WO2019130341A1 - Compositions de capsules comprenant du lopinavir et du ritonavir - Google Patents

Compositions de capsules comprenant du lopinavir et du ritonavir Download PDF

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Publication number
WO2019130341A1
WO2019130341A1 PCT/IN2018/050864 IN2018050864W WO2019130341A1 WO 2019130341 A1 WO2019130341 A1 WO 2019130341A1 IN 2018050864 W IN2018050864 W IN 2018050864W WO 2019130341 A1 WO2019130341 A1 WO 2019130341A1
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WO
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Prior art keywords
ritonavir
lopinavir
composition
soft gelatin
gelatin capsule
Prior art date
Application number
PCT/IN2018/050864
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English (en)
Inventor
Bandi Parthasaradhi Reddy
Podile Khadgapathi
Sunil Deviprasad Tiwari
Soni Rajeev
Original Assignee
Hetero Labs Limited
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
Application filed by Hetero Labs Limited filed Critical Hetero Labs Limited
Publication of WO2019130341A1 publication Critical patent/WO2019130341A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to pharmaceutical compositions of lopinavir and ritonavir and process for preparation thereof.
  • Chemically ritonavir is lO-Hydroxy-2-methyl-5-(l-methylethyl)-l- [2-(l- methylethyl)-4thiazolyl]-3,6-dioxo-8,l l-bis(phenylmethyl)-2,4,7,l2- tetraazatridecan-l3-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,l0R*, l lR*)].
  • Its empirical formula is: CsylUsNgOsS ⁇ corresponding to a molecular weight of 720.95 having the following structural formula:
  • Ritonavir is marketed under the trade name NORVIR® in United States by Abbott in the form of lOOmg tablets, lOOmg capsules and 80mg/ml oral solution for the treatment of human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • Chemically lopinavir is [lS-[lR*,(R*), 3R*, 4R*]]-N-[4-[[(2,6- dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]tetrahydro- alpha-(l-methylethyl)-2-oxo-l(2H)-pyrimidineacetamide. Its empirical formula is: C37H48N4O5, corresponding to a molecular weight of 628.80 having the following structural formula:
  • Combination of Lopinavir and Ritonavir is marketed under the trade name Kaletra® in United States by Abbott in the form of 200mg:50mg and l00mg:25mg tablets; l33.3mg:33.3mg capsules; and 80mg/ml:20mg/ml oral solution.
  • US6458818 assigned to Abbott describes solution composition of lopinavir and ritonavir using organic solvent which comprises a long chain fatty acid or a mixture of long chain fatty acids, an alcohol and optionally a surfactant.
  • Composition of‘818 patent pose solubility and crystallization problems for ritonavir, which may impact the dissolution as well as bioavailability of final dosage form. Accordingly, inventors of the present invention were developed the improved pharmaceutical composition comprising lopinavir and ritonavir by addressing the said issues.
  • the present invention relates to capsule composition comprising lopinavir, ritonavir and one or more pharmaceutically acceptable excipients.
  • a soft gelatin capsule composition comprising thermodynamically stable solution comprising lOOmg to 200mg of lopinavir, 25mg to 50mg of ritonavir and at least one pharmaceutically acceptable excipient.
  • thermodynamically stable solution comprising lopinavir, ritonavir, an amphipathic lipid having an HLB value of 2 to 10.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition shows at least 70% of dissolution in 15 minutes.
  • Another embodiment of this invention relates to a process for preparing a soft gelatin capsule of lopinavir and ritonavir comprising: (a) mixing glyceryl mono caprylate, an oil and a solvent and heating gradually to the temperature of 40°C to 50°C, (b) dispersing lopinavir and ritonavir sequentially in the mixture of step (a) and increasing the temperature up to 65°C, followed by rapid cooling to 25°C to 35°C within 30 minutes, to get the required solution, and finally, (c) encapsulating the solution of step (b) as soft gelatin capsules.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition comprise not more than 0.9% of hydantoin amino alcohol impurity.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition shows at least 70% of dissolution in 15 minutes and comprise not more than 0.9% of hydantoin amino alcohol impurity.
  • the capsule composition of this invention is useful for treating HIV-l infection. DETAILED DESCRIPTION OF THE INVENTION
  • active ingredient or“active agent” used interchangeably, is defined to mean active drug (e.g. lopinavir or ritonavir), that induce a desired pharmacological or physiological effect.
  • active drug e.g. lopinavir or ritonavir
  • ritonavir as used here in according to the present invention includes ritonavir in the form of free base, in the form of a pharmaceutically acceptable salt thereof, amorphous ritonavir, crystalline ritonavir or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof.
  • lopinavir as used here in according to the present invention includes lopinavir in the form of free base, in the form of a pharmaceutically acceptable salt thereof, amorphous lopinavir, crystalline lopinavir or any isomer, derivative, hydrate, solvate, or prodrug or combinations thereof.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
  • excipients means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
  • composition refers to a solid dosage form suitable for oral administration, such as a capsule, tablet, spheroids, mini-tablets, pellets, granules, pills, solution, emulsion, suspension and the like.
  • Preferred dosage form is capsule.
  • thermodynamically stable refers to a system which is at its lowest energy state i.e. lower the potential energy of a system more stable it is.
  • Thermodynamic stability is a term used in chemistry to describe a chemical system that is neither consuming nor releasing heat energy. In the absence of a change in thermal energy, the substance is not undergoing a chemical reaction and is therefore stable. In mixtures that are thermodynamically stable, the stable state occurs either before any of the reactants have been transformed into products or after that process is complete. If a system is thermodynamically stable, there is no movement of heat within a system or between a system and the surrounding environment.
  • the present invention relates to capsule composition
  • capsule composition comprising lopinavir, ritonavir and one or more pharmaceutically acceptable excipients.
  • thermodynamically stable solution comprising lOOmg to 200mg of lopinavir, 25mg to 50mg of ritonavir and at least one pharmaceutically acceptable excipient.
  • thermodynamically stable solution comprising lOOmg of lopinavir, 25mg of ritonavir and at least one pharmaceutically acceptable excipient.
  • thermodynamically stable solution comprising 200mg of lopinavir, 50mg of ritonavir and at least one pharmaceutically acceptable excipient.
  • thermodynamically stable solution comprising lopinavir, ritonavir, an amphipathic lipid having an HLB value of 2 to 10.
  • Excipients of the present invention comprise one or more of the following: a lipidic vehicle, an emulsifier and a water miscible glycol and optionally a rheology controlling agent, an antioxidant and water.
  • Lipidic vehicle according to the present invention refers to either an oil or amphipathic lipids and a mixture of oil with amphipathic lipids can also be employed.
  • Class of oils refers to triglycerides or free fatty acids. Triglycerides are composed of triesters of free fatty acids with glycerol (l,2,3-trihydroxypropane) also known as triacylglycerols. Triglycerides that are solid or semisolid at room temperature are classified as fats. Those triglycerides that are liquid at room temperature are called oils.
  • Suitable long chain triglycerides for use in the invention include, but are not limited to, arachis oil, soya bean oil, castor oil, corn oil, safflower oil, olive oil, apricot kernel oil, sesame oil, cotton seed oil, sunflower seed oil, palm oil and rapeseed oil.
  • Free fatty acid refers to a group of aliphatic saturated or unsaturated carboxylic acids. The chains are usually unbranched and have 6 to 30, preferably 8 to 22, and in particular 8 to 18, carbon atoms.
  • the saturated fatty acids include, for example, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachdic acid, behenic acid, lignoceric acid, cerotic acid and melissic acid.
  • the unsaturated fatty acids may be unsaturated one or more times, in particular unsaturated once, twice, three times, four times, five times or six times.
  • singly unsaturated fatty acids include palmitoleic acid, oleic acid and erucic acid
  • doubly unsaturated fatty acids include sorbic acid and linoleic acid
  • triply unsaturated fatty acids include linolenic acid and eleostearic acid
  • quadruply unsaturated fatty acids include arachidonic acid
  • quintuply unsaturated fatty acids include clupanodonic acid
  • sextuply unsaturated fatty acids include docosahexaenoic acid.
  • a preferred singly or multiply pharmaceutically acceptable fatty acids are, especially oleic acid, palmitoleic acid, erucic acid, linoleic acid and linolenic acid.
  • a most preferred pharmaceutically acceptable fatty acid is oleic acid which is liquid at room temperature.
  • Amphipathic lipids refers to pharmaceutically acceptable lipids with optimal balance of hydrophobic-hydrophillic moieties to enhance or facilitate solubilization/ wettability of hydrophobic drugs.
  • Amphipathic lipids which can be used in the compositions of present invention selected from medium chain length triglycerides or long chain tri- and diglyceride mixtures which may contain monoglycerides, mono- and/or diglycerides of fatty acids; acetic, succinic, lactic, citric and/or tartaric esters of mono and/or diglycerides of fatty acids; propylene glycol mono- and/or di-esters of fatty acids; polyglycerol esters of fatty acids; castor oil ethoxylates; acid and ester ethoxylates; and sorbitan esters of fatty acids.
  • Suitable long chain mono-glycerides which can be used include glyceryl mono-oleate, triglycerol monooleate and linoleoyl polyoxyl-6 glycerides.
  • Suitable medium chain triglycerides include fractionated coconut oil and caprylic/capric triglyceride.
  • Suitable medium chain mono or diglycerides which can be used include propylene glycol dicaprylocaprate, glyceryl caprylate/ caprate, glyceryl monocaprylate, a sorbitan fatty acid ester (including sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate and the like) and caprylic/capric mono/diglycerides.
  • amphipathic lipids are glyceryl monocaprylate, propylene glycol monocaprylate, glyceryl monosteate, and linoleoyl polyoxyl-6 glycerides with optimal balance of hydrophobic-hydrophillic moieties (HLB: 2- 10).
  • Emulsifier according to the present invention refers to o/w non-ionic surfactant or mixture of non-ionic surfactants can also be employed.
  • Nonionic surfactant which can be used in the compositions of the present invention selected from polyoxyethylene castor oil derivatives (such as polyoxyethyleneglycerol triricinoleate, polyoxyl 35 castor oil, polyoxyethyleneglycerol oxystearate, polyethyleneglycol 60 castor oil, caprylocaproyl poloxyglycerides and the like, block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropylene glycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 338, Poloxamer® 407, and the like, a mono fatty acid ester of polyoxyethylene (20) sorbitan, (for example, polyoxyethylene (20) sorbitan
  • a preferred pharmaceutically acceptable non-ionic surfactant is polyoxyl 35 castor oil (Kolliphor® EL), polyoxyethylene (20) sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monooleate (Tween® 80).
  • a most preferred pharmaceutically acceptable non-ionic surfactants are polyoxyl 35 castor oil (Kolliphor® EL) and polyoxyethylene sorbitan monooleate (Tween® 80).
  • Water miscible glycols are solvents that include but are not limited to propylene glycol, diethylene glycol monoethyl ether (Transcutol®), glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like, and mixtures thereof which are non-volatile at controlled room temperature.
  • a preferred pharmaceutically acceptable solvent is diethylene glycol monoethyl ether or propylene glycol used within permissible daily exposure (PDE) for oral use.
  • Rheology controlling agent include but are not limited to colloidal sililcon dioxide (Aerosil 200), hydrophobic fumed silica (Aerosil R 972), precipitated silicon dioxide (RxCipients GL200), precipitated calcium silicate (Zeopharm ® 600), spray dried dibasic calcium phosphate (Fujicalin SG ® ), magnesium ahimino metasilicate (Neusilin US2, Neusilin UFL2), silicon dioxide (Syloid ® grades).
  • Antioxidants according to the present invention include but are not limited to ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate) and the like for chemical stability.
  • a preferred pharmaceutically acceptable antioxidant is butylated hydroxytoluene.
  • water is used optionally in an amount ranging up to 6% based on total weight of the medicament fill.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition shows at least 70% of dissolution in 15 minutes.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition comprise not more than 0.9% of hydantoin amino alcohol impurity.
  • thermodynamically stable solution comprising lopinavir, ritonavir, glyceryl mono caprylate, wherein the composition shows at least 70% of dissolution in 15 minutes and comprise not more than 0.9% of hydantoin amino alcohol impurity.
  • Present invention addresses the solubility and crystallization problems of ritonavir by one or more of the following ways: (i) Enabling preferential wettability of drug in lipidic phase;
  • Another aspect of this invention relates to a process for preparing a soft gelatin capsule of lopinavir and ritonavir comprising: (a) mixing glyceryl mono caprylate, an oil and a solvent and heating gradually to the temperature of 40°C to 50°C, (b) dispersing lopinavir and ritonavir sequentially in the mixture of step (a) and increasing the temperature up to 65°C, followed by rapid cooling to 25°C to 35°C within 30 minutes, to get the required solution, and finally, (c) encapsulating the solution of step (b) as soft gelatin capsules.
  • the capsule composition of this invention is useful for treating HIV - 1 infection.
  • Capsule compositions comprising solution of lopinavir and ritonavir:
  • colloidal silicon dioxide was added to the step (a) bulk and increased the temperature up to 40°C to 50°C,
  • step (c) lopinavir and ritonavir were sequentially dispersed in the bulk of step (b) and increased the temperature up to 65°C, followed by rapid cooling to 25°C to 35°C within 30 minutes to get the required solution, and finally,
  • step (d) the solution of step (c) was encapsulated as soft gelatin capsules. Dissolution study:
  • Capsule compositions comprising solution of lopinavir and ritonavir:
  • Amphipathic lipid glyceryl mono caprylate/ glyceryl mono stearate /linoleoyl polyoxyl-6 5 glycerides/ propylene glycol monocaprylate type V type II
  • oleic acid butylated hydroxy toluene, polyoxyl 35 castor oil and propylene glycol were mixed and heated gradually to the temperature of 30°C to 35°C
  • colloidal silicon dioxide/ hydrophobic fumed silica was added optionally to the step (a) bulk and increased the temperature up to 40°C to 50°C,
  • step (c) lopinavir and ritonavir were sequentially dispersed in the bulk of step (b) and increased the temperature up to 65°C, followed by optionally adding water and rapid cooling to 25°C to 35°C within 30 minutes to get the required solution, and finally,
  • step (d) the solution of step (c) was encapsulated as soft gelatin capsules.
  • Capsule compositions comprising solution of lopinavir and ritonavir:
  • Amphipathic lipid glyceryl mono caprylate/ sorbitan monooleate/ glyceryl mono stearate/ propylene glycol monocaprylate type I
  • oleic acid glyceryl mono caprylate/ sorbitan monooleate/ glyceryl mono stearate/ propylene glycol monocaprylate type I
  • oleic acid polyoxyl 35 castor oil and propylene glycol, butyl ated hydroxy toluene and optionally polyoxyethylene sorbitan monooleate were mixed and heated gradually to the temperature of 40°C to 50°C
  • step (b) lopinavir and ritonavir were sequentially dispersed in the bulk of step (a) and increased the temperature up to 65 °C, followed by optionally adding water and rapid cooling to 25 °C to 35°C within 30 minutes to get the required solution, and finally,
  • step (c) the solution of step (b) was encapsulated as soft gelatin capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques de lopinavir et ritonavir ainsi que des procédés de préparation de celles-ci. En particulier, l'invention concerne des compositions de capsules pharmaceutiques de lopinavir et ritonavir, ainsi que des procédés de préparation de celles-ci. Plus particulièrement, la présente invention concerne une composition de capsule de gélatine molle comprenant une solution de lopinavir et de ritonavir, ainsi que le procédé de préparation de celle-ci.
PCT/IN2018/050864 2017-12-26 2018-12-21 Compositions de capsules comprenant du lopinavir et du ritonavir WO2019130341A1 (fr)

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IN201741046596 2017-12-26
IN201741046596 2017-12-26

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WO2019130341A1 true WO2019130341A1 (fr) 2019-07-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021105922A1 (fr) * 2019-11-27 2021-06-03 Douglas Pharmaceuticals Limited Compositions pharmaceutiques
US11738024B2 (en) 2018-05-24 2023-08-29 Douglas Pharmaceuticals Limited Lopinavir and ritonavir for the treatment of cervix disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096395A1 (fr) * 2001-05-25 2002-12-05 Abbott Laboratories Capsules molles elastiques contenant du ritonavir et /ou du lopinavir
WO2005007070A2 (fr) * 2003-07-23 2005-01-27 Cristália Produtos Químicos Farmacêuticos Ltda. Composition pharmaceutique stable permettant l'administration d'inhibiteurs de la protease vih et procede de preparation d'une composition pharmaceutique concentree en vue de l'administration d'inhibiteurs de la protease de vih
US20160271132A1 (en) * 2013-10-23 2016-09-22 The University Of Manchester Treatment of cancer and benign proliferative disorders
NZ630248A (en) * 2012-05-07 2016-11-25 Bristol Myers Squibb Holdings Ireland Solubilized capsule formulation of 1,1-dimethylethyl [(1s)-1-{ [(2s,4r)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2-({ (1r,2s)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl} carbamoyl)pyrrolidin-1-yl]carbonyl} -2,2-dimethylpropyl]carbamate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096395A1 (fr) * 2001-05-25 2002-12-05 Abbott Laboratories Capsules molles elastiques contenant du ritonavir et /ou du lopinavir
WO2005007070A2 (fr) * 2003-07-23 2005-01-27 Cristália Produtos Químicos Farmacêuticos Ltda. Composition pharmaceutique stable permettant l'administration d'inhibiteurs de la protease vih et procede de preparation d'une composition pharmaceutique concentree en vue de l'administration d'inhibiteurs de la protease de vih
NZ630248A (en) * 2012-05-07 2016-11-25 Bristol Myers Squibb Holdings Ireland Solubilized capsule formulation of 1,1-dimethylethyl [(1s)-1-{ [(2s,4r)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2-({ (1r,2s)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl} carbamoyl)pyrrolidin-1-yl]carbonyl} -2,2-dimethylpropyl]carbamate
US20160271132A1 (en) * 2013-10-23 2016-09-22 The University Of Manchester Treatment of cancer and benign proliferative disorders

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11738024B2 (en) 2018-05-24 2023-08-29 Douglas Pharmaceuticals Limited Lopinavir and ritonavir for the treatment of cervix disorders
WO2021105922A1 (fr) * 2019-11-27 2021-06-03 Douglas Pharmaceuticals Limited Compositions pharmaceutiques

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