic molecules, such as, [14C]mannitol, molecular weight (MW) 182.2 and a fluorescein-dextran (MW4400) in Caco-2 cell monolayers (Artursson et al. 1994; Borchard et al., 1996; Schipper et al., 1996). Similarly, the transport of the peptide drug 9-deglycinamide, 8-arginine vasopressin (DGAVP, MW 1412) was markedly increased after coadministration with chitosan glutamate in Caco-2 cell monolayers (Luessen et al. 1997). Chitosan salts, such as chitosan glutamate and chitosan hydrochloride, are used in vivo as peptide drug absorption enhancers. Nasal application of insulin with chitosan glutamate significantly reduced blood glucose levels in rats and sheep (Ilium et al. 1994), and intraduodenal application of buserelin (MW 1299.5) and chitosan hydrochloride in a gel formulation increased the absolute bioavailability of buserelin from 0.1 ± 0.1 to 5.1 ± 1.5% (Luessen et al. 1996a). These increases in absorption could be attributed to the effect of chitosan on the integrity of epithelial tight junctions. Tight junctions play a crucial role in maintaining the selective barrier function of cell membranes and in sealing cells to form a continuous cell layer through which not even small molecules can penetrate. However, tight junctions are permeable to water, electrolytes, and other charged and uncharged molecules up to a certain size (Madara 1989; Wilson and Washington 1989). Tight junctions are known to respond to changes in calcium, cyclic AMP (cAMP), osmolarity, pH, and cytoskeletal status (Cereijido et al., 1993).

Chitosan salts are proposed to open tight junctions in a concentration- and pH-dependent manner to allow paracellular transport of large hydrophilic compounds. The increase in transport of these compounds could be attributed to an interaction of a positively charged amino group at the C-2 position of chitosan with negatively charged sites on cell membranes and tight junctions of mucosal epithelial cells to allow tight junction opening. Chitosan glutamate is known to induce changes in F-actin distribution (Artursson et al. 1994). Pharmacological agents that interact with cytoskeletal F-actin are also known to simultaneously increase paracellular permeability (Meza et al. 1982). This is consistent with the hypothesis that F-actin is directly or indirectly associated with proteins at tight junctions such as ZO-1 (Madara 1987). Schipper et al. (1997) have shown that chitosan induces a redistribution of cytoskeletal F-actin and the tight junction protein ZO-1. Laser scanning confocal microscopy has confirmed that chitosan is able to open tight junctions to allow paracellular transport of large hydrophilic compounds (Borchard et al. 1996; Schipper et al. 1997). Mucoadhesion may play an additional role in this process by increasing the residence time of drugs on cell surfaces.

In embodiments, the mucoadhesive/bioadhesive excipient is typically present in a range of about 1% to about 50% w/w, or in a range of about 1% to about 40% w/w, or in a range of about 2% to about 30% w/w. A single mucoadhesive or bioadhesive, or combinations thereof, may be used. Bioadhesion increases the residence time of a dosage form at the site of absorption and may therefore result in increased bioavailability of the drug. The use of a mucoadhesive facilitates prolonged contact between the pharmaceutical composition and the oral mucosal membrane. Upon contact of the pharmaceutical composition with the mucosal membrane, moisture in the mucus plasticizes the mucoadhesive, which may then consolidate with the mucosal membrane by forming weak bonds with glycoproteins in the mucus and/or by mechanically crosslinking with the glycoproteins and lipids in the mucus. The mucoadhesive may increase the contact residence time of the pharmaceutically active agent and the absorption surface and may facilitate the absorption of the pharmaceutically active agents by the absorption surface.

The following examples are provided to illustrate some of the concepts described in this disclosure. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperature, etc.) in the following examples, but some experimental errors and deviations should be noted. Unless otherwise indicated, temperature is given in degrees Celsius, and pressure is at or near atmospheric pressure.

Examples 1-5 are according to synthesis scheme 1. Examples 6-8 are according to synthesis scheme 2. From synthesis scheme 1

Example 1: Preparation of 2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one

A 100 mL round-bottom flask fitted with a stir bar and nitrogen inlet/outlet was charged with (D4)benzene-1,2-diamine (1 eq, 2 g, 17.83 mmol) and 30 mL of dry DMF and then stirred under nitrogen to dissolve before charging 1-(1H-imidazole-1-carbonyl)-1H-imidazole (1 eq, 2.89 g, 17.83 mmol) and stirring at room temperature for 22 h. The solvent was evaporated in vacuo to give a thick yellow oil which was diluted in a minimum amount of dichloromethane (DCM) to crystallize. The desired solid was collected by vacuum filtration, washed with DCM and dried in vacuo to give 2.09 g (15.13 mmol, 85%) of the desired product.

Example 2: Preparation of tert-butyl 2-oxo-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazole-1-carboxylate In a 100 mL three-necked round-bottom flask equipped with a stir bar and nitrogen inlet/outlet were charged 2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one (1 eq, 2.09 g, 15.13 mmol) and 40 mL of dry DMF. To this stirred solution, sodium hydride (1.1 eq, 197 mg, 8.200 mmol) was added portionwise and the reaction was left under the same conditions for 1.5 h. After this period, di-tert-butyl dicarbonate (1 eq, 3.30 g, 15.13 mmol), dissolved in 8 mL of dry DMF, was added dropwise and allowed to react for 3 h. The reaction was completed and treated with saturated NH4Cl solution, followed by dilution with H<2>O and extraction with 4x50 mL of EtOAc. The organic fractions were combined, dried over Na2SO4, filtered and concentrated in vacuo to dryness. The crude material thus obtained was purified by silica gel chromatography (Biotage ISOLERA™, 50 g KP-Sil cartridge, eluting with a 90:10 Cy:EtOAc gradient to neat AcOEt) to give 3.134 g (13.15 mmol, 87%) of the desired compound.

Example 3: Preparation of tert-butyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro(D4)-1H-1,3-benzodiazole-1-carboxylate

In a three-necked round-bottom flask, 2-oxo-2,3-dihydro-1H-1,3-benzodiazole-1-carboxylate tert-butyl ester (1 eq, 3.134 g, 13.15 mmol) was charged in 60 mL of dry DMF and stirred at room temperature. To this solution, potassium carbonate (3 eq, 5.452 g, 39.45 mmol) was added portionwise and left under the same conditions for 30 minutes. After this, 1-bromo-3-chloropropane (1 eq, 1.300 mL, 13.15 mmol) was added to the solution and stirred at room temperature overnight. The reaction was then quenched by diluting it with ethyl acetate (EtOAc) and H<2>O. The layers were separated and the aqueous phase was extracted with 3x25 mL of EtOAc and the organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to dryness. The crude material thus obtained was purified by silica gel chromatography (Biotage ISOLERA™, 50 g KP-Sil cartridge, eluting with a gradient of 90:10 Cy:EtOAc to 1:1 Cy:EtOAc) to give the desired compound (3.929 g, 12.48 mmol, 95%).

Example 4: Preparation of 1-(3-iodopropyl)-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one

A 250 mL round-bottom flask was charged with tert-butyl 3-(3-chloropropyl)-2-oxo-2,3-dihydro(D4)-1H-1,3-benzodiazole-1-carboxylate (1 eq, 3.929 g, 12.48 mmol), dissolved in 100 mL of acetonitrile, and stirred at room temperature. Sodium iodide (4.5 eq, 8.417 g, 56.16 mmol) was added portionwise and the reaction was refluxed overnight. After cooling to room temperature, the reaction was filtered and the solvent was removed in vacuo. The crude material thus obtained was purified with silica gel chromatography (Biotage ISOLERA™, 100 g KP-Sil cartridge, eluting with a gradient of neat DCM to neat DCM:MeOH/1:1) to give the desired compound (3.631 g, 11.86 mmol, yield = 95%).

Example 5: Preparation of 1-{3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1-yl]propyl}-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one (Compound 2)

A 500 mL round-bottom flask was charged with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (1.2 eq, 3.582 g, 14.23 mmol) and dissolved in 250 mL of dry THF and 25 mL of dry DMF. This solution was stirred under nitrogen at room temperature and a solution of 1-(3-iodopropyl)-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one (1 eq, 3.631 g, 11.86 mmol) in 120 mL of dry H2O was added dropwise over 10 minutes. The resulting yellow solution was stirred for 2 h before charging potassium carbonate (1.5 eq, 2.458 g, 17.79 mmol) and stirring at room temperature for 48 h until the yellow color disappeared. The reaction was filtered and the solid was washed with EtOAc and the filtrate was concentrated in vacuo to dryness. The crude material thus obtained was passed through silica gel chromatography (Biotage ISOLERA™, 340 g KP-Sil cartridge, eluting with a DCM:MeOH gradient from 98:2 to DCM:MeOH/1:1). At the end of the purification process, 3.245 g (7.45 mmol, 64%) of the desired compound 2 was obtained as a white crystalline solid.

From synthesis scheme 2

Illustrative Example 6: Preparation of 4,5,6,7-tetradeutero-2-ethoxy-1H-benzimidazole (Compound 15)

To a round-bottom flask equipped with a stir bar, thermocouple, condenser, and nitrogen inlet/outlet was charged 6.5 g (58 mmol, 1 eq) of 2-amino-3,4,5,6-tetradeuteroaniline, which was suspended in 13.3 mL (12.25 g, 63 mmol, 1.1 eq) of tetraethyl orthocarbonate and 0.3 mL (0.35 g, 5.8 mmol, 0.1 eq) of acetic acid. Absolute ethanol (19.5 mL) was added to the suspension, and the resulting mixture was heated under reflux where it was stirred for one hour until complete by HPLC analysis. The orange solution was distilled to remove 20.5 mL of ethanol before a solution of 13 mL of saturated sodium carbonate and 26 mL of water was added just below reflux to precipitate the product. After the addition was complete, the suspension was cooled to room temperature, where the solid was collected by vacuum filtration. The resulting wet cake was washed with water (26 mL) and then dried in a vacuum oven overnight at 50°C to obtain 9.34 g (97.4%) of the desired product, with a purity of >99.5% by HPLC.

Illustrative Example 7: Preparation of 1-(3-chloropropyl)-4,5,6,7-tetradeutero-2-ethoxy-benzimidazole (Compound 16)

Into a round-bottom flask equipped with a stir bar, nitrogen inlet/outlet, and condenser were charged 9.2 g (55.3 mmol, 1.0 eq) of Compound 15, potassium carbonate (15.3 g, 110.1 mmol, 2.0 eq), 1-bromo-3-chloropropane (8.21 mL, 83.1 mmol, 1.5 eq), and 55 mL of methyl isobutyl ketone (MIBK). The resulting suspension was heated under reflux and stirred for 3 h until HPLC analysis was complete. After cooling to room temperature, 36.8 mL of water was added, and the mixture was stirred to dissolve the salts before the phases were separated. The aqueous layer was extracted with MIBK (1 X 36.8 mL), the organic layers were combined, and then concentrated to an oil. MIBK (36.8 mL) was added to the oil and concentrated again. This procedure was repeated until 1H NMR analysis indicated that <1 mol % of 1-bromo-2-chloropropane remained. This oil was used directly in the next step.

Example 8: Preparation of 1-{3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1yl]propyl}-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one (Compound 2)

A 0.5 L jacketed reactor equipped with a mechanical stirrer, thermocouple, and condenser was charged under a nitrogen atmosphere with 5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (Compound 14, 13.8 g, 54.9 mmol, 1.0 eq), potassium iodide (9.1 g, 54.9 mmol, 1.0 eq), potassium bicarbonate (5.5 g, 54.9 mmol, 1.0 eq), and 60 mL of water. To this stirred suspension was charged a solution of 13.33 g (54.9 mmol, 1.0 eq) of compound 16 in 60 mL of isopropanol. After heating under reflux with a jacket temperature of 105 °C, the reaction was stirred at this temperature for 18 h until completion by HPLC analysis. An additional 30 mL of water and 30 mL of isopropanol were added and reflux was continued for 20 min to dissolve the solids, before 36 mL of 4M HCl (144 mmol, 2.6 eq) was added to the refluxing mixture. Reflux was continued for 2 h until deprotection was complete. While still at reflux, the batch was cooled to pH 11 with 12 M sodium hydroxide. Precipitation of the product was observed and was completed by cooling the batch to 15 °C and then collecting the solid by vacuum filtration. The wet cake was washed with water (3 x 51 mL) and then dried in vacuo to obtain 20.37 g (86.3%) of the desired product with a purity of 94.5%. Purity could be improved to >97% by recrystallization from DMSO/water or trituration with IPA/water or MeOH/water.

Example 9: Comparison of Deuterated and Non-Deuterated Domperidone

In this example, the activity of domperidone and d4-domperidone was compared. Briefly, oral exposure to domperidone and deuterated domperidone (d4-domperidone) was evaluated in Beagle dogs following oral administration of suspension formulations containing domperidone or d4-domperidone and 0.5% methocel, 0.2% polysorbate 80, and 0.72% lactic acid. Each compound was dosed orally at 3 mg/kg, 10 mg/kg, and 40 mg/kg. Blood samples were collected up to 24 hours post-dose, and plasma domperidone concentrations were determined by LCMS/MS. Pharmacokinetic parameters were determined using Phoenix WinNonlin (v7.0). See FIGS. 22A and 22B.

Claims (7)

CLAIMS 1. A compound that is d4-domperidone 2, d6-domperidone 3, or dio-domperidone 5, or a pharmaceutically acceptable salt: for use in the improvement of gastroesophageal reflux disease. 2. The compound for use of claim 1, wherein the compound is d4-domperidone 2 or a pharmaceutically acceptable salt thereof: 3. The compound for use of claim 1, wherein the compound is d6-domperidone 3 or a pharmaceutically acceptable salt thereof: 4. The compound for use of claim 1, wherein the compound is dio-domperidone 5 or a pharmaceutically acceptable salt thereof: 5. The compound for use according to any of the preceding claims, wherein the deuterated domperidone is administered orally, transdermally, parenterally, or a combination thereof, preferably orally. 6. The compound for use according to any of the preceding claims, wherein the therapeutically effective amount is in the range of 0.5 mg to 120 mg, preferably in the range of 1 mg to 60 mg, or preferably in the range of 2.0 mg to 40 mg. 7. The compound for use of any one of claims 1 to 7, wherein the therapeutically effective amount is in the range of 0.05% to 12.0% w/w, preferably in the range of 0.1% to 6.0% w/w, or preferably in the range of 0.2% to 4.0% w/w, or preferably in the range of 0.07 mg/kg to 1.71 mg/kg, or preferably in the range of 0.014 mg/kg to 0.86 mg/kg, or preferably in the range of 0.028 mg/kg to 0.57 mg/kg. Reference plasma levels and analogs normalized to 10 mg/kg oral in rats FIG. 1A FIG. IBPerfect release of the drug in the immediate and extended-release portions of the dosage form HG. 2 Simulated plasma profile of phloroglucinol from a modified-release dosage form FIG. 3 FIG, 7 FIG. 10 FIG. 11 FIG.16