WO2020092402A1 - Compositions pharmaceutiques de tiopronine et leurs procédés de préparation - Google Patents

Compositions pharmaceutiques de tiopronine et leurs procédés de préparation Download PDF

Info

Publication number
WO2020092402A1
WO2020092402A1 PCT/US2019/058611 US2019058611W WO2020092402A1 WO 2020092402 A1 WO2020092402 A1 WO 2020092402A1 US 2019058611 W US2019058611 W US 2019058611W WO 2020092402 A1 WO2020092402 A1 WO 2020092402A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
group
mass
tiopronin
oil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2019/058611
Other languages
English (en)
Inventor
Dennis Elias Saadeh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Harrow Inc
Original Assignee
Harrow Health Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/174,954 external-priority patent/US20190060266A1/en
Application filed by Harrow Health Inc filed Critical Harrow Health Inc
Publication of WO2020092402A1 publication Critical patent/WO2020092402A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates generally to the field of pharmaceuticals, and, more specifically, to pharmaceutical compositions that include as an active component a therapeutically effective quantity of tiopronin, or a derivative or analog thereof, and to methods of preparing and using such compositions.
  • Tiopronin formally, 2-mercaptopropionylglycine (MPG), is a thiol drug that is commonly used to treat cystinuria, an inherited condition that occurs when there is too much of the amino acid cystine in the urine, leading to the formation of stones in the kidneys, bladder, and/or ureter.
  • Cystine an amino acid formed of two cysteine molecules via a disulfide bond, has limited solubility.
  • Tiopronin an acylated sulfhydryl-containing derivative of glycine, breaks the disulphide bond of cystine and binds the sulfhydryl group of the resultant cysteine monomers. This leads to a reduction in the concentrations of urinary cystine and reduces cystine stone formation.
  • cystinuria The symptoms of cystinuria include strong intermittent or constant pain, hematuria, nausea, vomiting, and urinary urgency. In severe cases, nephrolithiasis can cause permanent kidney damage and even death. In pediatric patients, the incidence of urolithiasis (urinary tract calculi or stones) and nephrolithiasis (kidney calculi or stones) is on the rise due to dietary changes, metabolic abnormalities, and climate change, including in very young children that are pre-school-age. Although this is a less prevalent condition than in adults, its incidence should not be underestimated since the stones tend to recur and can be a cause of acute kidney injury (obstructive nephrolithiasis) in early childhood and significant morbidity.
  • urolithiasis urinary tract calculi or stones
  • nephrolithiasis kidney calculi or stones
  • THIOLA® (tiopronin) tablets are FDA-approved for prevention of cystinuria in patients with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, and who were not successfully treated with dietary changes and increased fluid intake, or patients who have had side effects with the drug d-penicillamine.
  • Dosing of THIOLA® for adults may be up to 1,000 mg/day administered in divided doses three time daily. For children 9 years of age or older, 15 mg/kg/day may be administered in three doses.
  • THIOLA® is only available as lOO-mg tablets. Patients must therefore take up to 10 tablets per day in lOO-mg increments without options for precise, intermediary dosing.
  • a pharmaceutical composition formulated as an anhydrous suspension includes a dispersed phase comprising a therapeutically effective quantity of tiopronin, derivatives or analogs thereof, related cystine-binding thiol drugs, or tiopronin prodrugs, and an anhydrous dispersion medium, and may further include at least one pharmaceutically acceptable surfactant or solubilizing and suspending agent, wherein the dispersed phase is dispersed within the dispersion medium.
  • the anhydrous dispersion medium includes at least one of a vegetable oil (e.g., castor oil, soybean oil, coconut oil, avocado oil, olive oil, almond oil) and a medium chain triglyceride.
  • a vegetable oil e.g., castor oil, soybean oil, coconut oil, avocado oil, olive oil, almond oil
  • a medium chain triglyceride e.g., castor oil, soybean oil, coconut oil, avocado oil, olive oil, almond oil
  • the acceptable surfactant or solubilizing and suspending agent may be any of non-ionic polyoxyethlene-polyoxypropylene block copolymers, a water-soluble derivative of cellulose, optionally partially cross-linked polyacrylates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates, polyoxyethylene sorbitan monooleates, glyceryl distearate, triglycerol monooleate, and combinations thereof.
  • compositions described herein may be orally administered to a mammalian subject in need of such treatment, to treat various diseases and maladies including, but not limited to, stones in the kidney, bladder, or ureter.
  • “About” as used herein means that a number referred to as“about” comprises the recited number plus or minus 1-10% of that recited number. For example,“about” 100 degrees can mean 95-105 degrees or as few as 99-101 degrees depending on the context. Whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; i.e., meaning only 1, only 2, only 3, etc., up to and including only 20, as well as to the numbers in between integers, e.g., 1.5 or 2.5, and the like.
  • composition is defined as a chemical or a biological compound or substance, or a mixture or combination of two or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment, or prevention of disease or pathology.
  • “suspension” is defined for the purposes of the present application as a two- phase solid-in-liquid dispersion system having a first phase and a second phase.
  • “suspension” is defined as a heterogeneous mixture in which the solute particles (i.e., those forming the solid phase) do not truly dissolve, but rather, are suspended throughout the bulk of the solvent, without undergoing any significant precipitation within prolonged periods of time. It is further specifically provided that dispersion systems having three, four or more phases are not within the meaning of“suspension” for the purposes of the instant application.
  • the above mentioned first phase of the suspension consists of a multitude of solid particles and is designated and defined as the dispersed phase.
  • the above mentioned second phase of the suspension is a liquid and is designated and defined as the dispersion medium, or, interchangeably and synonymously, the continuous phase.
  • the dispersed phase is dispersed in the dispersion medium, and the term“dispersed” is defined as meaning that the dispersed phase is statistically evenly distributed within the continuous phase throughout the entire volume of the suspension, with no statistically meaningful deviations in the concentrations of the dispersed phase in different portions of the suspension.
  • the term“medium-chain triglycerides” refers to triglycerides (i.e., tri-esters of glycerol and fatty acids) in which at least two of the three fatty acid moieties are derived from aliphatic (i.e., saturated open-chain) acids having between 6 and 12 carbon atoms; the fatty acids that are used for making medium-chain triglycerides are defined as medium-chain fatty acids and are caproic (IUPAC, hexanoic), enanthic (IUPAC, heptanoic), caprylic (IUPAC, octanoic), pelargonic (IUPAC, nonanoic), capric (IUPAC, decanoic), undecylic acid (IUPAC, undecanoic), or lauric (IUPAC, dodecanoic) acids.
  • the term“carrier” refers to a substance that serves as a vehicle for improving the efficiency of delivery and the effectiveness of a pharmaceutical
  • solubilizing agent for the purposes of the instant application refers broadly to chemical compounds that improve the process of incorporating the solubilizate (i.e., active components described herein) into micelles.
  • solubilizing agent makes the process of solubilization faster, easier, and/or more complete as compared with compositions without it.
  • sipending agent used herein interchangeably with the term “emulsifier” for the purposes of the instant application refers broadly to chemical compounds that help active pharmaceutical ingredients stay suspended in the formulation and prevent and/or reduce the phase separation of the two-phase dispersion systems described herein.
  • alkanizing agent refers to a chemical compound or drug that is administered to a patient having diseases or medical disorders associated with low pH of bodily fluids (e.g blood), in order to increase the pH thereof.
  • terapéuticaally effective amount is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, medical doctor or other clinician.
  • composition is defined as a chemical or biological compound or substance, or a mixture or combination of two or more such compounds or substances, intended for use in the medical diagnosis, cure, treatment, or prevention of disease or pathology.
  • pharmaceutically acceptable when used in reference to a carrier, whether diluent or excipient, refers to a carrier that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the terms“administration of a composition” or“administering a composition” are defined to include the act of providing a compound of the invention or pharmaceutical composition to a subject in need of treatment.
  • the terms“kidney stone disease” and“nephrolithiasis” refer to a urological or nephrological disease or condition manifesting itself by having renal calculi (nephroliths) formed and deposited in the patient’s kidneys.
  • blade stone disease and“ureter stone disease” refer to urological diseases or conditions manifesting themselves by having stone-like matter (cystoliths) formed and deposited in the patient’s urinary bladder or ureter, respectively.
  • reducing agent refers to an electron-donor compound, i.e., a compound that donates an electron to another chemical species in a redox chemical reaction.
  • thiol refers to an organic compound that is a sulfur-containing analog of an alcohol, i.e., a compound containing the group -SH.
  • amino acid refers to an organic compound having both a carboxyl (- COOH) and an amino (-NH2) group.
  • the term“glycine” refers to an aminoacetic acid having the structure NH2-CH2- COOH; and the term“cystine” refers to 2-amino-3-(2-amino-2-carboxyl- ethyl)disulfanylpropanoic acid (i.e., an amino acid having the structure HOOC-CH(NH 2 )- CH2-S-S-CH2-CH(NH 2 )- COOH).
  • compositions intended to prevent and/or treat various diseases and maladies including kidney stone disease, bladder stone disease or ureter stone disease are provided.
  • a pharmaceutical composition for treating, mitigating or preventing nephrolithiasis or urolithiasis is provided. It is further specifically provided that the compositions of the invention are formulated as suspensions.
  • the composition comprises a therapeutically effective quantity of at least one pharmaceutically acceptable reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide.
  • the reducing agent comprises a thiol moiety and an amino acid moiety and may be, e.g., N-(2-mercaptopropionyl) glycine having the chemical formula:
  • Tiopronin is capable of binding cystine by thiol-disulfide exchange to form a mixed disulfide of tiopronin-cysteine.
  • (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid also known as D-penicilamine or under the trade name CUPRIMINE® (Valeant Pharmaceuticals
  • penicilamine may be used as the sole reducing agent in the composition or in a combination with tiopronin, if desired.
  • captopril l-(3-mercapto 2-methyl-l-oxopropyl)-L-proline
  • CAPOTEN® Bristol-Myers Squibb
  • the concentration of the reducing agent(s) described above, in the compositions may be between 1.0 % mass % and 5.0 mass % of the total units of the suspension (weight/volume), for example, 1 mass %, 2 mass %, 3 mass %, or 4 mass %.
  • the composition comprising a therapeutically effective quantity of at least one pharmaceutically acceptable reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide may include a second active component consisting of a therapeutically effective quantity of a urine alkanizing agent such as potassium citrate, sodium citrate, magnesium citrate, sodium bicarbonate or combinations thereof may be used.
  • a urine alkanizing agent such as potassium citrate, sodium citrate, magnesium citrate, sodium bicarbonate or combinations thereof may be used.
  • concentrations of the urine alkanizing agent(s) in the compositions may be between 2 mass % and 20 mass %, for example, 4 mass %, 6 mass %, 8 mass %, 10 mass %, 12 mass %, 14 mass %, 16 mass %, or 18 mass %.
  • the compositions are in the form of a suspension.
  • the suspensions include, consist of, or consist essentially of, an anhydrous dispersion medium (i.e., the continuous phase), a dispersed phase that is dispersed within the dispersion medium, and a pharmaceutically acceptable carrier.
  • the dispersed phase includes, consists of, or consists essentially of, particles of a therapeutically effective quantity of at least one pharmaceutically acceptable reducing agent capable of undergoing thiol-disulfide exchange with cystine to form a mixed disulfide, or derivatives or analogs thereof.
  • the dispersion medium includes at least one of a vegetable oil or a medium chain triglyceride, and further comprises at least one emulsifier or solubilizing and suspending agent.
  • the anhydrous dispersion medium of the composition of the present invention is comprised of at least vegetable oil or at least one medium chain triglyceride or a combination of products of both classes.
  • the dispersion medium forms the major portion of the composition, its mass concentration in the composition being between about 80.0 mass % and about 99.0 mass %, such as between about 85.0 mass % and about 95.0 mass %, for example, about 90 mass %, 92.5 mass %, or 95.0 mass %.
  • anhydrous dispersion medium examples include, without limitation, castor oil, soybean oil, coconut oil, avocado oil, olive oil, almond oil, and combinations thereof.
  • Those having ordinary skill in the art may use (an)other vegetable oil(s) instead of, or in combination with, those mentioned above, if desired.
  • Those having ordinary skill in the art will understand that all these oils represent complex blends of organic compounds, as opposed to individual organic molecules.
  • castor oil is a complex mixture of several fatty acids, principally, ricinoleic acid, an unsaturated, 18-carbon fatty acid having a hydroxyl functional group on the l2 th carbon (IUPAC, l2-hydroxyoctadec-9-enoic acid).
  • ricinoleic acid an unsaturated, 18-carbon fatty acid having a hydroxyl functional group on the l2 th carbon
  • IUPAC unsaturated, 18-carbon fatty acid having a hydroxyl functional group on the l2 th carbon
  • castor oil has a very complex chemical structure and is a mixture of triglycerides that varies, but commonly comprises ricinoleic acid (about 70%) plus triglycerides of linoleic (IUPAC, 9,l2-octadecadienoic) and oleic (IUPAC, octadec-9-enoic) acids (about 20% combined).
  • Almond oil is another complex mixture of several fatty acids, which varies but typically comprises 65 to 70 mass % of oleic, 20 to 25% of linoleic, up to 4% of palmitic (IUPAC, hexadecanoic) and small quantities of palmitoleic (IUPAC, hexadec-9-enoic) and stearic (IUPAC, octadecanoic) acids.
  • IUPAC hexadecanoic
  • IUPAC palmitoleic
  • stearic octadecanoic
  • Coconut oil is yet another complex mixture of several fatty acids, which also varies, but commonly comprises about 45 to 50% of lauric acid, the balance being a combination of other medium-chain fatty acids described above, as well as palmitic and stearic acids.
  • Olive oil is yet another mixture of several fatty acids, which also varies, but its principal ingredient is oleic acid (about 75 to 85%), the balance being a combination of other fatty acids including linoleic and palmitic acids.
  • a variety of medium-chain triglycerides can be used for forming the anhydrous dispersion medium of the compositions of the invention.
  • triglyceride(s) containing the aliphatic tails derived from caprylic acid or caproic acid may be so used.
  • Those having ordinary skill in the art may use (an)other medium-chain triglyceride(s) instead of, or in combination with, those based on caprylic or caproic acids, if desired.
  • One specific product comprising medium-chain triglycerides that may be used is UNISPEND® anhydrous sweetened liquid (Fagron, Inc., St. Paul, Minnesota).
  • the anhydrous dispersion medium used herein further comprises at least one emulsifier or solubilizing and suspending agent which may be present in the compositions of the instant invention at mass concentrations between about 0.1 mass % and about 10.0 mass %, such as between about 1.0 mass % and about 5.0 mass %, for example, about 1.0 mass %, 2.0 mass %, 3.0 mass % or 4.0 mass %.
  • emulsifier or solubilizing and suspending agent emulsifier or solubilizing and suspending agent that may be used is a non-ionic polyoxyethlene-polyoxypropylene block copolymer having the general structure:
  • Polyoxyethlene- polyoxypropylene block copolymer(s) that can be used may be those belonging to the PLURONIC® or POLOXAMER® families, chemically, poly(ethylene glycol)-block- poly(propylene glycol)-block-poly(ethylene glycol), both available from BASF Corp. and from several other vendors and having the following general chemical structure:
  • a specific and non-limiting example of a non-ionic polyoxyethlene- polyoxypropylene block copolymer that can be used is the product known under the trade name PLURONIC® L64, which is described by the chemical structure above, with the molecular weight of the polyoxypropylene portion of about 1,750 Daltons, about a 40% polyoxyethylene content (mass), and the average overall molecular weight of about 2,900 Daltons.
  • non-ionic polyoxyethlene- polyoxypropylene block copolymer that can be used is the product known under the trade name POLOXAMER 407® (also known as PLURONIC® F127), which is also described by the chemical structure above, with the molecular weight of the polyoxypropylene portion of about 4,000 Daltons, about a 70% polyoxyethylene content (mass), the overall molecular weight of between about 9,840 Daltons and about 14,600 Daltons.
  • POLOXAMER 407® also known as PLURONIC® F127
  • Some non-limiting examples of other emulsifiers or solubilizing and suspending agents that may be used in combination with, or instead of, non-ionic polyoxyethlene- polyoxypropylene block copolymers, include derivatives of cellulose, optionally partially cross-linked polyacrylates, polyoxyethylene sorbitan monolaurates, glyceryl isostearate, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates, polyoxyethylene sorbitan monooleates (e.g., members of POLYS ORB ATE® family of products), glyceryl distearate, triglycerol monooleate, and polysaccharide thickening agents such as xanthan gum.
  • derivatives of cellulose optionally partially cross-linked polyacrylates, polyoxyethylene sorbitan monolaurates, glyceryl isostearate, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates
  • suitable derivatives of cellulose include, without limitations, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose (Dow Chemical, Midland, Michigan).
  • suitable partially cross-linked polyacrylates include, without limitations, polymers of the CARBOPOL® family (Lubrizol, Wickliffe, Ohio).
  • the cross-linking agents that may be used to cross-link such polyacrylates are allyl sucrose or allyl pentaerythritol.
  • Suitable products of the POLYSORBATE® family i.e., ethoxylated sorbitan esterified with fatty acids
  • Suitable products of the POLYSORBATE® family include, without limitations, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates, or polyoxyethylene sorbitan monooleates, some of which are also known as TWEEN® products, such as POLYSORBATE® 80) (Croda, Wilmington, Delaware).
  • POLYSORBATE 80® chemically, polyoxyethylene (20) sorbitan monooleate, also known as sorbitan mono-9- octadecenoate poly(oxy-l,2-ethanediyl), i.e., a product of poly condensation of
  • polyethoxylated sorbitan and oleic acid having 20 units derived from ethylene glycol), which is a nonionic surfactant and emulsifier having the structure.
  • the pharmaceutical composition may further optionally include one or several pharmaceutically acceptable excipient(s).
  • an excipient that can be used may be one or several filler(s) to be selected by those having ordinary skill in the art, such as polyacrylate dispersion, e.g., Eudagrit NE 30 D® (available from Evonik Industries, Parsippany, New Jersey), which is a component allowing delayed or controlled release.
  • polyacrylate dispersion e.g., Eudagrit NE 30 D® (available from Evonik Industries, Parsippany, New Jersey)
  • Such excipients can be used for preparing the formulations in the form of a suspension to protect from gastric acid and delay pH dependent dissolution. Therefore, in some embodiments, formulations may be optionally compounded as delayed release compositions.
  • the concentration of such excipient(s), if used, in the compositions may be between about 50.0 mass % and about 80.0 mass % of the total mass of the suspension.
  • excipients that can be used for fabricating the pharmaceutical compositions described herein may optionally include one or more of various taste modifiers such as sweeteners (e.g., sucrose and derivatives, sodium saccharin, aspartame, stevioside, monosodium glycyrrhizinate), flavoring agents (e.g., those introducing any natural or artificial fruit, vegetable, flower, beverage or candy flavor, such as cherry, citrus (lemon, orange, tangerine), raspberry, vanillin and vanilla, marshmallow, chocolate, etc.), or anesthetic agents (e.g. menthol, peppermint, cinnamon).
  • sweeteners e.g., sucrose and derivatives, sodium saccharin, aspartame, stevioside, monosodium glycyrrhizinate
  • flavoring agents e.g., those introducing any natural or artificial fruit, vegetable, flower, beverage or candy flavor, such as cherry, citrus (lemon, orange, tangerine), raspberry, van
  • the pharmaceutical compositions described herein are formulated as stable two-phase suspensions as defined above. More specifically, according to these embodiments, the suspensions consist of two phases, i.e., the dispersed phase that is dispersed within the dispersion medium.
  • the dispersed phase includes particles comprising a therapeutically effective quantity of the
  • the dispersion medium is a liquid that includes all other compounds that are present in the pharmaceutical compositions described in the application. The application therefore envisions no embodiment where tiopronin can be used outside the dispersed phase, such as being a part of the dispersion medium.
  • the dispersed phase may optionally contain other compounds, such as, without limitation, stabilizers, anti-oxidants, preservatives, various flavoring agents or sweeteners.
  • a one-batch formulation method may be used, where the components of the pharmaceutical formulation can be combined in single container; the components may be added to the container simultaneously or consecutively.
  • Those having ordinary skill in the art can choose the best method for preparing the compositions.
  • compositions described herein can typically be administered orally.
  • An ordinarily skilled physician may prescribe delivery by any other acceptable method if so desired and indicated.
  • the medication prepared as described above may then be prescribed and given to a patient for treating, mitigating or preventing kidney stone disease, bladder stone disease or ureter stone disease.
  • kidney, bladder or ureter stone disease that may be treated, one kind of treatment that is particularly envisioned according to
  • embodiments of the present invention is the treatment, mitigation or prevention of cystinuria.
  • diseases or conditions that may be treated using the compositions described herein include rheumatoid arthritis and mucolytic treatments (i.e., treatments for clearing of mucus from the airways, lungs, bronchi, and trachea of a patient).
  • Example 1 Preparing a Pharmaceutical Composition No. 1 [0066] A pharmaceutical composition was prepared as described below. The following products were used in the amounts specified:
  • Tiopronin was triturated using a mortar and pestle according to standard techniques of mixing solids to achieve uniformity. A small quantity of glycerol was added to wet the powder followed by trituration again to form a smooth paste.
  • a pharmaceutical composition was prepared as described below. The following products were used in the amounts specified:
  • a small quantity of glycerol was added to wet the powder followed by trituration again to form a smooth paste.
  • the artificial caramel flavor liquid and POLYSORBATE® 80 were then added, with trituration followed by addition of Eudacrit NE 30 D® and the anhydrous sweetened medium chain triglyceride with mixing.
  • the product was the transferred to the dispensing bottle.
  • the mortar was washed using a small quantity of anhydrous sweetened medium chain triglyceride, and the wash was then transferred to the bottle to ensure the entire quantity of active components has been so transferred followed by packaging and labeling.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques, les compositions étant constituées essentiellement de suspensions anhydres d'une quantité thérapeutiquement efficace d'un agent réducteur pharmaceutiquement acceptable pouvant subir un échange thiol-disulfure avec de la cystine pour former un disulfure mélangé (tel que le tiopronine). Dans certains modes de réalisation, la suspension contient également un ou plusieurs agents d'alcanisation d'urine. L'invention concerne en outre des procédés de fabrication des compositions et d'utilisation de celles-ci.
PCT/US2019/058611 2018-10-30 2019-10-29 Compositions pharmaceutiques de tiopronine et leurs procédés de préparation Ceased WO2020092402A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16/174,954 US20190060266A1 (en) 2015-12-22 2018-10-30 Pharmaceutical compositions of tiopronin and methods for preparing thereof
US16/174,954 2018-10-30

Publications (1)

Publication Number Publication Date
WO2020092402A1 true WO2020092402A1 (fr) 2020-05-07

Family

ID=70464508

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/058611 Ceased WO2020092402A1 (fr) 2018-10-30 2019-10-29 Compositions pharmaceutiques de tiopronine et leurs procédés de préparation

Country Status (1)

Country Link
WO (1) WO2020092402A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100361653C (zh) * 2004-09-29 2008-01-16 上海华源医药科技发展有限公司 硫普罗宁软胶囊
US20100204324A1 (en) * 2007-07-12 2010-08-12 Nanjing Sanhome Pharmaceutical Co., Ltd. Optically Active N-(Alpha-Mercaptopropionyl)Glycine
US20170087179A1 (en) * 2015-09-28 2017-03-30 M.G. Therapeutics, Ltd. Thiol and Disulfide-Containing Agents for Increasing Meibomian Gland Lipid Secretion
US20170112804A1 (en) * 2015-10-07 2017-04-27 Buck Institute For Research On Aging Lipoic acid and derivatives thereof for the treatment of cystinuria
US20170172960A1 (en) * 2015-12-22 2017-06-22 Imprimis Pharmaceuticals, Inc. Pharmaceutical formulations for treating kidney stones and methods for fabricating and using thereof
US9701656B2 (en) * 2015-11-07 2017-07-11 Mark Quang Nguyen Tiopronin prodrugs, pharmaceutical compositions thereof, and methods of use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100361653C (zh) * 2004-09-29 2008-01-16 上海华源医药科技发展有限公司 硫普罗宁软胶囊
US20100204324A1 (en) * 2007-07-12 2010-08-12 Nanjing Sanhome Pharmaceutical Co., Ltd. Optically Active N-(Alpha-Mercaptopropionyl)Glycine
US20170087179A1 (en) * 2015-09-28 2017-03-30 M.G. Therapeutics, Ltd. Thiol and Disulfide-Containing Agents for Increasing Meibomian Gland Lipid Secretion
US20170112804A1 (en) * 2015-10-07 2017-04-27 Buck Institute For Research On Aging Lipoic acid and derivatives thereof for the treatment of cystinuria
US9701656B2 (en) * 2015-11-07 2017-07-11 Mark Quang Nguyen Tiopronin prodrugs, pharmaceutical compositions thereof, and methods of use
US20170172960A1 (en) * 2015-12-22 2017-06-22 Imprimis Pharmaceuticals, Inc. Pharmaceutical formulations for treating kidney stones and methods for fabricating and using thereof

Similar Documents

Publication Publication Date Title
ES2908290T3 (es) Composiciones de corticosteroides
KR100848344B1 (ko) 담즙산 함유 청정 수용액 제형의 제조
EP2616046B1 (fr) Système d'administration aqueux de médicament comportant un agent masquant une saveur désagréable
MXPA06013481A (es) Composicion de suspension farmaceutica.
JP2002522357A5 (fr)
CN102470183B (zh) 一种含二甲硅油/西甲硅油的药物组合物
WO2006020962A2 (fr) Excipient de suspension sapide pour ingredients pharmaceutiques
RU2668882C2 (ru) Жидкая фармацевтическая композиция
WO2012098562A2 (fr) Compositions liquides pour administration par voie orale de sels de lanthane
CN114555124A (zh) 药物共晶盐制剂
EP4061333B1 (fr) Compositions injectables d'acide ursodésoxycholique
JP2017533274A (ja) メトトレキサート製剤
US11213505B2 (en) Product based on iron bis-glycinate chelate and alginic acid and/or water-soluble salts thereof, formulations thereof, and pharmaceutical uses thereof
WO2020242543A1 (fr) Compositions pharmaceutiques liquides de baclofène pour administration orale
CA1242974A (fr) Nutrition parenterale a l'aide de triglycerides a chaines longues et moyennes
EP2538923A2 (fr) Poudre à goût masqué pour compositions en suspension de méthylprednisolone
US20190060266A1 (en) Pharmaceutical compositions of tiopronin and methods for preparing thereof
JP2511577B2 (ja) アルギン酸プロピレングリコ―ルエステルからなる徐放性製剤
JP4264105B2 (ja) イソソルビド含有ゼリー製剤
WO2020092402A1 (fr) Compositions pharmaceutiques de tiopronine et leurs procédés de préparation
JP2009531379A (ja) 鉄代謝機能障害を治療するためのストロビルリンの使用
AU2019280828A1 (en) Pyrimethamine-based pharmaceutical compositions and methods for fabricating thereof
US20210069237A1 (en) Pharmaceutical compositions comprising heparinoids and methods for preparing thereof
RU2751772C2 (ru) Новая улучшенная композиция, содержащая по меньшей мере один кадотрил
US11865099B2 (en) Product based on iron bis-glycinate chelate and alginic acid and/or water-soluble salts thereof, formulations thereof, and pharmaceutical uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19878393

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19878393

Country of ref document: EP

Kind code of ref document: A1