OA10880A - 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 PDF

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OA10880A
OA10880A OA9800171A OA9800171A OA10880A OA 10880 A OA10880 A OA 10880A OA 9800171 A OA9800171 A OA 9800171A OA 9800171 A OA9800171 A OA 9800171A OA 10880 A OA10880 A OA 10880A
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tpgs
vitamin
compound
water soluble
hiv protease
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OA9800171A
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Arup K Roy
Lioyd Gary Tillman
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Glaxo Group Ltd
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Priority claimed from GBGB9606372.2A external-priority patent/GB9606372D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of OA10880A publication Critical patent/OA10880A/en

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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

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  • Tropical Medicine & Parasitology (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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Abstract

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 141W94), and a tocopherol, and their use in medical therapy are described.

Description

01 0880 -
COMPOSITIONS COMPRIS ING AN HIV PROTEASE INHIBITOR SUCH AS VX 478 AND A WATERSOLUBLE VITAMIN E COMPOUNO SUCH AS VITAMIN E-TPGS
The présent invention relates to novel pharmaceutical formulations containingHIV 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 (altemativelyknown as VX 478 or 141W94), and a tocopherol, and their use in medicaltherapy.
The présent invention is within the field of pharmaceutical science, in particularin the area of drug delivery, specifically the delivery of HIV protease inhibitors.
Inhibitors of HIV protease hâve potent activity against Human ImmunodeficiencyVirus (HIV), the causative agent of Acquired Immune Deficiency Syndrome(AIDS) and related conditions such as AIDS-related Complex (ARC). Examplesof protease-inhibiting compounds include those disclosed in WO94/05639,WO95/24385, WO94/13629, WO92/16501, WO95/16688, WOZUS94/13085,WO/US94/12562, US93/59038, EP541168, WO94/14436, WO95/09843,WO95/32185, WO94/15906, WO94/15608, WO94/04492, W092/08701,WO95/32185, and US Patent No., 5,256,783, in particular (S)-N-((.alpha.S)-((1 R)-2-((3S, 4aS,8aS)-3-(tert-Butylcarbomoyl)octahydro-2-(1 H)-isoquinolyl)-1-hydroxyethyl)phenethyl)-2-quinaldaminosucdnamide monomethanesulfonate(saquinavir), N-(2(R)-Hydroxy-1(S)indanyl)-2(RHphenylmethyl)-4(S)-hydroxy-5-[1-{4-(3-pyridyimethyl)-2(S)-(N-tert-butylcarbamoyl)piperazinyl]jpentaneamide(indinavir), 10-hydroxy-2-methyl-5-(1 -methylethyl)-1 -[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oicacid, 5-thiazofylmethyl ester (ritonavir), (N-(1,1-dimethyl)decahydro-2-{2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide monomethanesulfonate (nelfinavir), and relatedcompounds.
In particular 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-
01 08 8 Q 2 aminobenzenesulfonyl)amino-2-(S)-hydroxy-4-phenylbutane;4-amino-N-(2(R)-hydroxy-4-phenyl-3-(SHtetrahydrofuran-3-(S)-yioxycarbonytamino)butyl)-N-isobutyibenzenesulfonamide (altematively known as VX 478 or 141W94) asshown as the structure of compound of formula (I) below
The compound of formula (I), disclosed in WO94/05639 and incorporated hereinby reference, has been found to be especially effective as an inhibitor of HIV-1and HIV-2. Particulariy preferred is the compound of formula (I).
It may be that an HIV protease inhibitor has a high degree of potency againstHIV but it is, of course, essentia, that when administered to a patient that theHIV protease inhibitor reaches the site of action at an amount and for a durationsufficient for a therapeutic effect to occur, but yet not to reach such levels thatexcessive and unavoidable toxic effects are présent. Therefore in common withother drugs the bioavailability of the HIV protease inhibitor is determined so asto deduce the amount of drug needed to be administered to the patient in orderto satisfy the above criteria. A définition of "bioavailability" can be found in Pharmaceutical Sciences,Remington, 17th Ed., page 1424, quoted below. "Bioavailability is an absolute term that indicates measurement of both thetime (rate) and total amount (extent) of drug that reaches the generalcirculation from an administered dosage form". JM IAmI. 01 0880 3
There are many factors which affect the bioavatlability of a drug. A drug mustfirst go into solution prior to absorption and, therefore, a key factor is thedissolution rate of a drug. Typical of the class of drugs HIV protease inhibitorshâve poor physical characteristics of low solubility and wettability and 5 accordingly their dissolution rate is low. Therefore, simple tablet or capsuleformulations of such drugs will hâve a low bioavailability and need to beadministered in much higher quantities in order to achieve a therapeutic effect.
Current formulations of HIV protease inhibitors for oral administration are in10 powder or tablet form. However, HIV protease inhibitors in these oral formulations are generally poorly soluble and, therefore, poorly bioavailable forthe above reasons. For example, the aqueous solubility of the compound offormula (I) is only 0.095 mg/mL at room température and does not significantlyvary with pH (Figure 1). In addition, the compound of formula (I) is poorly 15 wetted. Therefore, formulating the compound using standard formularytechniques is diffîcult and leads in any event to a formulation with lowbioavailability.
Therefore, improvements in the bioavailability of HIV protease inhibitors is an 20 important goal in this field offering many advantages, such as, lower quantitiesof drug administered to achieve the same therapeutic effect and fewer dosagesrequired at less frequent intervals thereby improving patient compliance.
To avoid a dissolution rate limiting formulation and improve bioavailability we 25 formulated the compound of formula (I) as a solution suitable for oral administration. Wefoundthat 10 mg/mL of the compound of formula (I) inPolyethylene Glycol 400 (PEG400) solution had an oral bioavailability of 25-30%(Table 1 ). However, at higher concentrations of the compound of formula (I) inPEG400 (250 mg compound of formula (l)/gram solution), the bioavailability 30 dropped to half the value achieved with the 10 mg/mL solution and the maximalconcentration (Cmax) achieved was also drastically reduced (Table 1).
Surprisingly, we hâve found that when the compound of formula (I) isadministered as a solution comprising d-Alpha Tocopheryl Polyethylene Glycol
Il « 01 0880 4 1000 Succinate (Vitamin E-TPGS) the bioavailability of the compound offormula (I) is greatly improved.
Vitamin E-TPGS is a water soluble form of vitamin E and has been recognisedas an excipient to pnomote émulsification of lipophilie substances, acting as anon-ionic surfactant, and in improving the bioavailability of certain drugs.
In The Lancet, 1991. 338, 212-214 Sokol R.J. et a/teaches thatcoadministration of Vitamin E-TPGS with cyclosporin improves the bioavailabilityof cyclosporin.
In WO95/31217 (Dumex Ltd) it is taught that tocopherols can be used as asolvents and/or emulsifiers of drugs substantially insoluble in water, in particularfor the préparation of topical formulations. Use of Vitamin E-TPGS is specificallymentioned at pages 7-8 and 12 as an emulsifier for use in formulationscontaining high levels of α-tocopherol as the lipid layer. Examples offormulations for topical administration disclosed containing Vitamin E-TPGS,such as Examples 1 to 5, typically comprises a lipid layer (an α-tocopherol), thedrug and Vitamin E-TPGS, in quantities of less than 25% w/w of the formulation,as an emulsifier. There is no reference to formulation of HIV protease inhibitors.
In WO96/36316 (Abbott Laboratories), which published afterthe priority date butbefore the filing date of this application, it is taught that Vitamin E-TPGS can beused for the enhanced delivery of lipophilie compounds as a self-emulsifyingpreconcentrate formulation comprising a) a lipophilie drug (a cyclosporin isspecifically exemplified), b) vitamin E-TPGS and c) a lipophilie phase. Typicalexamples of formulations disclosed, such as Examples 2 and 4, contain lessthan 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.
We hâve now found that the bioavailability of an HIV protease inhibitor can besignificantly enhanced by formulation as a liquid formulation comprising a watersoluble tocopherol dérivative, in particular Vitamin E-TPGS. 010880 5
We surprisingly found that formulations comprising (a) an HIV protease inhibitorand (b) a water soluble tocopherol dérivative in a ratio of from about 1:0.5 toabout 1:10 w/w hâve advantageous properties in terms of bioavailabiiity. 5 The présent 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 dérivative in a ratio of from about 1:0.5 to about 1:10w/w. 10 We hâve further found that formulations comprising a) an HIV protease inhibitorb) at least 20% w/w of a water soluble tocopherol dérivative such as Vitamin E-TPGS hâve good bioavailabiiity even when the HIV protease inhibitor is présentat high concentrations. 15 We hâve found that for formulations of HIV protease inhibitors and water solubletocopherol dérivatives a lipophilie phase is not needed thus reducing costs andmaking formulation more convenient. The absence of a lipophilie phase and theability to dissolve the HIV protease inhibitor at much higher concentrationswithout adversely affecting bioavailabiiity means that smaller, more convenient, 20 cheaper and easier to manufacture formulations resuit.
The présent invention thus provides, in a further or alternative aspect, apharmaceutical formulation for oral administration comprising (a) an HIVprotease inhibitor and (b) at least 20% of a water soluble tocopherol dérivative in 25 the absence of a lipophilie phase.
In a further alternative aspect, the présent invention provides a pharmaceuticalformulation for oral administration comprising (a) an HIV protease inhibitor and(b) at least 20% of a water soluble tocopherol dérivative wherein the ratio of (a) 30 to (b) is from about 1:0.5 to about 1:10 w/w.
Preferably the water soluble tocopherol dérivative is Vitamin E-TPGS.
Preferably the formulations of the invention comprise from about 10% to about 35 60% w/w water soluble tocopherol dérivative, preferably Vitamin E-TPGS, more . «ι «.· ι11Λ «WHI». 010880 6 preferably about 20% to about 50% such as about 30% to about 50% w/w, forexample, about 30%.
Preferably the HIV protease inhibitor is the compound of formula (I).
The ratio of HIV protease inhibitor to water soluble tocopherol dérivative in theformulations of the invention is preferably from about 1:0.5 to about 1:3, suchas, for example, from about 1:0.67 to about 1:2.6 w/w, more preferably fromabout 1:1.3 to about 1:3.
Water soluble tocopherol dérivatives, in particular Vitamin E-TPGS, exist atroom température as waxy solids. Whereas the HIV protease inhibitorcompound may be administered to a patient in the water soluble tocopheroldérivative alone it is préférable that additional pharmaceutical excipients areadded to improve the physical properties of the formulation, for example by theaddition of a hydrophiiic non-aqueous solvent miscible with the water solubletocopherol dérivative to achieve a flowable liquid more suitable for massformulation as, for example, in a soft gélatine capsule. Furthermore, we hâvefound that the addition of a hydrophiiic non-aqueous solvent miscible with thewater soluble tocopherol dérivative enhances the solubility of the HIV proteaseinhibitor allowing further réduction of the volume of the formulation required todeliver an effective dose. Preferred pharmaceutically acceptable solvents arepolyethylene glycol and propylene glycol. Polyvinyl pyrrolidones can also beused. The addition of polyethylene glycol and propylene glycol to a formulationof an HIV protease inhibitor in Vitamin E-TPGS results in a flowable liquid whichmay suitably be filled into a soft gélatine capsule and représente a preferredfeature of the invention.
When the compound of formula (I) was formulated in a mixture of Vitamin E-TPGS, PEG400 and propylene glycol, the bioavailability of the compound offormula (I) was not affected adversely as compared to formulation in Vitamin E-TPGS alone.
According to a preferred embodiment, the présent invention provides a
pharmaceutical formulation for oral administration comprising (a) an HIV ^VSHÜHÎ 0108807 protease inhibrtor (b) a water soluble tocopherol dérivative and (c) a hydrophilicnon-aqueous solvent miscible with said water soluble tocopherol dérivativewherein the ratio of (a) to (b) is frorn about 1:0.5 to about 1:10 w/w.
Preferably the hydrophilic non-aqueous solvent is selected from potyethyteneglycol. propylene glycol and polyvinyl pyrrolidinone. More preferably thehydrophilic non-aqueous solvent is a mixture of polyethylene glycol. such aspolyethylene glycol 400, and propylene glycol. The amount of hydrophilic non-aqueous solvent in the formulations of the invention may be in the range ofabout 15% to about 95%, such as about 25% to about 60% w/w. in a preferred aspect, the présent invention provides a pharmaceuticalformulation for oral administration consisting essentially of (a) an HIV proteaseinhibitor (b) Vitamin E-TPGS (c) polyethylene glycol and (d) propylene glycol.
In a further preferred aspect, the invention provides a pharmaceutical formulation consisting essentially of (a) 3S-[3R*(1R*, 2S*)]-[3-[[(4- aminophenyl)sulphonyi](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 ofcapsules, more preferably soft gelatin capsules.
Included in the invention are the pharmaceutically acceptable salts, esters, orsalts of such esters of HIV protease-inhibiting compounds, particulariy thecompound of formula (I), or any other compound which, upon administration of asafe and therapeutically effective amount of the compound to a human subject,is capable of providing (directly or indirectly) the antivirally active métabolite orresidue thereof. HIV protease-inhibiting compounds can be prepared as disclosed inWO95/24385, WO94/13629, WO92/16501, WO95/16688, WO94/13085,
C ~ - p010880 8 WO/US94/12562. US93/59038, EP 541168, WO94/14436, WO95/09843,WO95/32185, WO94/15906, WO94/15608, WO94/04492, W092/08701,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 hereinby référencé.
Compounds of Formula (I) may be prepared as disclosed in WO94/05639, whichis incorporated herein by reference.
The water soluble tocopherol dérivatives may be prepared by appropriateestérification procedures. Suitable procedures will be readily apparent to thoseskilled in the art. For example, Vitamin E-TPGS may be prepared by theestérification of polyethylene glycol 1000 to the acid group of crystalline d-alphatocopheryl acid succinate as disclosed in US Patent No. 2,680,649 and5.234,695.
As used herein, the term "solvent" means a solvent or cosolvent which ispharmaceutically or medicinally acceptable and which will dissolve an HIVprotease inhibiting compound to form a solution and is not substantiallydestructive of the capsule Shell.
Polyethylene glycols containing 300 to 1000 polyethylene glycol monomer units(CH2CH2O) can advantageously be used as solvents and polyethylene glycolshaving average molecular weights between 300 to 1000 and containing about300 to 400 ethylene glycol monomer units as above may advantageously beused as solvents.
Other solvents or cosolvents which may also be suitable include, but are notlimited to, propylene glycol, alcohol, glycerin, and sorbitol. Concentrations ofsolvents or co-solvents may suitable be in the range of 0.1% to 10%. In addition0-10% water may be used as a co-solvent.
As used herein, the term lipophilie phase dénotés one or more hydrophobiecomponents such as, for example, fatty acid esters of glycerol, fatty acid estersof propylene glycol and vegetable oil. 010880
Where the formulations of the invention are presented as capsules, the capsuleshell may suitably be made of gelatin and may include plasticizers such asanidrisorb, glycerin or sorbitol, water, preservatives, coloring agent(s), and 5 opacifying agent(s). Référencé may be made to Remington's Practice ofPharmacy, Martin and Cook, Twelfth Edition, Pages 467 underthe headingElastic Capsules to page 469 for a description of gelatin capsules rapidlydissolvable in the gastrointestinal tract and the manufacture of such capsules,ail of which are incorporated by référencé herein. Référencé may also be made 10 to US Patent No. 2,899,361 as well as 2,928,128 for a description of soft gelatincapsules and their manufacture, both of said patents being Incorporated hereinby référencé hereto. In addition référencé may also be had to the book TheTheory and Practice of Industrial Pharmacy" by Lackman, Lieberman and Kanig(1970) pages 359-389 published by Lea and Febiger, Philadelphia, 15 Pennsylvania for a discussion of soft gelatin capsule technology said text pages359-389 being incorporated herein by référencé hereto.
The capsules of this invention may be of any shape, suitably the capsules maybe elongated such as ellipsoidal, oval or cylîndrical with rounded ends. A range 20 of about 10 to 1500 mg of the compound of formula (I) may suitably be used.Preferably the capsules may contain 25mg, 50mg ,150 mg or 200mg of thecompound of formula (I). Particulariy, each capsule contains the compound offormula (I) in solution at a concentration of 10 to 1000 mg/mL with aconcentration of 25 to 500 mg/mL being most preferred. As used herein, 25 concentration means mg of the compound of formula (l)/mL of solution. The softgelatin capsule may be chosen from those available from various manufacturersto hold the volume of the following examples to provide the concentration setforth therein. Preferably, the capsules are Size No. 12 oblong, or size No. 3oval, white opaque soft gelatin capsules manufactured by R P Scherer, North 30 America. A preferred formulation according to the invention comprises an HIV protease-inhibiting compound (preferably a compound of formula (I)), in the amount offrom about 1% to about 50% by weight of the total solution, and Vitamin E- 35 TPGS in the amount of from about 5% to about 100% by weight of the total
AkUt UUuk.idtLik'ü.'aÜAiï» 010880 10 solution, polyethyiene glycol in the amount of from about 15% to about 95% byweight of the total solution and propylene glycol in the amount of from about0.1% to 10% by weight of the total solution. The formulation may optionallycontain water in the amount of from about 0% to 10%.
As used herein the term “therapeutically effective amount” of the compound offormula (I) means one or more capsules of the type disclosed herein, with eachcapsule preferably containing 25mg, 50mg, 150mg or 300mg of the compoundof formula (I). For initial treatment of patients, a dose of about 100 to 3000mg ofthe compound of formula (I) followed by about 100mg to 500Qmg of thecompound of formula (I) may be used. Thereafter maintenance doses of 100 to5000mg of the compound of formula (I) may be administered depending on thepatient. A suitable dosage regimen may be, for example, 1200mg of thecompound of formula (I) twice daily.
The formulations according to the invention may be presented in various formsadapted for direct oral administration including liquid forms, for example, syrups,suspensions, or solutions. The formulations, according to the invention, mayinclude other pharmaceutically acceptable carriers as excipients conventionallyused in such formulations. Thus, for example, syrups may include sugar syrup,sorbitol or hydrogenated glucose syrup or artificial sweeteners such asaspartame, sodium saccharin, acesulfame K, etc. Suspensions may includemethylcellulose, microcrystalline cellulose, carmellose sodium or dispersiblecellulose. Solutions may include liquid glucose, laevulose or xylitol.
The formulations of the présent invention may be made using methods andtechniques that are commonly employed in preparing préparations within thepharmaceutical industry.
The formulations according to the invention may be prepared in conventionalmanner, for example, by appropriate mixing of the ingrédients in one or morevessels, the ingrédients being dissolved or suspended using establishedpharmaceutical techniques. An HIV protease-inhibiting compound may bedissolved in the liquefied emulsifier-solvent mixture which has been heated toapproximately 65°C to facilitate dissolution. After the compound is completely !.. ι .1-.-L...J'i 1. i. jU.il-
01 0880 11 solubilised, propylene glycoi may be added to the resulting solution. The finalsolution, a clear flowable liquid between 28-35°C, may suitably be filled into softgelatin capsules. Such a formulation when dissolved in water forms a clearsolution with an improved bioavailability. ,n the formulations according to the invention, the amount required of thecompound of formula (I) will dépend upon a number of factors including theseverity of the condition to be treated and the âge and condition of the récipientand will ultimately be at the discrétion of the attendant physician. In general,however, a suitable, effective dose may be in the range of 5 to 100 mg/kg bodyweight of récipient per day, advantageously 8 to 70 mg/kg body weight andpreferably 8 to 50mg/kg body weight. The desired dose may preferably bepresented at one, two, three, four or more sub-doses administered in unitdosage forms, for example, containing 25 to 500mg of active ingrédient per unitdosage form.
The formulations, according to the invention, may be used for the treatment orprophylaxis of human retroviral infections including HIV infections, and theconséquent clinical conditions resulting from such infections, for example, AIDS,ARC, progressive generalised lymphadenopathy (PGL) and HIV-seropositiveand AIDS-antibody-positive conditions.
The formulations according to the invention may be employed in medicaltherapy in combination with other therapeutic agents suitable in the treatment ofHIV infections, such as nucleoside reverse transcriptase inhibitors for examplezidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2’,3‘-dideoxy-3’-fluorouridine and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)1,3-oxathiolan-5-yl]cytosÎne; non-nucleoside reverse transcriptase inhibitors forexample nevirapine, TIBO, and α-APA; HIV protease inhibitors for examplesaquinavir, indinavir and ritonavir; other anti-HIV agents for example solubleCD4; immune modulators for example interieukin 11, erythropoetin, tucaresol;and interferons for example a-interferon.
010880 12
The components of such combination therapy may be administeredsimultaneously, in either separate or combined formulations or at different times,e.g. sequentially such that a combined effect is achieved.
Figure 1 shows the solubility of the compound of formula (I) with varying pH.
The following examples are included to illustrate the présent invention but arenot intended to limit the reasonable scope thereof.
Example 1 A liquid formulation was prepared as follows: 1) Composition
Ingrédient
Quantitv (mg/caosule)
Compound of formula (I)Vitamin E-TPGSPolyethylene Glycol 400 NFPropylene Glycol USP 150.0 400.0 200.5 39.5 2) Method of Préparation
Four (4) kilograms (kg) of Vitamin E-TPGS (obtained from Eastman ChemicalCo.) was heated at 50°C until liquefied. To the liquefied Vitamin E-TPGS, 2.005kg of polyethylene glycol 400 (PEG400) (low aldéhyde, <10 ppm, obtained fromUnion Carbide or Dow Chemical Co.) heated to 50°C was added and mixed untila homogenous solution was formed. The résultant solution was heated to 65°C. 1.5 kg of the compound of formula (I) was dissolved in the liquefied solution ofVitamin E-TPGS and PEG400. 0.395 kg of propylene glycol at roomtempérature was added and mixed until a homogenous solution was formed.
The solution was cooied to 28-35°C. The solution was then de-gassed. Themixture was preferably encapsulated at 28-35°C at a fill weight équivalent to 150mg of volatiles-free compound, into Size 12 oblong, white opaque soft gelatincapsules using a capsule filling machine. The capsule shells were dried to a 01 0880* 13 constant fill moisture of 3-6% water and a Shell hardness of 7-10 newtons, andplaced in a surtable container.
Example 2
Pharmacokinetics of the Compound of Formula (I) in Rats and Beagle Dogs
The pharmacokinetics of the compound of formula (I) after intravenous and oraladministration was assessed in Hsd: Sprague Dawley SD rats after doses of 10, 24.1, and 50 mg/kg, dissolved in PEG400. Pharmacokinetics were alsoconducted with D-alpha tocopheryl PEG1000 Succinate (TPGS) and mixtures ofVitamin E-TPGS, PEG400, and propylene glycol in Hsd rats and beagle dogs.
Rat Pharmacokinetics
The compound of formula (I) was administered individually to groups of fourcannulated Hsd rats by intravenous injection at doses of 10 and 50 mg/kg orgavage at doses of 10, 24.1, and 50 mg/kg dissolved in PEG400. Four otheranimais received individual capsules containing the compound of formula (I) insolution 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. Theprincipal pharmacokinetic parameters of the compound of formula (I) aresummarized in Table 1.
Beagle dog pharmacokinetics
The principal pharmacokinetic parameters of the compound of formula (I) inbeagle dogs are summarized in Table 2. 010880 14 » Table 1
Pharmacokinetics of the compound of formula (I) in rats with different- formulations
Formulation % w/w dose/route (mg/kg) Cmax (μΜ). Tmax (hr) AUC (μΜ.ΙΐΓ) F 10 mg/mL (I) in a PEG400 solution 10mg/kg iv PO 42.6±12.2 2.6±1.3 2 min® 0.4±0.2 9.0±1.0 2.6±0.3 29% 10 mg/mL (I) in aPEG400 solution 50mg/kg iv po 107±11 7.9±3.4 2 min8 0.9±0.2 71.5±43 18.218.6 25% 250 mg/gm (I) in aPEG400 solution 24.1 mg/kg Po 0.8±0.3 2.5±2.2 2.5±0.8 11.6%b 21.8% (I) 63.3% Vit E-TPGS 14.9% other buffer ingrédients 11 mg/kg PO 1.4±0.7 2.3±2.3 2.611.2 26.3%b 25% (I) 60.75% Vit E-TPGS 14.25% other buffer ingrédients 21 mg/kg Po 2.7±1.4 2.7±2.0 5.212.5 27.5%b 23.2% (I) 27.2% PEG400 44.8% Vit E-TPGS 4.8% Propylene Glycol 11 mg/kg po 2.8±1.1 1.1±0.6 4.211.6 42.4%b
Each set of values are averages ± standard déviation8 earliest time taken, concentration not extrapolated to originb F value normalised with iv 10 mg/kg data
Cmax: The maximum concentration observed, were calculated from individual10 observed levels. tmax: the time the maximum concentration observed, were calculated from individualobserved levels. AUC: Area under the concentration time curve, were determined for individual animais.F, Bioavailability determined by AUC ρο/AUC iv 15 Ail percentages are based on w/w basis 01 0880 15
Table 2
Pharmacokinetics of the compound of formula (I) in Beagle dogsDifferent formulations with 150mg the compound of formula (I) per capsule
Formulation % w/w Cmax (μΜ) Tmax (hr) AUC (pM.hr) dose (mg/kg) 21.8% (I) 63.3% Vit E-TPGS 14.9% other buffer ingrédients 11.1±1. 8 1.6±0.9 29.3±5.3 15.3 23.2% (I) 27.2% PEG400 44.8% Vit E-TPGS 4.8% Propylene Glycol 13.6±2. 3 1.1±0.6 32.9±7.4 15.3 20.0% (I) 39.0% PEG400 39.0% Vit E-TPGS 2% Propylene Glycol 13.1+4. 4 0.6±0.4 30.5±11.2 15.3
Each set of values are averages ± standard déviation
Cmax: The maximum concentration observed, were calculated from individualobserved levels. tmax: the time the maximum concentration observed, were calculated from10 individual observed levels. AUC: Area under the concentration time curve, were determined for individualanimais.
Ail percentages are based on w/w basis 16 010880
Table 3
Pharmacokinetic para me ter estimâtes (average ± SD; n=3) after oraladministration of the compound of Formula (I) (300 mg) to dogs.
Formulation Cmax (gg/mL)) Tmax (h) (h) AUC (0 to 24 h) (h x gg/mL) Dry Fiil 0 0 0 0 PVP suspension3 0.03 ± 0.01e 3.0 ±0 1.2 ±0.1 0.12 ± 0.04e PEG400 3.85 ± 1.25 1.1 ±0.9 4.2 ± 1.7 12.2 ±1.46 20% Vit E-TPGS 5.41 ± 0.69 1.7 ±0.6 3.6 ±0.8 22.1 ±4.52 25% Vit E-TPGS 5.03 ± 0.44 1.7 ±0.6 2.0 ± 0.8 20.6 ± 4.85 30% Vît E-TPGS 8.24 ±0.12 1.3 ±0.6 2.0 ±0.7 23.5 ± 4.97 40% Vit E-TPGS 6.92 ± 0.94 1.7 ±0.6 1.9 ±0.6 24.4 ± 4.55 50% Vit E-TPGS 7.63 ± 1.46 1.7 ±0.6 2.5 ±1.3 26.8 ± 8.27 (CTM) a (n=1) b Normalized to 300mg dose

Claims (8)

  1. CLAIMS: . Lr.l.JK^ltkAVi ; A' < 010880
    1. A pharmaceutical formulation for oral administration comprising (a) an HIV5 protease inhibitor (b) a water soluble tocopherol dérivatives and (c) a hydrophilicnon-aqueous solvent miscible with said water soluble tocopherol dérivative wherein the ratio of (a) to (b) is from about 1:0.5 to about 1:10 w/w.
  2. 2. A pharmaceutical formulation as claimed in claim 1 comprising at leasi10 20% of a water soluble tocopherol dérivative.
  3. 3. A pharmaceutical formulation as claimed in claim 1 or 2 wherein the ratioof (a) to (b) is from about 1:0.5 to about 1:1.3 w/w. 15 4. A pharmaceutical formulation as claimed in any preceding claim wherein the water soluble tocopherol dérivative is Vitamin E-TPGS.
  4. 5. A pharmaceutical formulation as claimed in any preceding claim whereinthe hydrophilic non aqueous solvent is a polyethylene glycol, propylene glycol or 20 polyvinyl pyrrolidone.
  5. 6. A pharmaceutical formulation for oral administration consisting essentiallyof (a) an HIV protease inhibitor (b) Vitamin E-TPGS (c) polyethylene glycoi and (d) propylene glycol. 25
  6. 7. A pharmaceutical formulation as claimed in any preceding claim wherein the HIV protease inhibitor is 3S-[3R*(1R*, 2S‘)]-[3-[[(4-aminophenyl)sulphonyl]-(2-methylpropyl)amino]-2-hydroxy-1-phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester. 30
  7. 8. A formulation as claimed in any preceding claim présent in. the form of acapsule.
  8. 9. Λ method of preparing a formulation as claimed in any preceding claim35 which method comprises dissolving an HIV protease inhibitor in a mixture of a water soluble tocopherol dérivatives and a hydrophilic non-aqueous solvent.
OA9800171A 1996-03-22 1998-09-18 Compositions comprising an hiv protease inhibitor such as vx 478 and a water soluble vitamin e compound such as vitamin e-tpgs OA10880A (en)

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JP2001523221A (en) * 1996-09-01 2001-11-20 ファーモス コーポレイション Solid co-precipitates for enhanced bioavailability of lipophilic substances
AU8145198A (en) * 1997-06-16 1999-01-04 Vertex Pharmaceuticals Incorporated Methods of increasing the bioavailability of stable crystal polymorphs of a compound
US5891845A (en) * 1997-11-21 1999-04-06 Fuisz Technologies Ltd. Drug delivery systems utilizing liquid crystal structures
ES2140329B1 (en) * 1997-12-04 2000-10-16 Univ Granada USE OF MASLINIC ACID AS A PROTEASE INHIBITOR FOR THE TREATMENT OF DISEASE CAUSED BY THE VIRUSES OF ACQUIRED IMMUNODEFICIENCY.
GB9812189D0 (en) * 1998-06-05 1998-08-05 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
AU2002350719A1 (en) * 2002-11-29 2004-06-23 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
JP2006518380A (en) 2003-01-31 2006-08-10 スミスクライン・ビーチャム・コーポレイション Solid dispersion composition
JP4977611B2 (en) * 2004-09-24 2012-07-18 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド A new class of surfactant-like substances
JP2008514714A (en) * 2004-09-30 2008-05-08 イーストマン ケミカル カンパニー Pharmaceutical formulations containing vitamin ETPGS molecules solubilizing lipophilic drugs that do not exhibit significant spill inhibition and the use of such pharmaceutical formulations
EP1880715A1 (en) * 2006-07-19 2008-01-23 Abbott GmbH & Co. KG Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same
SA109300195B1 (en) 2008-03-28 2013-04-20 Astrazeneca Ab A Novel Anti-Cancer Pharmaceutical Composition
ITRM20120331A1 (en) 2012-07-12 2014-01-13 Guidotti & C Spa Labor LIQUID ORAL PEDIATRIC COMPOSITIONS CONTAINING NEPADUTANT.

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WO1992016501A1 (en) * 1991-03-20 1992-10-01 Vertex Pharmaceuticals Incorporated Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease
IL103613A (en) * 1991-11-08 1999-05-09 Merck & Co Inc Hiv protease inhibitors process and intermediats for their preparation and pharmaceutical compositions containing them
IS2334B (en) * 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl protease inhibitor of a new class of sulfonamides
WO1994013629A1 (en) * 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
US5484926A (en) * 1993-10-07 1996-01-16 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
ATE230402T1 (en) * 1992-12-29 2003-01-15 Abbott Lab RETROVIRAL PROTEASE INHIBITORS
WO1994015608A1 (en) * 1993-01-15 1994-07-21 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
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ATE215952T1 (en) * 1993-12-15 2002-04-15 Merck & Co Inc HIV PROTEASE INHIBITORS
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CO4790151A1 (en) 1999-05-31
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