WO1997035587A1 - Compositions comprising an hiv protease inhibitor such as vx 478 and a water soluble vitamin e compound such as vitamin e-tpgs - Google Patents
Compositions comprising an hiv protease inhibitor such as vx 478 and a water soluble vitamin e compound such as vitamin e-tpgs Download PDFInfo
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- 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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- hiv protease
- water soluble
- tpgs
- compound
- vitamin
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Classifications
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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
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- 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.
Abstract
Description
Claims
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EE9800323A EE04093B1 (en) | 1996-03-22 | 1997-03-21 | Preparations containing the HIV protease inhibitor VX 478 and the water-soluble vitamin E derivative vitamin E-TPGS |
UA98094710A UA67723C2 (en) | 1996-03-26 | 1997-03-21 | Pharmaceutical formulations for peroral administration and method for its preparation |
SK1269-98A SK284244B6 (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 |
CA002249336A CA2249336C (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 |
HU9901887A HU228026B1 (en) | 1996-03-22 | 1997-03-21 | Compositions comprising an hiv protease inhibitor and a water soluble vitamin e compound |
DK97914287T DK0906107T3 (en) | 1996-03-22 | 1997-03-21 | Formulations containing VX478 and a water-soluble Vitamin E compound such as Vitamin E-TPGS |
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 |
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 |
EP97914287A EP0906107B1 (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 |
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 |
DE69718315T DE69718315T2 (en) | 1996-03-22 | 1997-03-21 | PREPARATION, CONTAINING VX 478 AND A WATER-SOLUBLE VITAMIN E COMPOUND LIKE VITAMIN E-TPGS |
RO98-01407A RO119923B1 (en) | 1996-03-22 | 1997-03-21 | Pharmaceutical composition for oral administration |
BR9708238A BR9708238A (en) | 1996-03-22 | 1997-03-21 | Pharmaceutical formulation for oral administration and process for preparing the same |
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. |
PL32891697A PL187919B1 (en) | 1996-03-22 | 1997-03-21 | Compositions containing inhibitors of hiv protease, such as vx 478 and water-soluble vitamin e compound such as vitamin e-tpgs |
JP09534017A JP3117726B2 (en) | 1996-03-22 | 1997-03-21 | Compositions comprising an HIV protease inhibitor such as VX478 and a water-soluble vitamin E such as vitamin E-TPGS |
AT97914287T ATE230602T1 (en) | 1996-03-22 | 1997-03-21 | PREPARATION CONTAINING VX 478 AND A WATER-SOLUBLE VITAMIN E COMPOUND SUCH AS VITAMIN E-TPGS |
EA199800755A EA001484B1 (en) | 1996-03-22 | 1997-03-21 | Compositions comprising an hiv protease inhibitor such as vx 478 and a water soluable vitamin e compound such as vitamin e-tpgs |
IS4840A IS2066B (en) | 1996-03-22 | 1998-08-28 | Compositions comprising VX 478 and a water-soluble vitamin E compound such as vitamin E-TPGS |
NO19984386A NO317639B1 (en) | 1996-03-22 | 1998-09-21 | Compositions comprising an HIV protease inhibitor such as VX 478 and a water-soluble vitamin E compound such as vitamin E TPGs |
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 (en) | 1996-03-22 | 2000-01-17 | PHARMACEUTICAL FORMULATIONS OF 3S- (3R * (1R *, 2S *)) - (3 - (((4-AMINOFENIL) SULFONIL) (2-METHYLPROPYL) -AMINO) -2-HYDROXY- ESTER TETRAHIDRO-3-FURANILICO 1-PHENYL METHYL) PROPIL CARBAMIC |
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 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997035587A1 true WO1997035587A1 (en) | 1997-10-02 |
Family
ID=26308992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/001438 WO1997035587A1 (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 |
Country Status (12)
Country | Link |
---|---|
JP (1) | JP3117726B2 (en) |
AR (1) | AR006345A1 (en) |
BG (1) | BG64457B1 (en) |
CO (1) | CO4790151A1 (en) |
HU (1) | HU228026B1 (en) |
ID (1) | ID16781A (en) |
IL (1) | IL126185A (en) |
MY (1) | MY126358A (en) |
OA (1) | OA10880A (en) |
PL (1) | PL187919B1 (en) |
TW (1) | TW455491B (en) |
WO (1) | WO1997035587A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998057648A1 (en) * | 1997-06-16 | 1998-12-23 | Vertex Pharmaceuticals Incorporated | Methods of increasing the bioavailability of stable crystal polymorphs of a compound |
WO1999026607A1 (en) * | 1997-11-21 | 1999-06-03 | Fuisz Technologies Ltd. | Drug delivery systems utilizing crystal structures |
WO1999064001A2 (en) * | 1998-06-05 | 1999-12-16 | Glaxo Group Limited | Methods and compositions for increasing penetration of hiv protease inhibitors |
ES2140329A1 (en) * | 1997-12-04 | 2000-02-16 | Univ Granada | Use of maslinic acid as a protease inhibitor for the treatment of the disease caused by acquired immunodeficiency viruses. |
EP1017366A1 (en) * | 1996-09-01 | 2000-07-12 | Pharmos Corporation | Solid coprecipitates for enhanced bioavailability of lipophilic substances |
WO2002051414A1 (en) * | 2000-12-22 | 2002-07-04 | Takeda Chemical Industries, Ltd. | Medicinal compositions for oral use |
WO2006039268A2 (en) * | 2004-09-30 | 2006-04-13 | Eastman Chemical Company | Pharmaceutical formulations containing vitamin e tpgs molecules that solubilize lipophilic drugs without significant efflux inhibition, and use of such formulations |
EP1880715A1 (en) * | 2006-07-19 | 2008-01-23 | Abbott GmbH & Co. KG | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
US7423004B2 (en) | 2003-01-31 | 2008-09-09 | Smithkline Beecham Corporation | Solid dispersion compositions |
KR101107328B1 (en) | 2002-11-29 | 2012-01-20 | 얀센 파마슈티카 엔.브이. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiolosically tolerable water-soluble acid respectively base |
US20120114750A1 (en) * | 2008-03-28 | 2012-05-10 | Array Biopharma, Inc | Pharmaceutical composition 271 |
WO2014009926A1 (en) | 2012-07-12 | 2014-01-16 | Laboratori Guidotti S.P.A. | Pediatric oral liquid compositions containing nepadutant |
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CA2578356C (en) * | 2004-09-24 | 2013-05-28 | Boehringer Ingelheim Pharmaceuticals, Inc. | A new class of surfactant-like materials |
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- 1997-03-21 ID IDP970927A patent/ID16781A/en unknown
- 1997-03-21 HU HU9901887A patent/HU228026B1/en unknown
- 1997-03-21 CO CO97015457A patent/CO4790151A1/en unknown
- 1997-03-21 AR ARP970101146A patent/AR006345A1/en active IP Right Grant
- 1997-03-21 TW TW086103607A patent/TW455491B/en not_active IP Right Cessation
- 1997-03-21 WO PCT/EP1997/001438 patent/WO1997035587A1/en active IP Right Grant
- 1997-03-21 JP JP09534017A patent/JP3117726B2/en not_active Expired - Lifetime
- 1997-03-21 PL PL32891697A patent/PL187919B1/en unknown
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WO1995031217A1 (en) * | 1994-05-16 | 1995-11-23 | Dumex-Alpharma A/S | Tocopherol compositions for delivery of biologically active agents |
WO1996036316A1 (en) * | 1995-05-19 | 1996-11-21 | Abbott Laboratories | Self-emulsifying formulations of lipophilic drugs |
Cited By (22)
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EP1017366A4 (en) * | 1996-09-01 | 2006-03-22 | Pharmos Corp | Solid coprecipitates for enhanced bioavailability of lipophilic substances |
EP1017366A1 (en) * | 1996-09-01 | 2000-07-12 | Pharmos Corporation | Solid coprecipitates for enhanced bioavailability of lipophilic substances |
WO1998057648A1 (en) * | 1997-06-16 | 1998-12-23 | Vertex Pharmaceuticals Incorporated | Methods of increasing the bioavailability of stable crystal polymorphs of a compound |
WO1999026607A1 (en) * | 1997-11-21 | 1999-06-03 | Fuisz Technologies Ltd. | Drug delivery systems utilizing crystal structures |
ES2140329A1 (en) * | 1997-12-04 | 2000-02-16 | Univ Granada | Use of maslinic acid as a protease inhibitor for the treatment of the disease caused by acquired immunodeficiency viruses. |
WO1999064001A2 (en) * | 1998-06-05 | 1999-12-16 | Glaxo Group Limited | Methods and compositions for increasing penetration of hiv protease inhibitors |
WO1999064001A3 (en) * | 1998-06-05 | 2000-02-03 | Glaxo Group Ltd | Methods and compositions for increasing penetration of hiv protease inhibitors |
WO2002051414A1 (en) * | 2000-12-22 | 2002-07-04 | Takeda Chemical Industries, Ltd. | Medicinal compositions for oral use |
KR101107328B1 (en) | 2002-11-29 | 2012-01-20 | 얀센 파마슈티카 엔.브이. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiolosically tolerable water-soluble acid respectively base |
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 |
WO2006039268A2 (en) * | 2004-09-30 | 2006-04-13 | Eastman Chemical Company | Pharmaceutical formulations containing vitamin e tpgs molecules that solubilize lipophilic drugs without significant efflux inhibition, and use of such formulations |
WO2006039268A3 (en) * | 2004-09-30 | 2006-07-27 | Eastman Chem Co | Pharmaceutical formulations containing vitamin e tpgs molecules that solubilize lipophilic drugs without significant efflux inhibition, and use of such formulations |
EP1880715A1 (en) * | 2006-07-19 | 2008-01-23 | Abbott GmbH & Co. KG | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
CN101489537B (en) * | 2006-07-19 | 2013-02-13 | 阿伯特有限及两合公司 | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
US9078921B2 (en) | 2006-07-19 | 2015-07-14 | Abbvie Deutschland Gmbh & Co Kg | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
WO2008009689A1 (en) * | 2006-07-19 | 2008-01-24 | Abbott Gmbh & Co. Kg | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
CN103055316B (en) * | 2006-07-19 | 2016-01-13 | 阿伯特有限及两合公司 | Pharmaceutically acceptable solubilizing composition and the pharmaceutical dosage form comprising it |
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 |
WO2014009926A1 (en) | 2012-07-12 | 2014-01-16 | Laboratori Guidotti S.P.A. | Pediatric oral liquid compositions containing nepadutant |
Also Published As
Publication number | Publication date |
---|---|
CO4790151A1 (en) | 1999-05-31 |
HUP9901887A2 (en) | 1999-12-28 |
HUP9901887A3 (en) | 2000-02-28 |
ID16781A (en) | 1997-11-13 |
HU228026B1 (en) | 2012-08-28 |
OA10880A (en) | 2001-10-11 |
AR006345A1 (en) | 1999-08-25 |
TW455491B (en) | 2001-09-21 |
PL328916A1 (en) | 1999-03-01 |
IL126185A (en) | 2003-05-29 |
IL126185A0 (en) | 1999-05-09 |
JP3117726B2 (en) | 2000-12-18 |
JP2000500504A (en) | 2000-01-18 |
BG102838A (en) | 1999-09-30 |
BG64457B1 (en) | 2005-03-31 |
MY126358A (en) | 2006-09-29 |
PL187919B1 (en) | 2004-11-30 |
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