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WO1997035587A1 - Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs - Google Patents

Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs Download PDF

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Publication number
WO1997035587A1
WO1997035587A1 PCT/EP1997/001438 EP9701438W WO9735587A1 WO 1997035587 A1 WO1997035587 A1 WO 1997035587A1 EP 9701438 W EP9701438 W EP 9701438W WO 9735587 A1 WO9735587 A1 WO 9735587A1
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WO
WIPO (PCT)
Prior art keywords
hiv protease
water soluble
tpgs
compound
vitamin
Prior art date
Application number
PCT/EP1997/001438
Other languages
English (en)
Inventor
Arup K. Roy
Lloyd Gary Tillman
Original Assignee
Glaxo Group 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
Priority claimed from GBGB9606372.2A external-priority patent/GB9606372D0/en
Priority to CA002249336A priority Critical patent/CA2249336C/fr
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to PL32891697A priority patent/PL187919B1/pl
Priority to SI9730498T priority patent/SI0906107T1/xx
Priority to NZ331645A priority patent/NZ331645A/en
Priority to AT97914287T priority patent/ATE230602T1/de
Priority to APAP/P/1998/001343A priority patent/AP1150A/en
Priority to DE69718315T priority patent/DE69718315T2/de
Priority to JP09534017A priority patent/JP3117726B2/ja
Priority to HU9901887A priority patent/HU228026B1/hu
Priority to EE9800323A priority patent/EE04093B1/xx
Priority to EP97914287A priority patent/EP0906107B1/fr
Priority to AU21591/97A priority patent/AU724239B2/en
Priority to RO98-01407A priority patent/RO119923B1/ro
Priority to EA199800755A priority patent/EA001484B1/ru
Priority to IL12618597A priority patent/IL126185A/xx
Priority to SK1269-98A priority patent/SK284244B6/sk
Priority to DK97914287T priority patent/DK0906107T3/da
Priority to BR9708238A priority patent/BR9708238A/pt
Priority to UA98094710A priority patent/UA67723C2/uk
Publication of WO1997035587A1 publication Critical patent/WO1997035587A1/fr
Priority to IS4840A priority patent/IS2066B/xx
Priority to NO19984386A priority patent/NO317639B1/no
Priority to HK99102135A priority patent/HK1016896A1/xx
Priority to UY25926A priority patent/UY25926A1/es

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    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to novel pharmaceutical formulations containing HIV protease inhibitors, specifically including 3S-[3R*(1R*. 2S*)]-[3-[[(4- aminophenyl)sulphonyl](2-methylpropyl)-amino]-2-hydroxy-1- phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester (alternatively known as VX 478 or 141 W94), and a tocopherol, and their use in medical therapy.
  • the present invention is within the field of pharmaceutical science, in particular in the area of drug delivery, specifically the delivery of HIV protease inhibitors.
  • HIV protease has potent activity against Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome
  • protease-inhibiting compounds include those disclosed in WO94/05639, WO95/24385, WO94/13629, WO92/16501 , WO95/16688, WO/US94/13085, WO/US94/12562, US93/59038, EP541168, WO94/14436, WO95/09843, WO95/32185, WO94/15906, WO94/15608, WO94/04492, WO92/08701 ,
  • an HIV protease inhibitor has a high degree of potency against HIV but it is, of course, essential that when administered to a patient that the HIV protease inhibitor reaches the site of action at an amount and for a duration sufficient for a therapeutic effect to occur, but yet not to reach such levels that excessive and unavoidable toxic effects are present. Therefore in common with other drugs the bioavaUabiUty ofthe HIV protease inhibitor is determined so as to deduce the amount of drug needed to be administered to the patient in order to satisfy the above criteria.
  • Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.
  • a drug must first go into solution prior to abso ⁇ tion and, therefore, a key factor is the dissolution rate of a drug.
  • Typical ofthe class of drugs HIV protease inhibitors have poor physical characteristics of low solubility and wettability and accordingly their dissolution rate is low. Therefore, simple tablet or capsule formulations of such drugs will have a low bioavailability and need to be administered in much higher quantities in order to achieve a therapeutic effect.
  • HIV protease inhibitors for oral administration are in powder or tablet form.
  • HIV protease inhibitors in these oral formulations are generally poorly soluble and, therefore, poorly bioavailable for the above reasons.
  • the aqueous solubility ofthe compound of formula (I) is only 0.095 mg/mL at room temperature and does not significantly vary with pH ( Figure 1).
  • the compound of formula (I) is poorly wetted. Therefore, formulating the compound using standard formulary techniques is difficult and leads in any event to a formulation with low bioavailability.
  • the compound of formula (I) was formulated as a solution suitable for oral administration.
  • 10 mg/mL of the compound of formula (I) in Polyethylene Glycol 400 (PEG400) solution had an oral bioavailability of 25-30% (Table 1 ).
  • PEG400 Polyethylene Glycol 400
  • the bioavailability dropped to half the value achieved with the 10 mg/mL solution and the maximal concentration (Cmax) achieved was also drastically reduced (Table 1).
  • Vitamin E-TPGS is a water soluble form of vitamin E and has been recognised as an excipient to promote emulsification of lipophilic substances, acting as a non-ionic surfactant, and in improving the bioavailability of certain drugs.
  • Vitamin E-TPGS is specifically mentioned at pages 7-8 and 12 as an emulsifier for use in formulations containing high levels of ⁇ -tocopherol as the lipid layer.
  • formulations for topical administration disclosed containing Vitamin E-TPGS, such as Examples 1 to 5 typically comprises a lipid layer (an ⁇ -tocopherol), the drug and Vitamin E-TPGS, in quantities of less than 25% w/w of the formulation, as an emulsifier.
  • HIV protease inhibitors There is no reference to formulation of HIV protease inhibitors.
  • Vitamin E-TPGS can be used for the enhanced delivery of lipophilic compounds as a self-emulsifying preconcentrate formulation comprising a) a lipophilic drug (a cyclosporin is specifically exemplified), b) vitamin E-TPGS and c) a lipophilic phase.
  • Typical examples of formulations disclosed, such as Examples 2 and 4 contain less than 14% w/w Vitamin E-TPGS as an emulsifier, a lipid layer and the drug. There is no reference to formulation of HIV protease inhibitors.
  • an HIV protease inhibitor can be significantly enhanced by formulation as a liquid formulation comprising a water soluble tocopherol derivative, in particular Vitamin E-TPGS.
  • formulations comprising (a) an HIV protease inhibitor and (b) a water soluble tocopherol derivative in a ratio of from about 1 :0.5 to about 1:10 w/w have advantageous properties in terms of bioavailability.
  • the present invention thus provides, in a first aspect, a pharmaceutical formulation for oral administration comprising a) an HIV protease inhibitor and b) a water soluble tocopherol derivative in a ratio of from about 1:0.5 to about 1:10 w/w.
  • formulations comprising a) an HIV protease inhibitor b) at least 20% w/w of a water soluble tocopherol derivative such as Vitamin E- TPGS have good bioavailability even when the HIV protease inhibitor is present at high concentrations.
  • a lipophilic phase is not needed thus reducing costs and making formulation more convenient.
  • the absence of a lipophilic phase and the ability to dissolve the HIV protease inhibitor at much higher concentrations without adversely affecting bioavailability means that smaller, more convenient, cheaper and easier to manufacture formulations result.
  • the present invention thus provides, in a further or altemative aspect, a pharmaceutical formulation for oral administration comprising (a) an HIV protease inhibitor and (b) at least 20% of a water soluble tocopherol derivative in the absence of a lipophilic phase.
  • the present invention provides a pharmaceutical formulation for oral administration comprising (a) an HIV protease inhibitor and (b) at least 20% of a water soluble tocopherol derivative wherein the ratio of (a) to (b) is from about 1 :0.5 to about 1:10 w/w.
  • the water soluble tocopherol derivative is Vitamin E-TPGS.
  • the formulations of the invention comprise from about 10% to about 60% w/w water soluble tocopherol derivative, preferably Vitamin E-TPGS, more preferably about 20% to about 50% such as about 30% to about 50% w/w, for example, about 30%.
  • HIV protease inhibitor is the compound of formula (I).
  • the ratio of HIV protease inhibitor to water soluble tocopherol derivative in the formulations of the invention is preferably from about 1 :0.5 to about 1 :3, such as, for example, from about 1:0.67 to about 1:2.6 w/w, more preferably from about 1 :1.3 to about 1 :3.
  • Water soluble tocopherol derivatives in particular Vitamin E-TPGS, exist at room temperature as waxy solids.
  • the HIV protease inhibitor compound may be administered to a patient in the water soluble tocopherol derivative alone it is preferable that additional pharmaceutical excipients are added to improve the physical properties of the formulation, for example by the addition of a hydrophilic non-aqueous solvent miscible with the water soluble tocopherol derivative to achieve a flowable liquid more suitable for mass formulation as, for example, in a soft gelatine capsule.
  • a hydrophilic non-aqueous solvent miscible with the water soluble tocopherol derivative enhances the solubility of the HIV protease inhibitor allowing further reduction of the volume ofthe formulation required to deliver an effective dose.
  • Preferred pharmaceutically acceptable solvents are polyethylene glycol and propylene glycol.
  • Polyvinyl pyrrolidones can also be used.
  • the addition of polyethylene glycol and propylene glycol to a formulation of an HIV protease inhibitor in Vitamin E-TPGS results in a flowable liquid which may suitably be filled into a soft gelatine capsule and represents a preferred feature of the invention.
  • the present invention provides a pharmaceutical formulation for oral administration comprising (a) an HIV protease inhibitor (b) a water soluble tocopherol derivative and (c) a hydrophilic non-aqueous solvent miscible with said water soluble tocopherol derivative wherein the ratio of (a) to (b) is from about 1 :0.5 to about 1:10 w/w.
  • the hydrophilic non-aqueous solvent is selected from polyethylene glycol, propylene glycol and polyvinyl pyrrolidinone. More preferably the hydrophilic non-aqueous solvent is a mixture of polyethylene glycol, such as polyethylene glycol 400, and propylene glycol.
  • the amount of hydrophilic non- aqueous solvent in the formulations of the invention may be in the range of about 15% to about 95%, such as about 25% to about 60% w/w.
  • the present invention provides a pharmaceutical formulation for oral administration consisting essentially of (a) an HIV protease inhibitor (b) Vitamin E-TPGS (c) polyethylene glycol and (d) propylene glycol.
  • the invention provides a pharmaceutical formulation consisting essentially of (a) 3S-[3R*(1R*. 2S*)]-[3-[[(4- aminophenyl)sulphonyl](2-methylpropyl)-amino]-2-hydroxy-1- phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester, [3-(S)-N-(3- tetrahydrofuranyloxycarbonyl)amino-1-(N,N-isobutyl-4- aminobenzenesulfonyl)amino-2-(S)-hydroxy-4-phenylbutane (b) Vitamin E- TPGS (c) polyethylene glycol and (d) propylene glycol.
  • the formulations of the invention are preferably presented in the form of capsules, more preferably soft gelatin capsules.
  • the pharmaceutically acceptable salts, esters, or salts of such esters of HIV protease-inhibiting compounds particularly the compound of formula (I), or any other compound which, upon administration of a safe and therapeutically effective amount of the compound to a human subject, is capable of providing (directly or indirectly) the antivirally active metabolite or residue thereof.
  • HIV protease-inhibiting compounds can be prepared as disclosed in WO95/24385, WO94/13629, WO92/16501 , WO95/16688, WO94/13085, WO/US94/12562, US93/59038, EP 541168, WO94/14436, WO95/09843, WO95/32185, WO94/15906, WO94/15608, WO94/04492, WO92/08701, WO95/32185, US Patent No. 5,256,783; 5,475,136; 5,461 ,067; 5,484,926; 5,476,874; 5,475,027; 5,482,947; and 5,475,013 which are incorporated herein by reference.
  • Vitamin E-TPGS may be prepared by the esterification of polyethylene glycol 1000 to the acid group of crystalline d-alpha tocopheryl acid succinate as disclosed in US Patent No. 2,680,649 and 5,234,695.
  • solvent means a solvent or cosolvent which is pharmaceutically or medicinally acceptable and which will dissolve an HIV protease inhibiting compound to form a solution and is not substantially destructive of the capsule shell.
  • Polyethylene glycols containing 300 to 1000 polyethylene glycol monomer units can advantageously be used as solvents and polyethylene glycols having average molecular weights between 300 to 1000 and containing about 300 to 400 ethylene glycol monomer units as above may advantageously be used as solvents.
  • solvents or cosolvents which may also be suitable include, but are not limited to, propylene glycol, alcohol, glycerin, and sorbitol. Concentrations of solvents or co-solvents may suitable be in the range of 0.1% to 10%. In addition 0-10% water may be used as a co-solvent.
  • the term lipophilic phase denotes one or more hydrophobic components such as, for example, fatty acid esters of glycerol, fatty acid esters of propylene glycol and vegetable oil.
  • the capsule shell may suitably be made of gelatin and may include plasticizers such as anidrisorb, glycerin or sorbitol, water, preservatives, coloring agent(s), and opacifying agent(s).
  • the capsules of this invention may be of any shape, suitably the capsules may be elongated such as ellipsoidal, oval or cylindrical with rounded ends. A range of about 10 to 1500 mg of the compound of formula (I) may suitably be used.
  • the capsules may contain 25mg, 50mg ,150 mg or200mg of the compound of formula (I).
  • each capsule contains the compound of formula (I) in solution at a concentration of 10 to 1000 mg/mL with a concentration of 25 to 500 mg/mL being most preferred.
  • concentration means mg of the compound of formula (l)/mL of solution.
  • the soft gelatin capsule may be chosen from those available from various manufacturers to hold the volume ofthe following examples to provide the concentration set forth therein.
  • the capsules are Size No. 12 oblong, or size No. 3 oval, white opaque soft gelatin capsules manufactured by R P Scherer, North America.
  • a preferred formulation according to the invention comprises an HIV protease- inhibiting compound (preferably a compound of formula (I)), in the amount of from about 1% to about 50% by weight of the total solution, and Vitamin E- TPGS in the amount of from about 5% to about 100% by weight of the total solution, polyethylene glycol in the amount of from about 15% to about 95% by weight of the total solution and propylene glycol in the amount of from about 0.1% to 10% by weight ofthe total solution.
  • the formulation may optionally contain water in the amount of from about 0% to 10%.
  • the term "therapeutically effective amount" of the compound of formula (I) means one or more capsules of the type disclosed herein, with each capsule preferably containing 25mg, 50mg, 150mg or 300mg of the compound of formula (I).
  • a dose of about 100 to 3000mg of the compound of formula (I) followed by about 100mg to 5000mg of the compound of formula (I) may be used.
  • maintenance doses of 100 to 5000mg of the compound of formula (I) may be administered depending on the patient.
  • a suitable dosage regimen may be, for example, 1200mg ofthe compound of formula (I) twice daily.
  • the formulations according to the invention may be presented in various forms adapted for direct oral administration including liquid forms, for example, syrups, suspensions, or solutions.
  • the formulations, according to the invention may include other pharmaceutically acceptable carriers as excipients conventionally used in such formulations.
  • syrups may include sugar syrup, sorbitol or hydrogenated glucose syrup or artificial sweeteners such as aspartame, sodium saccharin, acesulfame K, etc.
  • Suspensions may include methylcellulose, microcrystalline cellulose, carmeliose sodium or dispersible cellulose. Solutions may include liquid glucose, laevulose or xylitol.
  • formulations of the present invention may be made using methods and techniques that are commonly employed in preparing preparations within the pharmaceutical industry.
  • the formulations according to the invention may be prepared in conventional manner, for example, by appropriate mixing of the ingredients in one or more vessels, the ingredients being dissolved or suspended using established pharmaceutical techniques.
  • An HIV protease-inhibiting compound may be dissolved in the liquefied emulsifier-solvent mixture which has been heated to approximately 65°C to facilitate dissolution.
  • propylene glycol may be added to the resulting solution.
  • the final solution a clear flowable liquid between 28-35°C, may suitably be filled into soft gelatin capsules.
  • Such a formulation when dissolved in water forms a clear solution with an improved bioavailability.
  • the amount required of the compound of formula (I) will depend upon a number of factors including the severity of the condition to be treated and the age and condition of the recipient and will ultimately be at the discretion of the attendant physician.
  • a suitable, effective dose may be in the range of 5 to 100 mg/kg body weight of recipient per day, advantageously 8 to 70 mg/kg body weight and preferably 8 to 50mg/kg body weight.
  • the desired dose may preferably be presented at one, two, three, four or more sub-doses administered in unit dosage forms, for example, containing 25 to 500mg of active ingredient per unit dosage form.
  • the formulations may be used for the treatment or prophylaxis of human retroviral infections including HIV infections, and the consequent clinical conditions resulting from such infections, for example, AIDS, ARC, progressive generalised lymphadenopathy (PGL) and HIV-seropositive and AIDS-antibody-positive conditions.
  • HIV infections including HIV infections, and the consequent clinical conditions resulting from such infections, for example, AIDS, ARC, progressive generalised lymphadenopathy (PGL) and HIV-seropositive and AIDS-antibody-positive conditions.
  • the formulations according to the invention may be employed in medical therapy in combination with other therapeutic agents suitable in the treatment of HIV infections, such as nucleoside reverse transcriptase inhibitors for example zidovudine, zalcitabine, lamivudine, didanosine, stavudine, ⁇ -chloro-2',3'- dideoxy-3'-fluorouridine and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)1 ,3- oxathiolan- ⁇ -yl]cytosine; non-nucleoside reverse transcriptase inhibitors for example nevirapine, TIBO, and ⁇ -APA; HIV protease inhibitors for example saquinavir, indinavir and ritonavir; other anti-HIV agents for example soluble CD4; immune modulators for example interleukin II, erythropoetin, tucaresol; and interferons for example ⁇ -interferon.
  • Figure 1 shows the solubility of the compound of formula (I) with varying pH.
  • a liquid formulation was prepared as follows:
  • Vitamin E-TPGS obtained from Eastman Chemical Co.
  • 2.00 ⁇ ⁇ kg of polyethylene glycol 400 (PEG400) low aldehyde, ⁇ 10 ppm, obtained from Union Carbide or Dow Chemical Co.
  • PEG400 polyethylene glycol 400
  • the resultant solution was heated to 6 ⁇ °C.
  • 1. ⁇ kg of the compound of formula (I) was dissolved in the liquefied solution of Vitamin E-TPGS and PEG400. 0.39 ⁇ kg of propylene glycol at room 0 temperature was added and mixed until a homogenous solution was formed.
  • the solution was cooled to 28-35°C.
  • the solution was then de-gassed.
  • the mixture was preferably encapsulated at 28-35°C at a fill weight equivalent to 1 ⁇ O mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatin capsules using a capsule filling machine.
  • the capsule shells were dried to a constant fill moisture of 3-6% water and a shell hardness of 7-10 newtons, and placed in a suitable container.
  • the pharmacokinetics of the compound of formula (I) after intravenous and oral administration was assessed in Hsd: Sprague Dawley SD rats after doses of 10, 24.1, and ⁇ O mg/kg, dissolved in PEG400. Pharmacokinetics were also 0 conducted with D-alpha tocopheryl PEG 1000 Succinate (TPGS) and mixtures of Vitamin E-TPGS, PEG400, and propylene glycol in Hsd rats and beagle dogs.
  • TPGS D-alpha tocopheryl PEG 1000 Succinate
  • the compound of formula (I) was administered individually to groups of four cannulated Hsd rats by intravenous injection at doses of 10 and ⁇ O mg/kg or gavage at doses of 10, 24.1 , and ⁇ O mg/kg dissolved in PEG400.
  • Four other animals received individual capsules containing the compound of formula (I) in solution with PEG400 and Vitamin E-TPGS at an average dose of 11 mg/kg.
  • Blood samples were drawn at various times from 2 min to 7 hr post-dose.
  • the principal pharmacokinetic parameters of the compound of formula (I) are summarized in Table 1.
  • Each set of values are averages 1 standard deviation
  • Cmax The maximum concentration observed, were calculated from individual observed levels.
  • tmax the time the maximum concentration observed, were calculated from individual observed levels.
  • AUC Area under the concentration time curve, were determined for individual animals.
  • Each set of values are averages ⁇ standard deviation
  • Cmax The maximum concentration observed, were calculated from individual observed levels.
  • tmax the time the maximum concentration observed, were calculated from individual observed levels.
  • AUC Area under the concentration time curve, were determined for individual animals.

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Abstract

L'invention porte sur des préparations pharmaceutiques contenant des inhibiteurs de la protéase du VIH comportant en particulier un tétrahydro-3-furanyl ester de l'acide 3S-[3R*(1R*,2S*)]-[3-[[(4-aminophényl)sulphonyl](2-méthylpropyl)-amino]-2-hydroxy-1-phénylméthyl)propyl] carbamique (également dénommé VX 478 ou 141W94) ainsi qu'un tocophérol, et sur leur emploi à des fins thérapeutiques.
PCT/EP1997/001438 1996-03-22 1997-03-21 Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs WO1997035587A1 (fr)

Priority Applications (23)

Application Number Priority Date Filing Date Title
RO98-01407A RO119923B1 (ro) 1996-03-22 1997-03-21 Compoziţie farmaceutică pentru administrare orală
AU21591/97A AU724239B2 (en) 1996-03-22 1997-03-21 Compositions comprising an HIV protease inhibitor such as VX 478 and a water soluble vitamin E compound such as vitamin E-TPGS
PL32891697A PL187919B1 (pl) 1996-03-22 1997-03-21 Preparat farmaceutyczny do podawania doustnego zawierający inhibitor proteazy HIV oraz sposób wytwarzania preparatu farmaceutycznego do podawania doustnego zawierającego inhibitor proteazy HIV
SI9730498T SI0906107T1 (en) 1996-03-22 1997-03-21 Compositions comprising vx 478 and a water soluble vitamin e compound such as vitamin e-tpgs
NZ331645A NZ331645A (en) 1996-03-22 1997-03-21 Compositions comprising an HIV protease inhibitor such as VX 478 and a water soluble vitamin E compound such as vitamin E-TPGS
AT97914287T ATE230602T1 (de) 1996-03-22 1997-03-21 Zubereitung, enthaltend vx 478 und eine wasserlösliche vitamin e verbindung wie vitamin e-tpgs
APAP/P/1998/001343A AP1150A (en) 1996-03-22 1997-03-21 Compositions comprising an HIV protease inhibitor such as Vx 478 and a water soluble vitamin E compound such as vitamin E-TPGS.
DE69718315T DE69718315T2 (de) 1996-03-22 1997-03-21 Zubereitung, enthaltend vx 478 und eine wasserlösliche vitamin e verbindung wie vitamin e-tpgs
JP09534017A JP3117726B2 (ja) 1996-03-22 1997-03-21 Ｖｘ４７８のようなｈｉｖプロテアーゼ阻害剤およびビタミンｅ―ｔｐｇｓのような水溶性ビタミンｅを含む組成物
HU9901887A HU228026B1 (en) 1996-03-22 1997-03-21 Compositions comprising an hiv protease inhibitor and a water soluble vitamin e compound
EE9800323A EE04093B1 (et) 1996-03-22 1997-03-21 HIV proteaasi inhibiitorit VX 478 ja vees lahustuva vitamiin E derivaati vitamiin E-TPGSi sisaldavad preparaadid
CA002249336A CA2249336C (fr) 1996-03-22 1997-03-21 Compositions contenant un inhibiteur de la protease du vih tel que le vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
EA199800755A EA001484B1 (ru) 1996-03-22 1997-03-21 Композиции, содержащие ингибитор вич протеазы, а именно as vx 478, и водорастворимое соединение витамина e, а именно витамин e-tpgs
EP97914287A EP0906107B1 (fr) 1996-03-22 1997-03-21 Compositions contenant vx 478 et un compose hydrosoluble de vitamine e tel que la vitamine e-tpgs
UA98094710A UA67723C2 (en) 1996-03-26 1997-03-21 Pharmaceutical formulations for peroral administration and method for its preparation
IL12618597A IL126185A (en) 1996-03-22 1997-03-21 Compositions comprising an hiv protease inhibitor, a water soluble vitamin e compound and a hydrophilic non-aqueous solvent
SK1269-98A SK284244B6 (sk) 1996-03-22 1997-03-21 Farmaceutický prostriedok na liečenie HIV infekcie na orálne podanie
DK97914287T DK0906107T3 (da) 1996-03-22 1997-03-21 Formuleringer indeholdende VX478 og en vandopløselig Vitamin E-forbindelse såsom Vitamin E-TPGS
BR9708238A BR9708238A (pt) 1996-03-22 1997-03-21 Formulação farmacêutica para administração oral e processo para preparar a mesma
IS4840A IS2066B (is) 1996-03-22 1998-08-28 Samsetningar sem samanstanda af VX 478 og vatnsleysanlegu E vítamín efnasambandi á borð við E-TPGS vítamín
NO19984386A NO317639B1 (no) 1996-03-22 1998-09-21 Blandinger omfattende en HIV-protease-inhibitor sa som VX 478 og en vannloselig vitamin E-forbindelse sa som vitamin E-TPG'er
HK99102135A HK1016896A1 (en) 1996-03-22 1999-05-12 Compositions comprising vx 478 and a water soluble vitamin e compound such as vitamin etpgs
UY25926A UY25926A1 (es) 1996-03-22 2000-01-17 Formulaciones farmaceuticas de ester tetrahidro-3-furanilico del acido 3s-(3r*(1r*,2s*))-(3-(((4-aminofenil)sulfonil)(2-metilpropil)-amino)-2-hidroxi-1-fenilmetil)propil carbamico

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1389396P 1996-03-22 1996-03-22
US60/013,893 1996-03-22
GB9606372.2 1996-03-26
GBGB9606372.2A GB9606372D0 (en) 1996-03-26 1996-03-26 Pharmaceutical formulations

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WO1997035587A1 true WO1997035587A1 (fr) 1997-10-02

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JP (1) JP3117726B2 (fr)
AR (1) AR006345A1 (fr)
BG (1) BG64457B1 (fr)
CO (1) CO4790151A1 (fr)
HU (1) HU228026B1 (fr)
ID (1) ID16781A (fr)
IL (1) IL126185A (fr)
MY (1) MY126358A (fr)
OA (1) OA10880A (fr)
PL (1) PL187919B1 (fr)
TW (1) TW455491B (fr)
WO (1) WO1997035587A1 (fr)

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WO1998057648A1 (fr) * 1997-06-16 1998-12-23 Vertex Pharmaceuticals Incorporated Procede d'amelioration de la biodisponibilite des polymorphes cristallins stables d'un compose
WO1999026607A1 (fr) * 1997-11-21 1999-06-03 Fuisz Technologies Ltd. Systemes d'administration de medicaments mettant en application des structures de cristaux liquides
WO1999064001A3 (fr) * 1998-06-05 2000-02-03 Glaxo Group Ltd Methodes et compositions destinees a accroitre la penetration des inhibiteurs de la protease du vih
ES2140329A1 (es) * 1997-12-04 2000-02-16 Univ Granada Utilizacion de acido maslinico como inhibidor de proteasas para el tratamiento de la enfermedad causada por los virus de la inmunodeficiencia adquirida.
WO2002051414A1 (fr) * 2000-12-22 2002-07-04 Takeda Chemical Industries, Ltd. Compositions médicinales s'administrant par voie orale
EP1017366A4 (fr) * 1996-09-01 2006-03-22 Pharmos Corp Coprecipites solides augmentant la biodisponibilite de substances lipophiles
WO2006039268A3 (fr) * 2004-09-30 2006-07-27 Eastman Chem Co Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations
EP1880715A1 (fr) * 2006-07-19 2008-01-23 Abbott GmbH & Co. KG Composition de solubilisation acceptable sur le plan pharmaceutique et forme posologique contenant celle-ci
US7423004B2 (en) 2003-01-31 2008-09-09 Smithkline Beecham Corporation Solid dispersion compositions
KR101107328B1 (ko) 2002-11-29 2012-01-20 얀센 파마슈티카 엔.브이. 염기성/산성 약물 화합물, 계면활성제 및 생리학적으로용인되는 수용성 산/염기를 포함하는 약제학적 조성물
US20120114750A1 (en) * 2008-03-28 2012-05-10 Array Biopharma, Inc Pharmaceutical composition 271
WO2014009926A1 (fr) 2012-07-12 2014-01-16 Laboratori Guidotti S.P.A. Compositions liquides orales pédiatriques contenant du nepadutant

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CA2578356C (fr) * 2004-09-24 2013-05-28 Boehringer Ingelheim Pharmaceuticals, Inc. Une nouvelle classe de matiere de type surfactant

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WO1995031217A1 (fr) * 1994-05-16 1995-11-23 Dumex-Alpharma A/S Compositions de tocopherol destinees a l'apport d'agents biologiquement actifs
WO1996036316A1 (fr) * 1995-05-19 1996-11-21 Abbott Laboratories Formulations auto-emulsifiantes de medicaments lipophiles

Cited By (20)

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Publication number Priority date Publication date Assignee Title
EP1017366A4 (fr) * 1996-09-01 2006-03-22 Pharmos Corp Coprecipites solides augmentant la biodisponibilite de substances lipophiles
WO1998057648A1 (fr) * 1997-06-16 1998-12-23 Vertex Pharmaceuticals Incorporated Procede d'amelioration de la biodisponibilite des polymorphes cristallins stables d'un compose
WO1999026607A1 (fr) * 1997-11-21 1999-06-03 Fuisz Technologies Ltd. Systemes d'administration de medicaments mettant en application des structures de cristaux liquides
ES2140329A1 (es) * 1997-12-04 2000-02-16 Univ Granada Utilizacion de acido maslinico como inhibidor de proteasas para el tratamiento de la enfermedad causada por los virus de la inmunodeficiencia adquirida.
WO1999064001A3 (fr) * 1998-06-05 2000-02-03 Glaxo Group Ltd Methodes et compositions destinees a accroitre la penetration des inhibiteurs de la protease du vih
WO2002051414A1 (fr) * 2000-12-22 2002-07-04 Takeda Chemical Industries, Ltd. Compositions médicinales s'administrant par voie orale
KR101107328B1 (ko) 2002-11-29 2012-01-20 얀센 파마슈티카 엔.브이. 염기성/산성 약물 화합물, 계면활성제 및 생리학적으로용인되는 수용성 산/염기를 포함하는 약제학적 조성물
US9192577B2 (en) 2002-11-29 2015-11-24 Janssen Pharmaceutica Nv Pharmaceutical compositions comprising a basic drug compound, a surfactant, and a physiologically tolerable water soluble acid
US7423004B2 (en) 2003-01-31 2008-09-09 Smithkline Beecham Corporation Solid dispersion compositions
WO2006039268A3 (fr) * 2004-09-30 2006-07-27 Eastman Chem Co Formulations pharmaceutiques renfermant des molecules tpgs de vitamine e solubilisant des medicaments lipophiles sans inhibition importante de l'ecoulement et utilisation de telles formulations
CN103055316B (zh) * 2006-07-19 2016-01-13 阿伯特有限及两合公司 药学上可接受的增溶组合物和包含其的药物剂型
CN101489537B (zh) * 2006-07-19 2013-02-13 阿伯特有限及两合公司 药学上可接受的增溶组合物和包含其的药物剂型
US9078921B2 (en) 2006-07-19 2015-07-14 Abbvie Deutschland Gmbh & Co Kg Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same
WO2008009689A1 (fr) * 2006-07-19 2008-01-24 Abbott Gmbh & Co. Kg Composition solubilisante de qualité pharmaceutique et forme galénique l'incluant
EP1880715A1 (fr) * 2006-07-19 2008-01-23 Abbott GmbH & Co. KG Composition de solubilisation acceptable sur le plan pharmaceutique et forme posologique contenant celle-ci
US9616130B2 (en) 2006-07-19 2017-04-11 Abbvie Deutschland Gmbh & Co Kg Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same
US20120114750A1 (en) * 2008-03-28 2012-05-10 Array Biopharma, Inc Pharmaceutical composition 271
US11813246B2 (en) 2008-03-28 2023-11-14 Astrazeneca Ab Pharmaceutical composition
US12220403B2 (en) 2008-03-28 2025-02-11 Astrazeneca Ab Pharmaceutical composition
WO2014009926A1 (fr) 2012-07-12 2014-01-16 Laboratori Guidotti S.P.A. Compositions liquides orales pédiatriques contenant du nepadutant

Also Published As

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ID16781A (id) 1997-11-13
IL126185A (en) 2003-05-29
JP2000500504A (ja) 2000-01-18
IL126185A0 (en) 1999-05-09
TW455491B (en) 2001-09-21
PL187919B1 (pl) 2004-11-30
HU228026B1 (en) 2012-08-28
PL328916A1 (en) 1999-03-01
JP3117726B2 (ja) 2000-12-18
BG102838A (en) 1999-09-30
AR006345A1 (es) 1999-08-25
HUP9901887A2 (hu) 1999-12-28
CO4790151A1 (es) 1999-05-31
MY126358A (en) 2006-09-29
OA10880A (en) 2001-10-11
BG64457B1 (bg) 2005-03-31
HUP9901887A3 (en) 2000-02-28

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