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WO2009011567A1 - Formes cristallines d'efavirenz - Google Patents

Formes cristallines d'efavirenz Download PDF

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Publication number
WO2009011567A1
WO2009011567A1 PCT/NL2008/000157 NL2008000157W WO2009011567A1 WO 2009011567 A1 WO2009011567 A1 WO 2009011567A1 NL 2008000157 W NL2008000157 W NL 2008000157W WO 2009011567 A1 WO2009011567 A1 WO 2009011567A1
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WO
WIPO (PCT)
Prior art keywords
efavirenz
sodium deoxycholate
sodium
degrees
theta
Prior art date
Application number
PCT/NL2008/000157
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English (en)
Inventor
Evantha Dova
Original Assignee
Ultimorphix Technologies B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ultimorphix Technologies B.V. filed Critical Ultimorphix Technologies B.V.
Publication of WO2009011567A1 publication Critical patent/WO2009011567A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • 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
    • A61K31/536—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 ortho- or peri-condensed with carbocyclic ring systems
    • 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 solid crystalline forms of Efavirenz, in particular co-crystal and/or clathrate forms between Efavirenz and sodium deoxycholate, processes for the preparation thereof and pharmaceutical compositions containing the solid from as well as its use as a medicament and for the treatment of ailments.
  • Efavirenz is a HIV reverse transcriptase and described in U.S. Patent No. 5,519,021.
  • Efavirenz is chemically known as, (4S) -6- chioro-4- (cyclopropylethyny] ) -1 , 4-dihydro-4- (trifluoromethyl) -2H-3, 1 -ben[sum]oxazin- 2-one, C14H9NC1F3O2, MW 315.675, CAS [154598-52-4]
  • Efavirenz has the following structural formula:
  • Efavirenz is used for the preparation of a medicament having non-nucleoside HIV-I reverse transcriptase inhibiting activity that is useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
  • Efavirenz is sold commercially as SUSTIVA(R) by Bristol Myers Squibb.
  • Efavirenz is also combined with Truvada and sold as Atripla.
  • the present invention relates to a novel solid form of Efavirenz, preferably a crystalline form.
  • the present inventors have identified a novel crystalline form, a co-crystal and/or a clathrate of Efavirenz with sodium deoxycholate, depicted as Efavirenz: sodium deoxycholate. It has been found that the presently found form expresses a strongly improved dissolution rate vis-a-vis currently known forms of Efavirenz.
  • the sodium deoxycholate may be mixed as an excipient with Efavirenz to result in the solid form of the invention.
  • Sodium deoxycholate is a secondary bile acid, C24H39NaO4 , CAS 302-95-4, MW 414.55.
  • Figure IA illustrates the X-Ray Powder Diffraction pattern of Efavirenz : sodium deoxycholate.
  • Figure IB illustrates the DSC pattern of Efavirenz : sodium deoxycholate.
  • Figure 1C illustrates the TGA pattern of Efavirenz : sodium deoxycholate. TGA/SDTA of DecNal. Mass-loss ⁇ 1% is observed below 200 0 C.
  • Figure ID Proton index numbering of Efavirenz for NMR
  • Efavirenz has shifted to lower ppm-values, indicating interaction between the H 1 and deoxycholate in solution. Also, the two hydroxyl groups of the sodium deoxycholate show in the region between 4.0 and 5.0 ppm. The rest of the protons associated with sodium deoxycholate are between 0.5 and 2.0 ppm. The magnitude of the integrated signal shows that the ratio between Efavirenz and sodium deoxycholate is approximately 1:1.
  • the present invention provides a solid crystalline form of Efavirenz and sodium deoxycholate herein defined as Efavirenz : sodium deoxycholate, characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four X-ray powder diffraction peaks selected from the group consisting of 9.5, 13.2, 14.5, 18.1 degrees two-theta +/- 0.3 degrees two-theta.
  • Efavirenz sodium deoxycholate can, in a preferred embodiment, be further characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably four, or even in particular five , six or seven X-ray powder diffraction peaks selected from the group consisting of 7.34, 11.9, 16.2, 19.3, 21.3, 22.1, 23.3 degrees two-theta +/- 0.3 degrees two- theta.
  • Efavirenz sodium deoxycholate can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities:
  • Efavirenz sodium deoxycholate can be characterized by an XRPD substantially according to Fig IA.
  • Efavirenz sodium deoxycholate can be characterized by an DSC substantially according to Fig IB.
  • Efavirenz sodium deoxycholate can be characterized by an TGA substantially according to Fig 1C.
  • Efavirenz sodium deoxycholate of the present invention can be characterized by DSC with an onset at 215 0 C and a characterizing peak at 222 0 C. From the thermal analysis, it is concluded that Efavirenz: sodium deoxycholate is anhydrous.
  • Efavirenz sodium deoxycholate is in a substantially pure form, preferably substantially free from other solid, amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound.
  • substantially free from other solid, amorphous, crystalline and/or polymorphic forms means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form Efavirenz : sodium deoxycholate comprising the steps of combining Efavirenz and sodium deoxycholate in a suitable solvent, preferably nitromethane and crystallizing Efavirenz : sodium deoxycholate.
  • the invention pertains to a method for the preparation of the slid form Efavirenz : sodium deoxycholate comprising the steps of combining
  • Efavirenz and sodium deoxycholate wherein the deoxycholate is used as an excipient and processed as such.
  • compositions comprising Efavirenz : sodium deoxycholate .
  • the present invention further relates to pharmaceutical formulations comprising the novel solid (co-) crystalline form of Efavirenz .
  • compositions of the present invention contain the crystalline form according to the present invention, such as
  • Efavirenz sodium deoxycholate as disclosed herein.
  • the invention also provides pharmaceutical compositions comprising the solid crystal form according to the present invention.
  • Pharmaceutical formulations of the present invention contain the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s).
  • the pharmaceutical formulations according to the invention may further comprise, in addition to Efavirenz : sodium deoxycholate, additional pharmaceutical active ingredients, preferably Anti-HIV agents and more preferably Tenofovir DF and/or Emtricitabine .
  • additional pharmaceutical active ingredients preferably Anti-HIV agents and more preferably Tenofovir DF and/or Emtricitabine .
  • the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel (R) ) , micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit (R) ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. Avicel (R)
  • micro fine cellulose lactose
  • lactose starch
  • pregelatinized starch calcium carbonate, calcium sul
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol) , carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel (R) ) , hydroxypropyl methyl cellulose (e.g.
  • Methocel (R) liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone (R) ) , pregelatinized starch, sodium alginate and starch.
  • povidone e.g. Kollidon(R), Plasdone (R)
  • pregelatinized starch sodium alginate and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium,
  • Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetra acetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to
  • the active ingredients When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween ⁇ 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers .
  • Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc) .
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.
  • a tabletting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection.
  • the crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection.
  • the formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Allen et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed, 2004.
  • the present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof.
  • a pharmaceutical composition of the present invention comprises the crystalline form ULT-I.
  • the crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition.
  • the invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV.
  • XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a
  • the XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings.
  • Samples were sealed in standard 40 microliter aluminum pans and heated in the DSC from 25°C to 300 0 C, at a heating rate of 20°C/min. Dry N 2 gas, at a flow rate of 50 ml/min, was used to purge the DSC equipment during measurement .
  • Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA.
  • the TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 300 0 C at a heating rate of 20°C/min. Dry N 2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
  • Efavirenz sodium deoxycholate .
  • Efavirenz sodium deoxycholate on milliliter scale. From nitromethane : 39.4 mg Efavirenz was placed together with 58.2 mg sodium deoxycholate and a Teflon-coated stirring bar in an HPLC-vial. 200 ⁇ L nitromethane was added and the vial was sealed. The vial was heated to 60 0 C and stirred at that temperature for 16h. The resulting suspension was centrifuged at 40 0 C with 3000 rpm for 12 min to settle the solids. The supernatant was decanted and the remaining solids were dried at reduced pressure. The resulting residue was analyzed by- X-ray powder diffraction, DSC and TGA and identified as Efavirenz: sodium deoxycholate .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention propose une nouvelle forme solide d'Efavirenz, une forme cristalline d'Efavirenz avec du désoxycholate de sodium, désignée sous le nom d'Efavirenz: désoxycholate de sodium, des procédés de préparation d'Efavirenz: désoxycholate de sodium, et l'utilisation d'Efavirenz: désoxycholate de sodium dans des applications pharmaceutiques, en particulier dans des médicaments anti-VIH. La forme cristalline d'Efavirenz: désoxycholate de sodium peut être utilisée en combinaison avec d'autres médicaments anti-VIH, tels que le Tenofovir DF et l'Emtricitabine.
PCT/NL2008/000157 2007-07-16 2008-06-23 Formes cristallines d'efavirenz WO2009011567A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2010112411A1 (fr) * 2009-03-30 2010-10-07 Tibotec Pharmaceuticals Co-cristal d'étravirine et de nicotinamide

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WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
US20030180352A1 (en) * 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
WO2006018853A2 (fr) * 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006040643A2 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication
WO2006134610A1 (fr) * 2005-06-16 2006-12-21 Hetero Drugs Limited Composition pharmaceutique d'efavirenz presentant un profil de dissolution ameliore

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US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
US20030180352A1 (en) * 1999-11-23 2003-09-25 Patel Mahesh V. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
WO2006018853A2 (fr) * 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006040643A2 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication
WO2006134610A1 (fr) * 2005-06-16 2006-12-21 Hetero Drugs Limited Composition pharmaceutique d'efavirenz presentant un profil de dissolution ameliore

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010112411A1 (fr) * 2009-03-30 2010-10-07 Tibotec Pharmaceuticals Co-cristal d'étravirine et de nicotinamide
CN102369009A (zh) * 2009-03-30 2012-03-07 泰博特克药品公司 依曲韦林和烟酰胺的共晶体
JP2012522026A (ja) * 2009-03-30 2012-09-20 テイボテク・フアーマシユーチカルズ エトラビリンとニコチンアミドの共結晶
US8754093B2 (en) 2009-03-30 2014-06-17 Janssen R&D Ireland Co-crystal of etravirine and nicotinamide
EA024299B1 (ru) * 2009-03-30 2016-09-30 Янссен Сайенсиз Айрлэнд Юси Сокристалл этравирина и никотинамида, способ его получения и применение

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