WO2004103317A2 - Regime posologique pour le traitement de la diarrhee par administration de buprenorphine par voie transdermique - Google Patents

Regime posologique pour le traitement de la diarrhee par administration de buprenorphine par voie transdermique Download PDF

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Publication number
WO2004103317A2
WO2004103317A2 PCT/US2004/009335 US2004009335W WO2004103317A2 WO 2004103317 A2 WO2004103317 A2 WO 2004103317A2 US 2004009335 W US2004009335 W US 2004009335W WO 2004103317 A2 WO2004103317 A2 WO 2004103317A2
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Prior art keywords
buprenorphine
dosage form
days
transdermal
dosage
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WO2004103317A3 (fr
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Bruce E. Reidenberg
Daniel A. Spyker
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Euro Celtique SA
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Euro Celtique SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4883—Capsule finishing, e.g. dyeing, aromatising, polishing

Definitions

  • the present invention relates to dosage regimens for controlling the symptoms of gastrointestinal conditions or disorders, including diarrhea and/or pain associated with the conditions.
  • the invention relates in particular to treating diarrhea associated with irritable bowel syndrome, short gut syndrome, microscopic colitis, and vasoactive intestinal polypeptide carcinoids.
  • IBS Irritable bowel syndrome
  • IBS Irritable bowel syndrome
  • Other examples of gastrointestinal conditions are microscopic colitis, in which the patients suffer from non-bloody, chronic secretory diarrhea believed to be associated with inflammation of the colon; short bowel syndrome, a group of problems affecting people who have had half or more of their small intestine removed; and elevated VIP (vasoactive intestinal polypeptide) plasma levels in the "VIPoma" syndrome, which leads to intestinal secretion with severe secretory diarrhea (Krejs, Am J Med 1987, 29 ;82(5B): 37-48).
  • VIP vasoactive intestinal polypeptide
  • Previous treatments for chronic diarrhea include restrictive diets, administration of fiber, loperamide, diphenoxylate, other opiates, anticholinergics, antispasmodics, cholestyr amine, tricylic and serotonin reuptake inhibitor antidepressants, sedatives, and psychological therapy.
  • Anticholinergic agents can also be used to reduce intestinal motility.
  • anti-inflammatory agents and anti-diarrheal medications such as Imodium and Lomotil are commonly administered to delay diarrhea.
  • prednisone a corticosteroid
  • antibiotics can be useful in stopping a severe attack
  • anticholinergics and smooth muscle relaxants such as cimetropium bromide, pinaverium bromide, octilium bromide, trimebutine, and mebeverine
  • smooth muscle relaxants such as cimetropium bromide, pinaverium bromide, octilium bromide, trimebutine, and mebeverine
  • Endogenous and exogenous opioid receptor ligands are known to modify and normalize gut function (Shook et al. , J Pharmacol Exp Ther 1989;249:83-90; Corazzi, Can J Gastroenterol 1999;13:71A-75A), and several opioids such as loperamide, diphenoxylate, and codeine phosphate, have been shown useful in treating diarrhea.
  • One particular opioid, buprenorphine is a potent, partial agonist of the D-opioid receptor that has been shown to be effective to control pain in a wide range of patients when delivered by a number of different routes of administration, including intravenously, epidurally, intrathecally, or sublingually in both young and elderly patients (Inagaki et al., Anesth Analg 1996, 83:530-536; Brema et al., Int J Clin Pharmacol Res 1996, 16:109-116; Capogna et al., Anaesthesia 1988, 43: 128-130; Adrianensen et al., Acta Anaesthesiol Belg 1985, 36:33-40; Tauzin-Fin et al., Eur J Anaesthesiol 1998, 15: 147-152; Nasar et al., Curr Med Res Opin 1986, 10:251-255).
  • the present invention provides a method for administering buprenorphine transdermal patches so that breakthrough symptoms such as pain and/or diarrhea are effectively reduced in patients suffering from one or more gut-related diseases or disorders, without substantially increasing the incidence of adverse side effects.
  • the invention provides a method of treating breakthrough symptoms of diarrhea in a patient comprising administering to the patient (1) a first buprenorphine- containing transdermal dosage form for a first dosing period that is no more than 5 days; (2) a second buprenorphine-containing transdermal dosage form for a second dosing period that is no more than 5 days, the second dosage form comprising the same dosage of buprenorphine as, or a greater dosage of buprenorphine than, the first dosage form; and (3) a third buprenorphine-containing transdermal dosage form for a third dosing period, the third dosage form comprising a greater dosage of buprenorphine than the second dosage form.
  • the first, second, and third transdermal dosage forms contain approximately the amounts of buprenorphine set forth in a row in the following table: First (mg) Second (mg) Third (mg)
  • the first, second, and third dosing periods are each at least 2 days. More preferably, the first and/or second dosing periods are 7 days, 5 days, 4 days or 3 days. In a specific embodiment, the first dosage period is 2 days. In another embodiment, the second dosage period is 2 or 3 days. In yet another embodiment, the first, second, and third dosage periods are each 7 days.
  • the method of the invention further comprises administering a fourth buprenorphine-containing transdermal dosage form for a fourth dosage period after the third dosing period.
  • the fourth dosing period could be 2 days, and the fourth dosage form could comprise 30 or 40 mg buprenorphine.
  • additional buprenorphine-containing dosage forms may be administered, preferably sequentially, after the fourth dosing period. In one embodiment, these additional dosage forms contain about the same dose as the third or fourth dosage form.
  • the first dosage form comprises 5 mg of buprenorphine.
  • the second dosage form comprises 10 mg of buprenorphine.
  • the third dosage form comprises 20, 30, or 40 mg of buprenorphine, and the subsequent dosage form comprises 30 or 40 mg of buprenorphine.
  • the first dosage form comprises up to 5 mg of buprenorphine, for a dosing period up to 3 days
  • the second dosage form comprises up to 5 mg of buprenorphine, for a dosing period up to 3 days
  • the third dosage form comprises up to 20 mg of buprenorphine, the third dosing period lasting up to 7 days.
  • the patients are pediatric or elderly, suffering from breakthrough symptoms of diarrhea.
  • Conditions where breakthrough symptoms of diarrhea may occur include, but are not limited to, those wherein the patient is suffering from irritable bowel syndrome, short gut syndrome, microscopic colitis, or carcinoid tumor secreting VIP.
  • the breakthrough symptoms include, but are not limited to abnormally loose or liquid feces, or abnormally frequent emptying of the bowels and cramping abdominal pain.
  • the invention also provides a method of treating breakthrough diarrhea symptoms in a patient in need thereof, by administering a first, a second, and a third transdermal dosage form of buprenorphine, wherein the third dosage form comprises a higher dosage of buprenorphine than the first and second dosage forms, and wherein the method does not increase the incidence of an adverse event selected from nausea, vomitmg, and headache as compared to only administering the same dosage of buprenorphine as the third dosage form.
  • the first dosage form comprises no more than 5, 10, or 20 mg buprenorphine
  • the second dosage form comprises no more than 10, 20, or 30 mg buprenorphine and is administered for 3 days
  • the third dosage form comprises at least 20, 30, or 40 mg buprenorphine and is administered for at least 2 days.
  • the transdermal administration can be produced by a transdermal system selected from a skin patch, a topical gel, a lotion, an ointment, a transmucosal system, a transmucosal device, and an iontophoretic delivery system.
  • FIG. 1 Plasma concentration versus time curves for buprenorphine after application of BTDS 5 (hours 0-72), BTDS 10 (hours 72-144), and BTDS 20 (hours 144- 312).
  • the present invention provides a method of more quickly achieving effective treatment of symptoms such as pain and diarrhea in a patient in need of such treatment, while reducing the incidence of certain adverse effects.
  • the method comprises administering to the patient an effective amount of buprenorphine in a series of transdermal dosage forms of buprenorphine.
  • the dosage regimen of the present invention yields important advantages over prior art dosage regimens for opioids in that it is a promising short-term and long-term treatment for controlling diarrhea as well as pain.
  • the present invention provides effective therapy for patients in need of such treatment, including but not limited to those individuals suffering from IBS, short gut syndrome, microscopic colitis, and VIP.
  • symptoms of diarrhea include, but are not limited to, abnormally soft or liquid feces, abnormally frequent emptying of bowels and cramping abdominal pain.
  • breakthrough symptoms refer to a situation where a patient treated for prolonged symptoms of diarrhea, using repeated doses of an orally or parenterally administered medicament, suffers from the return of symptoms of diarrhea. This may be caused by, for example, the patient missing a dose, or any other unforeseen event leading to reduced efficacy of the treatment, thereby leading to breakthrough symptoms.
  • the dosage regimen of the present invention may alternatively be described in terms of administration of a "series of transdermal dosage forms comprising at least one incremental dosage of buprenorphine" .
  • This refers to the application of at least two transdermal dosage forms to the patient, wherein at least one subsequently administered dosage form has a greater dosage of buprenorphine than the previous dosage form.
  • a series of three transdermal dosage forms may be administered in the dosage regimen, wherein the first dosage form contains 5 mg buprenorphine, the second dosage form contains 10 mg buprenorphine, and the third dosage form contains 20 mg buprenorphine, such that each subsequent dosage form in the series has twice the dosage of buprenorphine than its predecessor.
  • the series of dosage forms may include 20 mg, 30 mg, and 40 mg buprenorphine respectively, or 2 mg, 4 mg, and 8 mg buprenorphine, respectively, or 1 mg, 2 mg, or 3 mg buprenorphine, respectively.
  • Particular dosage regimens are 5-5-10, 5-10-10, 5-10-20, 5-20-40, 5-10-30, 5-30- 40, 10-10-20, 10-10-30, 10-10-40, 10-20-30, 10-20-40, and 10-30-40.
  • BTDS means "Buprenorphine Transdermal System”
  • BTDS X wherein "X" is a number higher than zero, means a transdermal dosage form containing X milligrams of buprenorphine.
  • BTDS 5" means a transdermal system containing 5 mg buprenorphine.
  • a BTDS contains buprenorphine in the form of a base or a salt, more preferably in the form of a base.
  • relative release rate is determined from the amount of drug released per unit time from a transdermal delivery system through the skin and into the bloodstream of a subject.
  • Mean relative release rate may be expressed, e.g. , as ⁇ g drug/hr or, for comparing delivery systems covering skin areas of different size, as ⁇ g drug/cm 2 /hr.
  • a transdermal delivery system that releases 1.2 mg of buprenorphine over a time period of 72 hours is considered to have a relative release rate of 16.67 ⁇ g/hr.
  • relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval.
  • the dose of buprenorphine administered to the patient is gradually escalated to a predetermined level, and the reduction in symptoms of the gastrointestinal condition assessed. If additional reduction in symptoms is desired, the dose of buprenorphine administered to the patient can be further escalated until any pain and/or diarrhea symptoms exhibited or experienced by the patient have been sufficiently reduced.
  • control of diarrhea in an IBS patient can be achieved, e.g. , by escalating the buprenorphine dosage to an effective dose, preferably BTDS 20.
  • control of cramping abdominal pain in an IBS patient can be achieved, e.g. , by escalating the buprenorphine dosage to an effective dose, preferably BTDS 20.
  • the physician in charge of the patient's care determines the BTDS level suitable for controlling symptoms of diarrhea and/or pain.
  • the invention further provides kits containing the desired dosage series.
  • the method of the present invention may be administered to any patient in need of control of diarrhea and/or pain.
  • the patient may be in the elderly (age over 65 years), young adult (age between 18 and 45 years), or pediatric (age between birth and 17 years) population, and is preferably, although not necessarily, classified as suffering from or having a gastrointestinal condition.
  • gastrointestinal condition means that the patient suffers from an existing condition having diarrhea as a major symptom, optionally diarrhea associated with pain.
  • Such conditions include IBS, short gut syndrome, microscopic colitis, and VIP (carcinoid).
  • the patient may be classified as, but need not be, an at risk patient.
  • the term "at risk” means that the patient suffers from an existing condition that is a relative contraindication for high-dose opioid therapy or intermittent-opioid therapy or increases the likelihood of adverse events from such therapy. Such conditions include age or respiratory compromise, for instance due to recurrent bronchospasm. At risk populations include the elderly and pediatric populations.
  • the term "predefined number of days” refers to a predetermined length of time during which the dosage form of the drug is administered to the patient.
  • the drug is an opioid and more preferably the opioid is buprenorphine.
  • the predefined number of days may vary between individuals and may be determined by one of ordinary skill in the art using the guidelines discussed within the present application. In one embodiment, the predefined number of days is three days. In another embodiment, the predefined number of days is seven days.
  • an “analgesically effective" amount of an analgesic agent means an amount of agent capable of lowering the level of pain experienced by a patient.
  • the level of pain experienced by a patient can be assessed by use of a visual analog scale (VAS) or a Likert- type scale.
  • VAS visual analog scale
  • a Likert-type scale is a rating scale, usually in the range of 1 to 5, based on degrees of agreement or disagreement to statements.
  • a similar type of scale although based on an 11 point scale (ranging from 0 to 10) can also be used.
  • Such pain scales can be applied to visualize an alteration of the level of pain a patient experiences during treatment, e.g. , a reduction of the level of pain a patient or a population of patients experiences before and after initiation of a pain therapy.
  • the present invention relates to buprenorphine or a pharmaceutically acceptable salt, ether derivative, ester derivative, acid derivative, enantiomer, diasteriomer, racemate, polymorph, or solvate thereof.
  • buprenorphine is considered in the art to be a partial agonist at ⁇ opioid receptors in the central nervous system ("CNS") and peripheral tissues.
  • Buprenorphine shares many of its actions, such as analgesia, of full ⁇ opioid agonists.
  • Partial agonists generally, include compounds with affinity for a receptor, but unlike full agonists, elicit an incomplete degree of the pharmacological effect, even if a high proportion of receptors are occupied by the compound.
  • a "ceiling effect" to analgesia is well documented with respect to buprenorphine in many animal models. It is highly lipophilic and dissociates slowly from opioid receptors. It is further thought that buprenorphine binds with high affinity to ⁇ and K receptors, and, with lower affinity, to ⁇ receptors. The intrinsic agonist activity at the receptor seems to be limited and most evidence suggests that buprenorphine has antagonist activity at D receptors. The lack of D agonism accounts for buprenorphine 's apparent lower incidence of the dysphoric and psychotomimetic effects that can be seen with K agonist opioid drugs (such as pentazocine) . Other studies suggest that the opioid antagonist effects of buprenorphine may be mediated via an interaction with D opioid receptors.
  • Buprenorphine is believed to bind slowly with, and dissociate slowly from, the ⁇ receptor.
  • the high affinity of buprenorphine for the D receptor and its slow binding to, and dissociation from, the receptor is thought to possibly account for the prolonged duration of analgesia and, in part, for the limited physical dependence potential observed with the drug.
  • the high affinity binding may also account for the fact that buprenorphme can block the D agonist effects of other administered opioids.
  • buprenorphine produces dose-related analgesia.
  • analgesia appears to result from a high affinity of buprenorphine for D and possibly D opioid receptors in the central nervous system.
  • the drug may also alter the pain threshold (threshold of afferent nerve endings to noxious stimuli).
  • the analgesic potency of parenteral buprenorphine appears to be about 25 to about 50 times that of parenteral morphine, about 200 times that of pentazocine, and about 600 times that of meperidine.
  • the present invention further includes the use of all active individual enantiomers, diastereomers, racemates, and other isomers of the compound.
  • the invention also includes the use of all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polymorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution.
  • Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or in
  • Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, gly colly larsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-memylglucamine ammonium salt
  • the present invention includes the use of prodrugs of the compound.
  • Prodrugs include, but are not limited to, functional derivatives of buprenorphine that are readily convertible in vivo into buprenorphine. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Transdermal Dosage Forms
  • Transdermal dosage forms are convenient dosage forms for delivering many different active therapeutically effective agents, including but not limited to analgesics, such as for example, opioid analgesics.
  • opioid analgesics include, but are not limited to, fentanyl, buprenorphine, etorphines, and other high potency narcotics.
  • Transdermal dosage forms are particularly useful for timed release or sustained release of active agents.
  • Transdermal dosage forms may be classified into transdermal dosage articles and transdermal dosage compositions.
  • the most common transdermal dosage article is a diffusion-driven transdermal system (transdermal patch) using either a fluid reservoir or a drug-in-adhesive matrix system.
  • Transdermal dosage compositions include, but are not limited to, topical gels, lotions, ointments, transmucosal systems and devices, and iontophoretic (electrical diffusion) delivery systems.
  • the transdermal dosage form is a transdermal patch.
  • transdermal dosage forms such as a diffusion-driven transdermal system (transdermal patch) using either a fluid reservoir or a drug-in-adhesive matrix system, topical gels, lotions, ointments, transmucosal systems and devices, and iontophoretic (electrical diffusion) delivery system.
  • transdermal dosage form is used in the dosage regimen of the present invention for timed release or sustained release of buprenorphine.
  • Transdermal dosage forms used in accordance with the invention preferably include a backing layer made of a pharmaceutically acceptable material which is impermeable to the buprenorphine.
  • the backing layer preferably serves as a protective cover for the buprenorphine, and may also provide a support function.
  • materials suitable for making the backing layer are films of high and low density polyethylene, polypropylene, polyvinylchloride, polyurethane, polyesters such as poly(ethylene phthalate), metal foils, metal foil laminates of such suitable polymer films, textile fabrics, if the components of the reservoir cannot penetrate the fabric due to their physical properties, and the like.
  • the materials used for the backing layer are laminates of such polymer films with a metal foil such as aluminum foil.
  • the backing layer can be any appropriate thickness to provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirable materials and thickness will be apparent to the skilled artisan.
  • the transdermal dosage forms used in accordance with the invention contain a pharmacologically or biologically acceptable polymer matrix layer.
  • the polymers used to form the polymer matrix are those capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate.
  • a non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylenevinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurefhanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride- vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly (ethylene terephthalate), ethylene- vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including sUicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g.
  • exemplary materials for inclusion in the polymer matrix layer are silicone elastomers of the general polydimethylsiloxane structures, (e.g. , silicone polymers). Preferred silicone polymers cross-link and are pharmaceutically or biologically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: silicone polymers that are cross-linkable copolymers having dimethyl and/or dimethylvinyl siloxane units that can be crosslinked using a suitable peroxide catalyst.
  • polymers consisting of block copolymers based on styrene and 1,3- dienes (particularly linear styrene-isoprene-block copolymers of styrene-butadiene-block copolymers), polyisobutylenes, polymers based on acrylate and/or methacrylate.
  • the polymer matrix layer may optionally include a pharmaceutically acceptable crosslinking agent.
  • Suitable crosslinking agents include, e.g. , tetrapropoxy silane.
  • Preferred transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for the desired period of administration. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive tape, e.g., surgical tape.
  • the adhesive layer preferably includes using any adhesive known in the art that is pharmaceutically compatible with the dosage form and preferably hypoallergenic, such as polyacrylic adhesive polymers, acrylate copolymers (e.g. , polyacrylate) and polyisobutylene adhesive polymers.
  • the adhesive is a hypoallergenic and pressure-sensitive contact adhesive.
  • the transdermal dosage forms that can be used in accordance with the present invention may optionally include a permeation enhancing agent.
  • Permeation enhancing agents are compounds that promote penetration and/or absorption of the buprenorphine through the skin or mucosa and into the blood stream of the patient.
  • a non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like.
  • permeation of buprenorphme may be enhanced by occlusion of the dosage form after application to the desired site on the patient with, e.g. an occlusive bandage. Permeation may also be enhanced by removing hair from the application site by, e.g. clipping, shaving or use of a depilatory agent. Another permeation enhancer is heat. It is thought that permeation can be enhanced by, among other things, the use of a radiating heat form, such as an infrared lamp, at the application site during at least a portion of the time the transdermal dosage form is applied on the skin or mucosa. Other means of enhancing permeation of buprenorphine such as the use of iontophoretic means, are also contemplated to be within the scope of the present invention.
  • a preferred transdermal dosage form that may be used in accordance with the present invention includes a non-permeable backing layer made, for example, of polyester; an adhesive layer made, for example, of a polyacrylate, and a matrix containing the buprenorphine and other desirable pharmaceutical aids such as softeners, permeability enhancers, viscosity agents and the like.
  • the active agent, buprenorphine may be included in the device in a drag reservoir, drug matrix or drug/adhesive layer. This area of the patch, and the amount of active agent per unit area, determine the limit dose, as one of ordinary skill in the art can readily determine.
  • Certain preferred transdermal delivery systems also include a softening agent in the reservoir or matrix.
  • Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, wherein the alcohol component may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladiapate, and triglycerides, particularly medium-chain triglycerides of caprylic/caproic acids or coconut oil.
  • softeners are, for example, multivalent alcohols such as glycerol and 1,2-propanediol, as well as softeners such as levulinic acid and caprylic acid, which can also be esterified by polyethylene glycols.
  • a buprenorphme solvent may also be included in the transdermal delivery systems of the present invention.
  • a solvent dissolves the buprenorphine to a sufficient extent thereby avoiding complete salt formation.
  • suitable solvents include those with at least one acidic group. Particularly suitable are monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate.
  • compositions that may be included in the reservoir or matrix include solvents, for example, alcohols such as isopropanol; permeation enhancing agents such as those described above; and viscosity agents, such as cellulose derivatives, natural or synthetic gums, such as guar gum, and the like.
  • solvents for example, alcohols such as isopropanol
  • permeation enhancing agents such as those described above
  • viscosity agents such as cellulose derivatives, natural or synthetic gums, such as guar gum, and the like.
  • the transdermal dosage form includes a removable protective or protective release layer.
  • the removable protective layer is removed prior to application, and may consist of the material used for the backing layer described above, provided that it is rendered removable, for example, by a silicone treatment.
  • Other removable protective layers for example, are polyletra-fluoroethylene, treated paper, allophane, polyvinyl chloride, and the like.
  • the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application.
  • the composition of the transdermal dosage form used in accordance with the invention and the type of device used are not considered critical to the method of the invention, provided that the device delivers the active agent, e.g. buprenorphine, for the desired time period and at the desired flux or delivery rate, i.e. , the rate of penetration of the active agent through the skin of an individual, of the transdermal dosage form.
  • Transdermal delivery systems of buprenorphine made by Lohmann Therapie-Systeme GmbH & Co., are currently sold in the European Union under the trademark name TRANSTEC ® . These patches contain 20, 30, and 40 mg of buprenorphine, with an approximate delivery or flux rate of 35, 52.5, and 70 ⁇ g/hr, respectively.
  • a preferred buprenorphine transdermal delivery system includes a laminated composite having an impermeable backing layer, and, optionally, a permeation enhancer, and a pressure-sensitive adhesive.
  • a transdermal dosage form in accordance with U.S. Patent No. 5,240,711 includes: (i) a polyester backing layer which is impermeable to buprenorphine; (ii) a polyacrylate adhesive layer; (iii) a separating polyester layer; and (iv) a matrix containing buprenorphine or a salt thereof, a solvent for the buprenorphine, a softener and a polyacrylate adhesive.
  • the buprenorphine solvent may or may not be present in the final formulation.
  • the matrix includes about 10 to about 95% (by weight) polymeric material, about 0.1 to about 40% (by weight) softener, and about 0.1 to about 30% (by weight) buprenorphine.
  • a solvent for the buprenorphine base or pharmaceutically acceptable salt thereof may be included as about 0.1 to about 30 % (by weight).
  • the dosing regimen of the present invention comprises several discrete dosing periods.
  • a dosing period is the time during which one of the transdermal dosage forms in the series is administered to the patient.
  • the dosing regimen will consist of a separate dosing period for administration of each transdermal dosage form in the series.
  • the first transdermal dosage form in the series may be worn by the patient for three consecutive days.
  • the second dosage form may then be worn by the patient for another three consecutive days, and thereafter, the third dosage form may be worn by the patient for another seven days.
  • the third dosage form corresponding to the third and final dosage level, is administered after six consecutive days of buprenorphine treatment.
  • the first dosage form is worn for seven days, the second dosage form for seven days, and the third dosage form for seven days, which means that the third dosage level is reached after 14 consecutive days of buprenorphine treatment.
  • This dose can then be maintained for as long as needed, or ⁇ definitely. If an increase in dosage is required, then the dosage may be increased at an appropriate interval, e.g. , every three or seven days.
  • the dosage forms of the present invention may also include one or more inactivating agents.
  • inactivating agent refers to a compound that inactivates or crosslinks the active agent, in order to decrease the abuse potential of the transdermal dosage form.
  • Non-limiting examples of a inactivating agents include, but are not limited to, polymerizing agents, photo-initiators, and formalin.
  • crosslinking or polymerizing agents include diisocyanates, peroxides, diimides, diols, triols, epoxides, cyanoacrylates, and UN- activated monomers.
  • the method of the present invention preferably comprises administering buprenorphine in a manner that achieves a rapid mcrease in the plasma concentration of buprenorphine in the patient.
  • the level of buprenorphine may be maintained indefinitely by the replacement of the set dosage level of the third patch every three or seven days.
  • Topical preparations typically contain a suspending agent and optionally, an antifoaming agent.
  • Such topical preparations may be liquid drenches, alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations (including, but not limited to aqueous solutions and suspensions).
  • buprenorphine can be administered in the form of a liposome delivery system.
  • a liposome delivery system for example, small unilamellar vesicles, large unilamellar vesicles and/or multilamellar vesicles that may be included in the transdermal article or transdermal composition.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the transdermal dosage form may be formulated by any method known in the art and may be administered as suggested. Such formulations are described in U.S. Patents 4,806,341; 5,240,711; and 5,968,547.
  • the unit dosage forms of the present invention are administered to a patient, preferably a human patient, suffering from symptoms of diarrhea.
  • the unit dosage forms of the present invention may be administered at the defined dosing regimen in order to rapidly achieve optimal activity while reducing the incidence of any potential adverse effects.
  • Such adverse effects may be, but are not limited to, nausea, vomiting, headache, dizziness, and somnolence.
  • the method of the invention preferably involves administering to the patient an analgesic effective amount of buprenorphine in a dosage regimen comprising a series of transdermal dosage forms of graduated and ascending dosages of buprenorphine.
  • the dosage regimen comprises administering to the patient:
  • a third buprenorphine-contaimng transdermal dosage form for a third dosing period wherein the third dosage form comprises a greater dosage of buprenorphine than the second dosage form.
  • the first dosage form comprises up to 5 mg buprenorphine, and the first dosing period is at least about 2 days;
  • the second dosage form comprises up to 10 mg buprenorphine, and the second dosing period is at least about 3 days;
  • the third dosage form comprises up to 20 mg buprenorphine, and the third dosing period is at least about 2 days.
  • first and second dosing periods are no more than about 7 days each, preferably no more than about 5 days, and even more preferably no more than about 3 days. In yet another specific embodiment, the first, second, and third dosing periods are each about 7 days.
  • the method of the present invention preferably administers buprenoi hine in a manner that achieves a gradual increase in the plasma concentration of buprenorphine in the patient.
  • the plasma profile achieved by the method of the present invention may be described as certain plasma concentration values at specific time points ("t") after the dosage regimen is begun, as follows:
  • a mean plasma buprenorphine concentration at t 24 hours of between 10- 100 pg/ml, preferably 20-50 pg/ml;
  • a mean plasma buprenorphme concentration at t 72 hours of between 25- 200 pg/ml, preferably 40-100 pg/ml;
  • the method of the present invention achieves a plasma profile that is substantially similar to that depicted in Figure 1.
  • “Substantially similar” refers to a profile of which the maximum plasma concentration (cmax) or area under the plasma concentration-time course profile (AUC) differs by no more than 30% from that of at least one of the reference profiles depicted in Figure 1.
  • the maximum plasma concentration (cmax) and/ or area under the plasma concentration-time course profile (AUC) differs no more than 20 % , even more preferably no more than 10 % , from that of a reference profile depicted in Figure 1.
  • the plasma profile is bioequivalent to the reference profile, as determined according to Food and Drug Administration (FDA) guidelines (see 21 C.F.R. ⁇ 320, and "Guidance for Industry - Statistical Approaches to Establishing Bioequivalence" U.S. Dept. of Health and Human Services, FDA, and CDER, January 2001).
  • subsequent dosages may be administered. For example, if the target analgesia level is attained with the third dosing period, fresh replacements of the third dosage form can be repeatedly administered for an extended period of time, changing patches with a frequency extending from about every 2 days to about weekly. If the target levels of analgesia and/or control of diarrhea are not attained within the third dosing period, subsequent dosage forms, comprising incrementally increasing levels of buprenorphine, can be applied, starting with 30 mg buprenorphine and 40 mg buprenorphine load.
  • the dosage of buprenorphine may vary according to a variety of factors such as underlying disease states, the individual's condition, weight, sex and age and the mode of administration.
  • the dosage predefined interval or regimen is selected in accordance with a variety of factors including species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the selected transdermal delivery system; the renal and hepatic function of the patient; and the particular form of buprenorphine used.
  • a physician or veterinarian of ordinary skill will readily be able to determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition in view of this disclosure.
  • Optimal precision in achievmg concentrations of drag within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the absorption, distribution, metabolism, and excretion of a drag.
  • composition or dosage form of the invention when administered as a transdermal dosage form, may be provided to any body part as determined by one of ordinary skill in the art.
  • the composition or dosage form may be provided to the arm, leg or chest of the patient.
  • the placement is preferably on the back to prevent the removal of the transdermal unit.
  • Repeated doses may or may not be administered to the same location each time.
  • the dosages are administered to the same location.
  • topical preparations contain from about 0.01 to about 100% by weight and preferably from about 3 to about 80% by weight of buprenorphine, based upon 100% total weight of the topical preparation.
  • transdermal dosage forms contain from about 0.01 to about 100% by weight and preferably from about 3 to about 50% by weight of the compound, based upon 100% total weight of the bupreno hine formulation in the dosage form.
  • the dosage forms used in the method of the present invention may be administered alone or in combination with other active agents.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the dosage amount may be adjusted when combined with other active agents as described above to achieve desired effects.
  • unit dosage forms of these various active agents may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either active agent were used alone.
  • kits of the invention provides a set number of buprenorphine patches at set dosages, wherein the dosages are set according to the needs of the patient.
  • Each kit will include the appropriate dosage regimen selected from the following table.
  • the dosage regimen is 5 mg, 10 mg, and 20 mg.
  • kits preferably includes packaging and instructions for its use, e.g. , on the packaging or package insert.
  • the buprenorphine patches within the kit may also be coded (i.e. , color, numerical by day, or numerical by dose, etc.) for the patient.
  • the kit will include a disposal container or device for disposal of used buprenorphine patches. Any such containers or devices known in the art can be used to prevent or limit potential abuse of the drag within the patch.
  • the term container has its broadest meaning, i.e. , any receptacle for holding material.
  • This example evaluates the physiologic effects of BTDS dose escalation in young and elderly subjects.
  • Young healthy subjects male or female subjects, aged 21-40 years, body weight ranging from 70-94 kg (males) and 55 to 81 kg (females). Patients were free of significant abnormal medical history, as evidenced by baseline physical examination, hematology, blood chemistries, urinalysis, ECG, and vital signs. Females had to have a negative serum pregnancy testing during screening visit and at predose. Barrier or IUD contraception with additional spermicidal foam or jelly was to be used from screenmg until discharge from the study.
  • Elderly healthy subjects male or female elderly subjects, aged 65-74 years, inclusive, body weight ranging from 70-94 kg (males) and 55 to 81 kg (females). Patients were free of significant abnormal medical history, as evidenced by baseline physical examination, hematology, blood chemistries, urinalysis, ECG, and vital signs. Females had to be postmenopausal, i.e. , at least one year without menses, or surgically sterile. A certain group of elderly patients suffered from hypertension (see data below).
  • Exclusion Criteria Any history of hypersensitivity to opioids or to psychotropic or hypnotic drags.
  • BTDS 5 from day 0 to day 3
  • BTDS 10 from day 3 to day 6
  • BTDS 20 from day 6 to day 13.
  • days After day 13, patients were monitored for an additional 4 days (day 17).
  • the vital signs tested included blood pressure (subjects remained supine for 5 minutes, then had their blood pressure measured; thereafter subjects stood, and blood pressure was measured after 1 minute of standing and after 2 minutes standing) , pulse (bpm, measured 5 mmutes supine, 1 minute standmg, and 2 minutes standing), respiratory rate (breaths/minute) , and transcutaneous oxygen saturation (SaO 2 ).
  • Blood pressure (mmHg): At each scheduled assessment time, subjects remained supine for 5 minutes, then had their BP measured. Subjects then stood, and BP was measured after 1 minute of standing and after 2 minutes of standing.
  • Pulse (bpm): Pulse was measured at 5 minutes supine, 1 minute standing, and 2 minutes standing.
  • Transcutaneous oxygen saturation (Sa ⁇ 2): Transcutaneous SaO ⁇ - was measured by pulse oximetry using a fingertip sensor that quantified SaO 2 by infrared spectrophotometry.
  • ECG ECG were conducted at screening and study completion. Vital signs were taken at these times in addition to those taken for pharmacodynamic evaluation.
  • Buprenorphine/Norbuprenorphine Assays The pharmacokinetic analysis included assaying plasma samples for concentrations of buprenorphine and norbuprenorphme.
  • Norbuprenorphme is the major known Phase I metabolite of buprenorphine and has lower pharmacologic activity than its parent compound. Briefly, buprenorphme and norbuprenorphme, and the internal standards deuterated d4-buprenorphine and deuterated d9-norbuprenorphine (Radian Corporation, Austin, TX) were measured by Liquid Chromatography-Electrospray/Mass Spectrometry/Mass Spectrometry (LC-ESI/MS/MS).
  • Solid Phase Extraction was used to isolate the two compounds of interest from 0.5 mL human plasma samples. Before extraction, all patient samples, standards, and controls were thawed at 37°C, vortexed, and centrifuged at 3000 rpm for at least 15 minutes. Buffer (8mM ammomum acetate) and internal standards were added to each plasma sample, including controls and standards (i.e. , samples containing known amounts of buprenorphine and/or norbuprenorphme).
  • HPLC High Performance Liquid Chromatography
  • the MS system consisted of a Micromass Qattro LC Mass Spectrometer equipped with an ESI source (Micromass Inc. , Beverly, MA) and operated in Multiple Reaction Monitoring Mode (MRM). Quantitation was performed using a calibration curve based on the peak area ratios of buprenorphine to d4-buprenorphine, and norbuprenorphme to d9- norbuprenorphine. The transition processes from precursor or molecular ion(s) to product ion(s) were used for both analytes to enhance the selectivity and sensitivity for buprenorphine and norbuprenorphine analysis.
  • transitions used were 468.1 to 55.1 (for buprenorphine), 472.4 to 59.1 (for d4-buprenorphine), 414.1 to 101.0 (for norbuprenorphine), and 423.1 to 110.0 (for d9-norbuprenorphine).
  • the exact transition of precursor to product ion can be fine-tuned based on the mass-tune report.
  • the Micromass MassLynx software was used to integrate the chromatographic peaks from the MS and determine the peak area ratios of buprenorphine/d4-buprenorphine and norbuprenorphine/d9-norbuprenorphine. The ratios of the areas were determined for each plasma standard, sample, and control. The standard peak area ratios were then used to prepare a calibration curve based on a weighted (1/x 2 ) linear regression. Sample and control concentrations were calculated from the regression line in pg/mL. The quantitation limit of the method was determined to be 25 pg/mL in human plasma for both analytes, with a concentration range from 25 to 600 pg/mL in human plasma.
  • Pharmacokinetic Metrics The following pharmacokinetic metrics were estimated from plasma buprenorphine and plasma norbuprenorphine concentrations following treatment with BTDS:
  • AUC a AUC t + 1
  • C max (pg/mL)— Measured plasma concentrations of buprenorphine and norbuprenorphine versus sampling time were plotted in plasma concentration-time course profiles for each individual. The maximum concentration of each substance was taken from each respective profile. The average maximum concentration of each substance was calculated as the arithmetic mean of all individual values.
  • nax W The time from dosing to the maximum observed concentration was taken directly from the plasma concentration-time course profile. The average time from dosing to the maximum observed concentration was calculated as the arithmetic mean of all mdividual values.
  • ⁇ z the first order rate constant associated with the terminal (log- linear) portion of the curve. This was estimated by linear regression of time versus log concentration. The apparent terminal half-life was considered reportable if the following criteria were met:
  • Pharmacokinetic metrics were log-transformed for analyses. For log-transformed variables, exponentiating the differences and the limits of the confidence intervals yielded corresponding mean ratio and confidence intervals in the original scale. Between-group comparison of pharmacokinetic metrics was performed using an analysis of variance (ANOVA) model. Pairwise comparisons between the 2 elderly groups and the group of young healthy subjects were performed. Statistical significance was assessed at the 5 % level with no adjustment for Type I error due to multiple comparisons. Confidence intervals (90%) were estimated around ratios (elderly healthy /young healthy and elderly hypertensive/young healthy) of the least squares means of AUC ⁇ , AUC ⁇ , and C max .
  • ANOVA analysis of variance
  • Pharmacokinetic metrics were log-transformed for analyses. For log-transformed variables, exponentiating the differences and the limits of the confidence mtervals yielded corresponding mean ratio and confidence intervals in the original scale. Between-group comparison of pharmacokinetic metrics was performed using an analysis of variance (ANOVA) model. Pairwise comparisons between the 2 elderly groups and the group of young healthy subjects were performed. Statistical significance was assessed at the 5% level with no adjustment for Type I error due to multiple comparisons. Confidence intervals (90%) were estimated around ratios (elderly healthy /young healthy and elderly hypertensive/young healthy) of the least squares means of AUCt, and Cmax.
  • ANOVA analysis of variance
  • Diastolic 67.9 (1.9) 75.3 (1.9) 71.6 (1.4)
  • Table 2 summarizes data for RR and %SaO 2 at baseline, at 6 to 8 hours following application of each BTDS, and 4 hours after removal of BTDS 20. In all groups, changes in mean RR were small. At baseline, mean %SaO 2 in the 2 elderly groups was slightly below the reference range. Compared to baseline, mean %SaO 2 values at each assessment did not change significantly in any of the 3 groups. No respiratory depression was observed.
  • a Change is from pre-BTDS (0.5 hour) to postapplication; mean change is the change for each subject averaged for the entire group at the specified assessment time.
  • b Assessment intervals were 6 to 8 hours following each BTDS application and 4 hours after BTDS removal. ⁇ leven young healthy subjects were evaluable for RR and %SaCh after application 3 and BTDS 20 removal. d Eleven elderly heathy subjects were evaluable for RR after BTDS 20 removal. "Reference range: 95% to 110%. •" Twelve elderly healthy subjects were evaluable for %SaU2 after BTDS 20 removal.
  • AUC (pg h/mL) 86026 (7808) 78674 (7707) 94022 (4242)
  • AUC (pg h/mL) 87485 (8867) a 81129 (8034) 99087 (4481)
  • Application Site Reactions Application site erythema and edema for each BTDS dose are summarized in Table 5. Most of the subjects experienced mild application site reactions. None of the reports of erythema or edema were severe or dose limiting.

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Abstract

La présente invention concerne un régime posologique pour l'administration de buprénorphine par voie transdermique, ce traitement permettant de réduire effectivement des symptômes tels que la douleur et/ou la diarrhée chez des patients souffrant d'une ou de plusieurs pathologies gastro-intestinales. Ce régime posologique réduit la gravité des symptômes de crise chez un patient traité pour les symptômes de la diarrhée. Les pathologies gastro-intestinales concernées sont la colopathie fonctionnelle, le syndrome de chasse intestinale, la colite microscopique, et la diarrhée associée à des carcinoïdes sécrétant des polypeptides intestinaux vasoactifs.
PCT/US2004/009335 2003-05-15 2004-03-26 Regime posologique pour le traitement de la diarrhee par administration de buprenorphine par voie transdermique Ceased WO2004103317A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1572167A4 (fr) * 2002-12-13 2007-01-10 Euro Celtique Sa Regime posologique de buprenorphine transdermique pour l'analgesie
EP1913938A1 (fr) * 2002-12-13 2008-04-23 Euro-Celtique S.A. Posologie transdermique de buprénorphine pour l'analgésie
USRE41408E1 (en) * 1997-02-24 2010-06-29 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorpine
US8637073B2 (en) 2003-07-25 2014-01-28 Purdue Pharma L.P. Treatment of dependence withdrawal
WO2015168031A1 (fr) * 2014-04-28 2015-11-05 OrphoMed LLC Dimère de la buprénorphine et son utilisation dans le traitement de troubles gastro-intestinaux

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968547A (en) * 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
US5900420A (en) * 1997-06-19 1999-05-04 Cole; William L. Method for treating chronic fatigue syndrome and fibromyalgia with buprenorphine
AU2063601A (en) * 1999-12-22 2001-07-03 Ortho-Mcneil Pharmaceutical, Inc. 4-(aryl(8-azabicyclo(3.2.1)octan-3-yl))aminobenzoic acid derivatives

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USRE41408E1 (en) * 1997-02-24 2010-06-29 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorpine
US9642850B2 (en) 1997-02-24 2017-05-09 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorphine
EP1572167A4 (fr) * 2002-12-13 2007-01-10 Euro Celtique Sa Regime posologique de buprenorphine transdermique pour l'analgesie
US7270830B2 (en) 2002-12-13 2007-09-18 Purdue Pharma L.P. Transdermal buprenorphine dosage regimen for analgesia
EP1913938A1 (fr) * 2002-12-13 2008-04-23 Euro-Celtique S.A. Posologie transdermique de buprénorphine pour l'analgésie
US8637073B2 (en) 2003-07-25 2014-01-28 Purdue Pharma L.P. Treatment of dependence withdrawal
KR20170005427A (ko) * 2014-04-28 2017-01-13 오르포메드, 인코포레이티드 부프레노르핀 이량체 및 위장질환의 치료에서 그의 용도
US9321780B2 (en) 2014-04-28 2016-04-26 Orphomed, Inc. Buprenorphine dimer and its use in treatment of gastrointestinal disorders
US9309256B2 (en) 2014-04-28 2016-04-12 Orphomed, Inc. Pharmaceutically active dimers linked through phenolic hydroxyl groups
US9549924B2 (en) 2014-04-28 2017-01-24 Orphomed, Inc. Use of buprenorphine dimer in the treatment of peripheral neuropathic pain
CN106470999A (zh) * 2014-04-28 2017-03-01 奥菲奥米德股份有限公司 叔丁啡二聚体及其在治疗肠胃失调中的应用
WO2015168031A1 (fr) * 2014-04-28 2015-11-05 OrphoMed LLC Dimère de la buprénorphine et son utilisation dans le traitement de troubles gastro-intestinaux
JP2017513918A (ja) * 2014-04-28 2017-06-01 オーフォームド，インコーポレイティド ブプレノルフィン二量体及び消化管疾患の治療におけるその使用
US9732096B2 (en) 2014-04-28 2017-08-15 Orphomed, Inc. Buprenorphine dimer and its use in treatment of gastrointestinal disorders
CN106470999B (zh) * 2014-04-28 2018-11-13 奥佛麦德公司 叔丁啡二聚体及其在治疗肠胃失调中的应用
KR102374506B1 (ko) 2014-04-28 2022-03-15 오르포메드, 인코포레이티드 부프레노르핀 이량체 및 위장질환의 치료에서 그의 용도

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