WO2011013110A1 - Formes posologiques unitaires d'inhibiteurs de protéase du vih - Google Patents

Formes posologiques unitaires d'inhibiteurs de protéase du vih Download PDF

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WO2011013110A1
WO2011013110A1 PCT/IB2010/053506 IB2010053506W WO2011013110A1 WO 2011013110 A1 WO2011013110 A1 WO 2011013110A1 IB 2010053506 W IB2010053506 W IB 2010053506W WO 2011013110 A1 WO2011013110 A1 WO 2011013110A1
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pharmaceutically acceptable
unit dosage
dosage form
hiv protease
solid dispersion
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PCT/IB2010/053506
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English (en)
Inventor
Ravindra Tiwari
Janakiraman Kailya
Ravindra Agarwal
Rajeev Singh Raghuvanshi
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Ranbaxy Laboratories Limited
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Publication of WO2011013110A1 publication Critical patent/WO2011013110A1/fr

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to a unit dosage form that includes a binary solid dispersion composition of at least one HIV protease inhibitor wherein the solid dispersion is substantially free of surfactant, also provided are processes for the preparation of the binary solid dispersion composition.
  • HIV Human immuno-deficiency virus
  • retroviruses which carry genetic information in the form of RNA.
  • RNA Ribonucleic acid
  • reverse transcriptase a virally encoded enzyme
  • the viral DNA enters the host cell nucleus, where it is integrated into the genetic material of the cell by a second virally encoded enzyme called integrase. Activation of the host cell results in the transcription of the viral DNA to messenger RNA, which is then translated onto viral proteins.
  • HIV protease a 99-amino acid homodimer
  • HIV protease a 99-amino acid homodimer
  • HIV protease inhibitors are a class of antiretro viral agents that competitively compete for this HIV proteinase or protease enzyme. These are peptide like molecules that mimic the gag-pol protein, binding onto HIV proteases to prevent the accumulation of structural proteins required for new virion formation.
  • the HIV protease inhibitors have contributed greatly to the reductions in HIV-associated morbidity and mortality over the last decade and remain a cornerstone of highly- active antiretroviral therapy (HAART).
  • Ritonavir is one of the prominent members of this class of compounds, which is commercialized as Norvir ® oral solution and soft gelatin capsules by Abbott Laboratories, USA.
  • U.S. Patent Nos. 5,542,206 and 5,648,497 disclose ritonavir and describes its use as an inhibitor of the HIV protease enzyme. Additionally, ritonavir is used extensively as a pharmacokinetic enhancer when co-administered with other protease inhibitors.
  • 6,037,157 and 6,703,403 disclose the use of ritonavir in combination with an HIV protease inhibitor, which is metabolized by cytochrome P450 monooxygenase, such that the amount of ritonavir is sufficient to improve the pharmacokinetics of the HIV protease inhibitor in a patient, relative to the pharmacokinetics of the HIV protease inhibitor when administered alone.
  • Ritonavir is dosed as a pharmacokinetic enhancer with amprenavir, atazanavir, fosamprenavir, lopinavir, saquinavir, tipranavir, darunavir, and the like.
  • Ritonavir is also available as a co-formulated composition with lopinavir, another potent HIV protease inhibitor, under the proprietary names Kaletra ® /Aluvia ® as soft gel capsules and tablets from Abbott Laboratories, USA. Lopinavir is described specifically in U.S. Patent No. 5,914,332.
  • HIV protease inhibitors exhibit low oral bioavailability.
  • Formulating the protease inhibitors in liquid dosage forms is not always a preferable solution to improve upon the problem of bioavailability, namely due to unpleasant taste, stability problems, handling and storage hazards, patient incompliance, etc.
  • a solid dispersion composition of a poorly soluble active ingredient, can be defined as an even dispersion of the active ingredient in an inert carrier in solid state.
  • the active ingredient is dispersed in the carrier by coprecipitation from a suitable solution containing both the active ingredient and carrier, by melting both components together or by some other process involving a phase change.
  • a surfactant in such solid dispersion compositions to form a ternary system is also well documented. Such systems have higher dissolution rates than binary dispersion systems (systems with two components), Pharmaceutical Solid Dispersion Technology by
  • composition comprising at least one HIV protease inhibitor and at least one
  • a stable bioavailable unit dosage form comprising a binary solid dispersion of at least one HIV protease inhibitor is provided, wherein the solid dispersion is substantially free of surfactant.
  • the present invention provides for a unit dosage form, which includes (a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and pharmaceutically acceptable carrier, and (b) a pharmaceutically acceptable surfactant and one or more pharmaceutically acceptable excipients.
  • Embodiments of the present invention may include one or more of the following features.
  • the solid dispersion is substantially free of surfactant.
  • a suitable pharmaceutically acceptable carrier is a hydrophilic polymer, and in particular is copovidone.
  • the solid dispersion may include two HIV protease inhibitors; wherein the two HIV protease inhibitors are present in a ratio of about 1:15 to about 15:1 by weight.
  • the HIV protease inhibitor includes ritonavir alone or in combination with one additional HIV protease inhibitor selected from lopinavir, atazanavir, amprenavir, fosamprenavir, saquinavir, tipranavir and darunavir.
  • the present invention provides for a process of preparation of a unit dosage form.
  • the process includes the following steps:
  • step (a) blending at least one HIV protease inhibitor with a pharmaceutically acceptable carrier and one or more pharmaceutically acceptable excipients in a suitable mixer; b) transferring the blend of step (a) to a suitable melt-extruder and melting at an appropriate temperature to form a molten extrudate mass;
  • step (b) cooling the molten extrudate mass of step (b) and sizing to obtain a solid
  • step (d) further blending the blend of step (d) with the solid dispersion of step (c) to obtain the final blend
  • step (e) processing the final blend of step (e) into a unit dosage form using appropriate tooling
  • the present invention provides for a process of preparation of a unit dosage form.
  • the process includes the following steps:
  • step (b) transferring the blend of step (a) to a suitable melt-extruder and melting at an appropriate temperature to form a molten extrudate mass;
  • step (b) cooling the molten extrudate mass of step (b), and sizing to obtain a solid
  • step (c) blending the dispersion of step (c) with one or more pharmaceutically
  • step (d) granulating the blend of step (d) using a solution/dispersion of
  • step (e) drying and blending the granules of step (e) with one or more pharmaceutically acceptable excipient(s) to obtain the final blend;
  • unit dosage form encompasses all standard
  • pharmaceutical unit dosage forms may be in the form of coated or uncoated tablets, multilayer tablets, hard gelatin capsules, soft gelatin capsules, pills, and the like.
  • the unit dosage form as described herein comprises of a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier.
  • solid dispersion refers to a group of solid products consisting generally of a pharmaceutically acceptable carrier matrix and at least one HIV protease inhibitor drug homogeneously dispersed therein.
  • the matrix may be either crystalline or amorphous.
  • the drug may be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles.
  • the solid dispersion composition is "substantially free of surfactant".
  • the term “substantially free of surfactant” defines that no surfactant is present in the herein described solid dispersion, or if any is present, it is not in an amount so as to provide an impact on the basic properties of the dispersion. It also refers that if any surfactant is present, it is in a non-intimate admixture with the HIV protease inhibitor drug(s).
  • the "HIV protease inhibitor”, as described herein, includes an effective amount of the compound, pharmaceutically acceptable salts, solvates, enantiomers, diastereomers or polymorphs thereof.
  • the suitable "HIV protease inhibitor”, for use herein, includes without limitation, ritonavir; lopinavir; indinavir; saquinavir; amprenavir; fosamprenavir; mozenavir; nelfinavir; atazanavir; tipranavir; palinavir; darunavir; Ro033-4649; DMP- 323; 5(S)-boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenyl methyl hexanoyl-(L)-V-al-(L)- Phe-morpholin-4-ylamide; [l-naphthoxyacetyl-beta-methylthio-ala-(2S,3S)3-amino
  • the term "effective amount" in the present invention refers to the HIV protease inhibitor in amounts suitable to elicit a particular biological, medicinal or clinical response being sought by the person skilled in the art.
  • the effective amount further refers to a
  • therapeutically effective amount which results in the alleviation of the symptoms of the disease or condition being treated by the drug.
  • the effective amount also refers to a "prophylactic ally effective amount” which results in prophylaxis of the symptoms of the disease or condition being prevented by the drug.
  • the effective amount also refers to an amount that would provide enhanced therapeutic activity of another drug that is coadministered with it, in a way that if the later drug was administered alone, would not have achieved the desired response, (e.g., unsatisfactory pharmacokinetic values for the drug and/or an unsatisfactory drug circulation level resulting in little or no efficacy).
  • the solid dispersion may comprise of more than one HIV protease inhibitor, including ritonavir plus one or more of lopinavir, atazanavir, amprenavir, fosamprenavir, saquinavir, tipranavir, darunavir.
  • the amount of HIV protease inhibitor may be in an amount ranging from lmg to 1500mg.
  • two HIV protease inhibitors may be present in a ratio of about 1:15 to about 15:1 by weight, particularly in a ratio of about 1:10 to about 10:1 by weight, more particularly in a ratio of about 1:4 to about 4:1 by weight.
  • the "pharmaceutically acceptable carrier”, as described herein, refers to both polymeric and non-polymeric carriers; hydrophilic and hydrophobic carriers; that are capable of dissolving and/or dispersing one or more of the HIV -protease inhibitor(s) and includes homopolymers and copolymers of N-vinyl lactams, e.g., N-vinyl-2-pyrrolidone, crosslinked N-vinyl-2-pyrrolidone, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (copovidone); cellulose esters and cellulose ethers, e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; cellulose phthalates or succinates;
  • N-vinyl lactams e.g., N-vinyl-2-pyrrolidone, crosslinked N-vinyl-2-pyrrolidone, copolymer of N-
  • copolymer of N-vinyl-2-pyrrolidone and vinyl acetate such as those which are available as Plasdone ® or Kollidon ® from ISP and BASF respectively may be used as the pharmaceutically acceptable carrier.
  • the amount of pharmaceutically acceptable carrier may vary from about 1% to about 99% by weight of the unit dosage form, more particularly from about 50% to about 85% by weight of the unit dosage form.
  • the solid dispersion composition may include one or more of pharmaceutically acceptable excipients, for example, lubricants and/or glidants which includes colloidal silica, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oils, wax, and the combinations thereof.
  • pharmaceutically acceptable excipients for example, lubricants and/or glidants which includes colloidal silica, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oils, wax, and the combinations thereof.
  • the unit dosage form as described herein, further comprises of pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients.
  • pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients.
  • pharmaceutically acceptable surfactant includes polyoxyethylene alkyl ethers, e.g., polyoxyethylene lauryl ether, polyoxyethylene cetyl ether,
  • polyoxyethylene stearyl ethers polyoxyethylene alkylaryl ethers, e.g., polyoxyethylene nonylphenyl ethers, polyoxyethylene octylphenyl ethers; polyethylene glycol fatty acid esters, e.g., PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g., propylene glycol monolaurate; sucrose fatty acid esters, e.g., sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; or sorbitan fatty acid mono esters such as sorbitan monolaurate (Span 20), sorbitan monooleate, sorbitan
  • Span 40 monopalmitate
  • sorbitan stearate polyoxyethylene castor oil derivates, e. g., polyoxyethyleneglycerol triricinoleate or (Cremophor ® EL; BASF Corp.) or
  • polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor ® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor ® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene
  • polypropyleneglycol such as Poloxamer ® 124, Poloxamer ® 188, Poloxamer ® 237, Poloxamer ® 388, Poloxamer ® 407 (BASF Wyandotte Corp.); Polyglycolized glycerides for example lauroyl macrogolglycerides (Gelucire ® 44/14), stearoyl macrogolglycerides (Gelucire ® 50/13); Labrasol ® , Transcutol ® (Gattefosse Canada Inc.); Vitamin E/TPGS: Tocopheryl propylene glycol 1000 succinate, sold by Eastman; polyethylene glycol 15 hydroxystearate (Solutol ® HS 15 sold by BASF); or a mono fatty acid ester of
  • polyoxyethylene (20) sorbitan e. g., polyoxyethylene (20) sorbitan monooleate (T ween ® 80), polyoxyethylene (20) sorbitan monostearate (Tween ® ), polyoxyethylene (20) sorbitan monopalmitate (Tween ® 40), polyoxyethylene (20) sorbitan monolaurate (Tween ® 20), or mixtures of one or more thereof.
  • the pharmaceutically acceptable surfactant is sorbitan monolaurate.
  • the amount of pharmaceutically acceptable surfactant may vary from about 1% to about 10% by weight of the unit dosage form.
  • One or more of other pharmaceutically acceptable excipients which includes fillers, disintegrants, glidants, lubricants, and combinations thereof, may be used in the unit dosage form as described herein.
  • Fillers may be selected from saccharides such as lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives such as powdered cellulose, microcrystalline cellulose; dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin, starch and starch derivatives such as pregelatinized starch, partially pregelatinized starch; cellulose ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose,
  • hydroxypropyl methylcellulose hydroxypropyl methylcellulose
  • carboxy vinyl polymers such as carbomers
  • acrylates such as Eudragits
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • xanthan gum guar gum and other such materials routinely used in the art of solid dosage form manufacturing.
  • Disintegrants may be selected from croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone, corn starch, potato starch, pregelatinized starch, low- substituted hydroxypropylcellulose, alginates, carboxymethyl starches, methacrylic acid divinylbenzene copolymer salts, and microcrystalline cellulose.
  • Lubricants and/or glidants that may be used include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil, talc, colloidal silicon dioxide, corn starch, and the like.
  • One or more of the solvent may be used to dissolve and/or disperse the
  • Such solvents or the solutions/dispersions formed may further be used as granulating solvents.
  • solvents include one or more of alcohols, e.g., isopropyl alcohol; aliphatic hydrocarbons, e.g., acetone and esters.
  • a unit dosage form includes:
  • a unit dosage form includes:
  • the ritonavir and lopinavir may be present in a ratio of 1:4 by weight.
  • a unit dosage form includes:
  • Atazanavir a pharmaceutically acceptable carrier, a glidant and a lubricant
  • the ritonavir and atazanavir is present in a ratio of 1:3 by weight.
  • a unit dosage form includes:
  • amprenavir pharmaceutically acceptable carrier, a glidant and lubricant;
  • the ritonavir and amprenavir is present in a ratio of 1:6 by weight.
  • a unit dosage form includes: (a) a solid dispersion composition which consists essentially of ritonavir, fosamprenavir, a pharmaceutically acceptable carrier, glidant and lubricant; and
  • the ritonavir and fosamprenavir is present in a ratio of 1:7 by weight.
  • a unit dosage form includes:
  • saquinavir pharmaceutically acceptable carrier, glidant and lubricant; and (b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
  • the ritonavir and saquinavir is present in a ratio of 1:10 by weight.
  • a unit dosage form includes:
  • tipranavir pharmaceutically acceptable carrier, glidant and lubricant
  • the ritonavir and tipranavir is present in a ratio of 2:5 by weight.
  • a unit dosage form includes:
  • darunavir pharmaceutically acceptable carrier, glidant and lubricant
  • the ritonavir and darunavir is present in a ratio of 1:6 by weight.
  • the solid dispersion is substantially free of surfactant.
  • the pharmaceutically acceptable carrier is a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (copovidone).
  • the unit dosage form may be prepared by employing conventional techniques known in the art, including dry granulation, aqueous and non-aqueous granulation, fluidized bed granulation, direct compression and roller compactation, melt granulation, melt extrusion, pelletization, solvent evaporation, and the combinations thereof.
  • the unit dosage form may be prepared by the following steps:
  • step (1) 2. transferring the blend of step (1) to a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
  • step (3) cooling the molten extrudate mass of step (2) and sizing to obtain a solid
  • step (4) further blending the blend of step (4) with the solid dispersion of step (3) to obtain the final blend
  • step (5) processing the final blend of step (5) into a unit dosage form using appropriate tooling.
  • the unit dosage form is prepared by the following steps: 1. blending effective amounts of ritonavir and another HIV protease inhibitor with a pharmaceutically acceptable carrier, glidant(s) and lubricant(s) in a suitable mixer;
  • step (1) 2. transferring the blend of step (1) to a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
  • step (3) cooling the molten extrudate mass of step (2) and sizing to obtain a solid
  • step (4) blending the pharmaceutically acceptable surfactant with filler, disintegrant, glidant and lubricant in a suitable blender; 5. further blending the blend of step (4) with the solid dispersion of step (3) to obtain the final blend; and
  • step (5) processing the final blend of step (5) into a unit dosage form using appropriate tooling.
  • the unit dosage form may also be prepared by the following steps:
  • step (1) 2. transferring the blend of step (1) to a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
  • step (3) cooling the molten extrudate mass of step (2) and sizing to obtain a solid
  • step (3) 4. blending he dispersion of step (3) with filler(s) to obtain a homogeneous blend;
  • step (5) the granules of step (5) are dried, sized and blended disintegrant(s), filler(s), glidant(s) and lubricant(s) to obtain the final blend;
  • step (6) processing the final blend of step (6) into a unit dosage form using appropriate tooling.
  • the unit dosage form may also be prepared by the following steps:
  • step (1) 2. transferring the blend of step (1) to a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
  • step (3) cooling the molten extrudate mass of step (2) and sizing to obtain a solid
  • step (3) 4. blending the dispersion of step (3) with filler(s) to obtain a homogeneous blend;
  • the granules of step (5) are dried, sized and blended disintegrant(s), filler(s), glidant(s) and lubricant(s) to obtain the final blend;
  • step (6) processing the final blend of step (6) into a unit dosage form using appropriate tooling.
  • the unit dosage form may further comprise of a non-functional coating.
  • Proprietary non-functional coating materials such as Opaspray® and Opadry®, obtainable from Colorcon Ltd., UK, may be used.
  • the effective amounts of ritonavir and lopinavir were blended with copovidone and colloidal silicon dioxide in a suitable mixer.
  • the blend so obtained was melted and the molten mass was subjected to extrusion under a temperature up to about 13O 0 C in a suitable Melt Extruder.
  • the molten extrudate mass was cooled and suitably sized.
  • Part (a) was blended with lactose and the resulting blend was granulated using a solution of the pharmaceutically acceptable surfactant (sorbitan monolaurate in Example 1, Cremophor ® RH 40 in Example 2, and a combination of Cremophor ® RH 40 and Gelucire ® 50/13 in Example 4) in isopropyl alcohol.
  • the granules so obtained were dried and sized.
  • the effective amounts of ritonavir and lopinavir were blended with copovidone and colloidal silicon dioxide in a suitable mixer.
  • the blend obtained was melted and the molten mass was subjected to extrusion under a temperature up to about 13O 0 C in a suitable Melt Extruder.
  • the molten extrudate mass was cooled and suitably sized.
  • Parts (a), (b) and (c) were admixed and compressed using appropriate tooling.
  • the tablets formed were finally coated using an aqueous dispersion of Opadry®.

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Abstract

L'invention porte sur une forme posologique unitaire biodisponible stable comprenant une dispersion solide binaire d'au moins un inhibiteur de protéase du VIH, dans lequel la dispersion solide est sensiblement exempte d'agents tensioactifs.
PCT/IB2010/053506 2009-07-31 2010-08-02 Formes posologiques unitaires d'inhibiteurs de protéase du vih WO2011013110A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028875A3 (fr) * 2013-08-29 2015-11-19 Teva Pharmaceuticals Industries Ltd. Forme pharmaceutique unitaire comprenant de l'emtricitabine, du ténofovir, du darunavir et du ritonavir et un comprimé monolithique comprenant du darunavir et du ritonavir

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5542206A (en) 1994-10-11 1996-08-06 Lisch; Albert Lure and tackle stacking container
US5648497A (en) 1989-05-23 1997-07-15 Abbott Laboraotries Retroviral protease inhibiting compounds
US5914332A (en) 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
US6037157A (en) 1995-06-29 2000-03-14 Abbott Laboratories Method for improving pharmacokinetics
WO2005039551A2 (fr) 2003-08-28 2005-05-06 Abbott Laboratories Forme posologique pharmaceutique solide
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
WO2009108865A2 (fr) * 2008-02-28 2009-09-03 Abbott Laboratories Comprimés et leur procédé de préparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5648497A (en) 1989-05-23 1997-07-15 Abbott Laboraotries Retroviral protease inhibiting compounds
US5542206A (en) 1994-10-11 1996-08-06 Lisch; Albert Lure and tackle stacking container
US6037157A (en) 1995-06-29 2000-03-14 Abbott Laboratories Method for improving pharmacokinetics
US6703403B2 (en) 1995-06-29 2004-03-09 Abbott Laboratories Method for improving pharmacokinetics
US5914332A (en) 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
WO2005039551A2 (fr) 2003-08-28 2005-05-06 Abbott Laboratories Forme posologique pharmaceutique solide
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
WO2006091529A2 (fr) 2005-02-23 2006-08-31 Abbott Laboratories Preparation pharmaceutique solide
WO2009108865A2 (fr) * 2008-02-28 2009-09-03 Abbott Laboratories Comprimés et leur procédé de préparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028875A3 (fr) * 2013-08-29 2015-11-19 Teva Pharmaceuticals Industries Ltd. Forme pharmaceutique unitaire comprenant de l'emtricitabine, du ténofovir, du darunavir et du ritonavir et un comprimé monolithique comprenant du darunavir et du ritonavir

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