WO2013111147A1 - Compositions à libération prolongée de névirapine - Google Patents

Compositions à libération prolongée de névirapine Download PDF

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Publication number
WO2013111147A1
WO2013111147A1 PCT/IN2012/000804 IN2012000804W WO2013111147A1 WO 2013111147 A1 WO2013111147 A1 WO 2013111147A1 IN 2012000804 W IN2012000804 W IN 2012000804W WO 2013111147 A1 WO2013111147 A1 WO 2013111147A1
Authority
WO
WIPO (PCT)
Prior art keywords
nevirapine
pharmaceutically acceptable
composition
extended release
iii
Prior art date
Application number
PCT/IN2012/000804
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Podili Khadgapathi
Pvrs SUBRAHMANYAM
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2013111147A1 publication Critical patent/WO2013111147A1/fr

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Classifications

    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • Technical field of the present invention relates to extended release pharmaceutical compositions comprising nevirapine, a release control polymer/ material and one or more pharmaceutically acceptable excipients.
  • Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against human immunodeficiency virus type 1 (HIV-1).
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • HMV-1 human immunodeficiency virus type 1
  • Nevirapine is structurally a member of the dipyridodiazepinoiie chemical class of compounds.
  • nevirapine 1 l-cyclopropyl-5,1 1 -dihydro-4-methyl- 6H-dipyndo [3,2- ⁇ 2',3'- ⁇ ][1,4] diazepin-6-one. It is a white to off-white crystalline powder with the molecular weight of 266.30, corresponding to the molecular formula C15H14N4O and has the following structural formula:
  • Nevirapine is marketed under the brand name VIRAMUNE in United States by Boehringer Ingelheim as 400mg extended release tablets, 200mg immediate release tablets and 50mg/ 5ml oral suspension. Nevirapine is indicated for use in combination with other antiretroviral agents for the treatment of HIV- 1 infection in adults.
  • U.S. Patent Application Publication No. 2010/0278918 assigned to Boehringer discloses extended release matrix composition of nevirapine comprising hydrophilic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose etc.
  • Inventors of the present invention have developed extended release pharmaceutical compositions of nevirapine with release control polymers/ materials using simplified process that were comparable with marketed VIRAMUNE ® XR tablets.
  • the present invention ' relates to extended release solid oral pharmaceutical composition comprising nevirapine, release control polymer/ material and one or more pharmaceutically acceptable excipients.
  • release control polymer/ material is selected from pregelatinized starch (SWELSTARTM MX-1), po!ymethacrylates, ethyl cellulose and povidone.
  • Release control polymer/ material according to the present invention is present in the core and/ or coated on to the core.
  • the present invention also provides a solid dosage form comprising nevirapine in micronized form.
  • nevirapine having a particle size dgo of from 1 to 50 ⁇ is used for preparing pharmaceutical composition.
  • extended release tablet composition comprises micronized nevirapine having a particle size dg 0 of from 1 to 50 ⁇ , a release control polymer/ material selected from pregelatinized starch (SWELSTARTM MX-1), polymethacrylates, ethylcellulose and povidone, and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30- 50% w/w of nevirapine, 25 to 35% w/w of pregelatinized starch having average particle diameter 20 to 40 ⁇ and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30- 50% w/w of nevirapine, 1 to 8% w/w of povidone having viscosity of more than about 300 mPas and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30- 50% w/w of nevirapine, 1 to 15% w/w of ammonio methacrylate copolymer (Type-B) and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30- 50% w/w of nevirapine, 1 to 8% w/w of ethyl cellulose and one or more pharmaceutically acceptable excipients.
  • the present invention provides method of preparing extended release compositions of nevirapine comprising the process of wet granulation or direct compression or dry granulation or extrusion and spheronization comprising release control polymer/ material and one or more pharmaceutically acceptable excipients.
  • the process for preparing extended release compositions of nevirapine comprises wet granulation.
  • the present invention also provides extended release pharmaceutical composition of nevirapine comprising carboxymethyl ethyl cellulose, waxes, hydrogenated castor oil or combinations thereof as a release controlling agent.
  • the present invention provides effective dissolution profiles of nevirapine for a period of up to about 24 hours.
  • nevirapine includes nevirapine in the form of free base or its pharmaceutically acceptable salt, amorphous nevirapine, crystalline nevirapine or any isomer or derivative, hydrate or solvate, 5 prodrug or combinations thereof, preferably nevirapine anhydrous.
  • extended release includes controlled release compositions or sustained release compositions that release the drug from its dosage form over a period of about 24 hrs.
  • ⁇ ективное amount or “therapeutically effective amount” as used J O herein interchangeably, are defined to mean the amount or quantity of the nevirapine or polymorph or isomer thereof, which is sufficient to elicit an appreciable biological response when administered to a patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, nature of the condition to be treated and will be at the ultimate discretion of the attendant 15 physician.
  • composition or “solid oral composition” as used herein interchangeably refers to the drug in combination with pharmaceutically acceptable carriers and additional inert ingredients.
  • the formulation can be administrable by a variety of means.
  • the present invention provides extended release compositions comprising nevirapine, release control polymer/ material and one or more pharmaceutically acceptable excipients thereof.
  • Release control polymer/ material according to the present invention selected from pregelatinized starch, polymethacrylates, ethyl cellulose and povidone. 5 .
  • Pregel tinized starch used according to the present invention have average particle diameter from 20 to 40 ⁇ , sold by Asahi Kasei Chemicals under the trade name of SWELSTARTM (MX-1).
  • Polymethacrylate is in the form of ammonio methacrylate copolymer (Type- B) including RSPO, RS30D, RS100 and RS12.5.
  • Ethyl cellulose is available from different suppliers with different brand names: for example., Ethocel std 4 premium, Ethocel std 7FP premium, Ethocel std 10FP premium, Ethocel std 14FP premium, Ethocel std 20P premium, Ethocel std 50P premium, Ethocel std 70P premium, Ethocel std 1 OOP premium.
  • Povidone polyvinyl pyrrolidone
  • Povidone K-30 MW: 44000-54000, and Viscosity of 5.5-8.5 mPa s
  • Povidone K-90 MW: 1000000-1500000, and Viscosity of 300-700 mPa s
  • Povidone K-90 having a viscosity of more than 300 mPas will control the release of nevirapine over a period of 24 hrs.
  • Povidone according to the present invention has a viscosity of at least 300 mPas, when measured at 10% w/v aqueous povidone (Kollidon) solutions at 20°C.
  • Release control polymer/ material according to the present invention is present in the core and/ or coated on to the core.
  • Coating layer comprises one or more excipients selected from release control polymer/ material, coating agents, opacifiers, coloring agents, anti -tacking agents and the like.
  • Solid oral pharmaceutical composition include tablets, capsules, caplets, granules, pellets, beads, pill, powder, sachet, , particles, mini-tablets and the like, preferably tablets.
  • Pharmaceutical compositions of the present invention relates to extended release tablets comprising nevirapine, release control polymer/ material and one or more pharmaceutically acceptable excipients.
  • compositions of nevirapine according to the present invention further comprises one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a lubricant, a glidant and a combination thereof.
  • Suitable diluents include, lactose, microcrystalline cellulose, starches, modified starches, sugar, mannitol, sorbitol, inorganic salts, calcium sulfate, xylitol, lactitol, starch, pregelatinized starch, kaolin, sucrose, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like and combinations thereof.
  • binders as used herein is intended to mean the substances used to cause adhesion of powder particles in tablet granulations. Suitable binders include, by way of example and without limitation, starches such as corn starch, potato starch, modified starches, pectin, microcrystalline cellulose, povidone, co-povidone, acacia, tragacanth, gelatin, liquid glucose, eudragit and pregelatinized starch, and the like and combinations thereof.
  • lubricant as used herein is intended to mean the substances used in tablet formulations to reduce friction during tablet compression.
  • Suitable lubricants include, by way of example and without limitation, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, talc, polyethylene glycols and the like and combinations thereof.
  • the glidant is talc and/or colloidal silicon dioxide.
  • the glidant is included in an amount of about 0.5% (w/w) to about 3% (w/w) of the composition.
  • the present invention particularly provides an advantageous solid dosage form comprising nevirapine in micronized form, having a particle size dg 0 of from 1 to 50 ⁇ for preparing pharmaceutical compositions.
  • nevirapine having a particle size d % of from 1 to 50 ⁇ is used for preparing pharmaceutical composition.
  • Desired particle size of nevirapine was obtained by any suitable micronization technique known in the art such dry milling, wet milling, air jet milling, sieving etc. Micronized nevirapine provides good invitro end release and invivo bioavailability.
  • extended release tablet composition comprises micronized nevirapine having a particle size dg 0 of from 1 to 50 ⁇ , a release control polymer/ material selected from pregelatinized starch having average particle diameter from 20 to 40 ⁇ (SWELSTAR , MX-1 ), polymethacrylates, ethylcellulose and povidone, and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30-50% w/w of nevirapine, 25 to 35% w/w of pregelatinized starch (SWELSTAR MX-1) and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30-50% w/w of nevirapine, 1 to 8% w/w of povidone having viscosity of more than about 300 mPas and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30-50% w/w of nevirapine, 1 to 15% w/w of ammonio methacrylate copolymer (Type-B) and one or more pharmaceutically acceptable excipients.
  • extended release tablet composition comprising 30-50% w/w of nevirapine, 1 to 8% w/w of ethyl cellulose and one or more pharmaceutically acceptable excipients.
  • Method of preparing extended release compositions of nevirapine comprises wet granulation, direct compression, dry granulation or extrusion and spheronization comprising release control polymer/ material and one or more pharmaceutically acceptable exicipients.
  • Wet granulation process comprise the steps of (i) sifting and blending nevirapine, release control polymer/ material and one or more excipients to form a dry mix, (ii) granulating the dry mix of step no. (i) using binder solution to form granules followed by drying, (iii) blending the granules of step no. (ii) with lubricant and finally compressing into tablets or filling into capsules.
  • Dry granulation process comprises the steps of: (i) sifting and blending the nevirapine, release control polymer/ material and one or more excipients, (ii) slugging/ compacting the blended mixture of step (i) to form slugs/ compacts and then sizing the resulting slugs/ compacts to form granules, (iii) blending the granules with lubricant, and (iv) compressing the granules of step (iii) into tablets or filling into capsules.
  • Direct compression process comprises the steps of: (i) sifting the nevirapine, release control polymer/ material with one or more excipients, followed by blending, (ii) lubricating the blend obtained in step (i), and (iii) finally compressing the lubricated blend of step (ii) into tablets or filling into capsules.
  • Extrusion and spheronization process comprise the steps of: (i) blending nevirapine, release control polymer/ material with one or more excipients, (ii) wet massing the blend of step no (i) with binder solution to form a wet mass, (iii) extruding the wet mass of step no (ii) followed by spheronization using spherodizer to obtain spheroids/ spherical granules, and (iv) lubricating the spheroids with remaining portion of the excipients and finally compressing into tablets or filling into capsules.
  • compositions described herein can be a modified-release, a controlled-release, an extended release, a prolonged-release, or a sustained-release unit dosage form.
  • the pharmaceutical composition includes a safe and effective amount of nevirapine and release control polymer/ material.
  • the release-retarding agent includes an agent selected from carboxymethyl ethyl DCiuiose, waxes, hydrogenated castor oil or mixtures thereof.
  • the pharmaceutical compositions of the present invention provide an effective dissolution profile of nevirapine for a period of up to about 24 hours.
  • a method of treating HIV-1 infection comprising administering a composition containing a therapeutically effective amount of nevirapine.
  • EXAMPLE 1 Extended release compositions of Nevirapine prepared by wet granulation process: S. No Ingredients Mg/ unit
  • step no (i) the blend of step no (i) was loaded in a rapid mixer granulator and granulated using granulating solution over a period of 2 minutes,
  • step no (ii) the granules of step no (ii) were dried until loss on drying of not more than 2.0% w/w,
  • step (iii) dried granules of step (iii) were milled and passed through mesh #20, v) . extra granular ingredients were sifted together through mesh # 60 and the dried granules of step no (iv) were lubricated for 5 minutes,
  • step (v) lubricated materials of step (v) were blended together and compressed into tablets or filled in capsules,
  • step (vi) the core tablets obtained in step (vi) were optionally film coated using coating solution.
  • Extended release compositions of Nevirapine prepared by direct compression process 3 Microcrystalline cellulose 140.00
  • composition of example-8 was made by direct compression method, which includes blending together all the excipients followed by compressing in to tablets.
  • step (i) intra granular ingredients were dry mixed, followed by wet massing with binder solution of step (i) using rapid mixer granulator,
  • step no (ii) was extruded and the resulted extrudes were spheronized using spherodizer to obtain spheroids/ spherical granules, iv) spherical granules of step (iii) were dried completely, and
  • step (iv) spherical granules of step (iv) were lubricated with extra granular ingredients and finally compressed into tablets or filled into capsules.
  • step no (i) the blend of step no (i) was slugged/ compacted and the resulted slugs/ compacts were milled using multimill or cone mill,
  • step (ii) milled granules of step (ii) were sifted through mesh # 30 completely, iv) extra granular magnesium stearate was sifted through mesh # 60,
  • step (iii), and (iv) materials of step (iii), and (iv) were blended together and finally compressed into tablets,
  • compressed tablets were optionally coated with Opadry ® II Pink.
  • step no (i) the blend of step no (i) was loaded in a rapid mixer granulator and granulated using purified water over a period of 2 minutes,
  • step no (ii) the granules of step no (ii) were dried until loss on drying of not more than 2.0% w/w,
  • step (iii) dried granules of step (iii) were milled and passed through #20 mesh, v) extragranular ingredients were sifted together through mesh # 60 and the dried granules of step no (iv) were lubricated for 5 minutes,
  • step (v) lubricated materials of step (v) were blended together and finally compressed into tablets or filled into capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention se rapporte à des compositions pharmaceutiques à libération prolongée comprenant de la névirapine, un matériau/polymère de commande de libération et un ou plusieurs excipients acceptables d'un point de vue pharmaceutique, à un procédé pour sa préparation et son utilisation dans le traitement de l'infection par Le VIH-1 chez l'adulte.
PCT/IN2012/000804 2011-12-19 2012-12-10 Compositions à libération prolongée de névirapine WO2013111147A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4435CH2011 2011-12-19
IN4435/CHE/2011 2011-12-19

Publications (1)

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WO2013111147A1 true WO2013111147A1 (fr) 2013-08-01

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PCT/IN2012/000804 WO2013111147A1 (fr) 2011-12-19 2012-12-10 Compositions à libération prolongée de névirapine

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052570A1 (fr) * 1997-05-17 1998-11-26 Glaxo Group Limited Combinaisons antivirales contenant le nucleoside carbocyclique 1592u89
WO2005048978A2 (fr) * 2003-10-01 2005-06-02 Lupin Limited Composition pharmaceutique a liberation controlee et procede de preparation de cette composition
CN101199487A (zh) * 2006-12-15 2008-06-18 珠海华澳进出口有限公司 奈韦拉平片及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052570A1 (fr) * 1997-05-17 1998-11-26 Glaxo Group Limited Combinaisons antivirales contenant le nucleoside carbocyclique 1592u89
WO2005048978A2 (fr) * 2003-10-01 2005-06-02 Lupin Limited Composition pharmaceutique a liberation controlee et procede de preparation de cette composition
CN101199487A (zh) * 2006-12-15 2008-06-18 珠海华澳进出口有限公司 奈韦拉平片及其制备方法

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