WO2013111147A1

WO2013111147A1 - Extended release compositions of nevirapine

Info

Publication number: WO2013111147A1
Application number: PCT/IN2012/000804
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Podili Khadgapathi; Pvrs SUBRAHMANYAM
Original assignee: Hetero Research Foundation
Current assignee: Hetero Research Foundation
Priority date: 2011-12-19
Filing date: 2012-12-10
Publication date: 2013-08-01
Anticipated expiration: 2014-06-19

Description

EXTENDED RELEASE COMPOS ITIONS OF NEVIRAPINE

PRIORITY

This patent application claims priority to Indian application number 4435/CHE/201 1 , filed on December 19, 201 1 , the contents of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

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.

BACKGROUND

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against human immunodeficiency virus type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinoiie chemical class of compounds.

The chemical name of nevirapine is 1 l-cyclopropyl-5,1 1 -dihydro-4-methyl- 6H-dipyndo [3,2-^2',3'-ε][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 No. 5,366,972 assigned to Boehringer discloses nevirapine.

U.S. Patent No. 6,172,059 assigned to Boehringer describes oral liquid suspension composition of nevirapine.

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.

SUMMARY '^***"^* The present invention^' relates to extended release solid oral pharmaceutical composition comprising nevirapine, release control polymer/ material and one or more pharmaceutically acceptable excipients.

According to another embodiment of the present invention, release control polymer/ material is selected from pregelatinized starch (SWELSTAR™ 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. In another embodiment, nevirapine having a particle size dgo of from 1 to 50μ is used for preparing pharmaceutical composition.

In a specific embodiment, extended release tablet composition comprises micronized nevirapine having a particle size dg₀ of from 1 to 50μ, a release control polymer/ material selected from pregelatinized starch (SWELSTAR™ MX-1), polymethacrylates, ethylcellulose and povidone, and one or more pharmaceutically acceptable excipients.

In another embodiment, 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 40μ and one or more pharmaceutically acceptable excipients.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In one embodiment, 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.

In a preferred embodiment, the process for preparing extended release compositions of nevirapine comprises wet granulation.

In a further aspect, 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.

In a further aspect, the present invention provides effective dissolution profiles of nevirapine for a period of up to about 24 hours.

A method of treating HIV-1 infection comprising administering a composition comprising a therapeutically effective amount of nevirapine. DETAILED DESCRIPTION in accordance with the present invention the term "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.

The term "extended release" as used herein, according to the present invention includes controlled release compositions or sustained release compositions that release the drug from its dosage form over a period of about 24 hrs.

The term "effective 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.

The terms "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.

20 Accordingly, 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 40μ, sold by Asahi Kasei Chemicals under the trade name of SWELSTAR™ (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) is available in different grades having different molecular weights and viscosities like 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.

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" according to the present invention 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.

Pharmaceutical 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.

The term "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. The term "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. In certain aspects of the present invention, the glidant is talc and/or colloidal silicon dioxide. In a further aspect of the present invention, 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 dg₀ of from 1 to 50μ for preparing pharmaceutical compositions.

In another aspect, nevirapine having a particle size d_% of from 1 to 50μ 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.

In a specific aspect, extended release tablet composition comprises micronized nevirapine having a particle size dg₀ of from 1 to 50μ, a release control polymer/ material selected from pregelatinized starch having average particle diameter from 20 to 40μ (SWELSTAR^, MX-1 ), polymethacrylates, ethylcellulose and povidone, and one or more pharmaceutically acceptable excipients.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

The pharmaceutical compositions described herein can be a modified-release, a controlled-release, an extended release, a prolonged-release, or a sustained-release unit dosage form.

In a more particular implementation of certain aspects of the invention, the pharmaceutical composition includes a safe and effective amount of nevirapine and release control polymer/ material.

In certain aspects of the present invention, the release-retarding agent includes an agent selected from carboxymethyl ethyl ceiiuiose, 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. '

EXAMPLES The following examples further illustrate the invention and do not limit the scope of the invention.

EXAMPLE 1 : Extended release compositions of Nevirapine prepared by wet granulation process: S. No Ingredients Mg/ unit

Intragranular ingredients:

1 Nevirapine anhydrous 400.00

2 Lactose monohydrate 160.00

3 Eudragit RSPO 1 10.00

4 Microcrystalline cellulose 240.00

Granulation:

5 Eudragit RS 30D 80.00

6 Purified water q.s.

Extragranular ingredients:

7 Magnesium stearate 10.00

Total Tablet weight 1000.00

Brief manufacturing process: i) Intragranular ingredients were sifted and blended,

ii) the blend of step no (i) was loaded in a rapid mixer granulator and granulated using granulating solution over a period of 2 minutes,

iii) the granules of step no (ii) were dried until loss on drying of not more than 2.0% w/w,

iv) 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,

vi) lubricated materials of step (v) were blended together and compressed into tablets or filled in capsules,

vii) the core tablets obtained in step (vi) were optionally film coated using coating solution.

EXAMPLE 2:

Extended release compositions of Nevirapine prepared by wet granulation process:

S.No Ingredients Mg/ unit

Intragranular ingredients:

1 Nevirapine 400.00

2 Lactose monohydrate 250.00

3 Microcrystalline cellulose 240.00

4 Eudragit RSPO 50.00

Granulation:

5 Eudragit RS 30D 50.00

6 Purified water q.s.

Extragranular ingredients:

Total Tablet weight .

Brief manufacturing process: Same as given for example 1 .

EXAMPLE 3:

Brief manufacturing process: Same as given for example 1 .

Brief manufacturing process: Same as given for example 1.

EXAMPLE 5:

S. No I ingredients Mg/ unit Intragranular Ingredients:

1 Nevirapine anhydrous 400.00

2 Lactose monohydrate 440.00

3 Microcrystalline cellulose 140.00

Granulation:

4 Ethylcellulose std 7 FP 10.00

5 Isopropyl alcohol q.s.

Extragranular Ingredients:

6 Magnesium stearate 10.00

Total Tablet weight 1000.00

Film Coating:

7 Eudragit RS30D 90.00

8 Triethyl citrate 9.000

9 Talc 1.000

10 Purified water q.s.

Film coated tablet weight 1 100.00

Brief manufacturing process: Same as given for example 1.

Dissolution study:

Dissolution Medium pH 6.8 buffer. with 2% SLS

Volume 900 ml

Apparatus USP I (Basket)

Speed 100 rpm

^■Ths dissolution results of nevirapine tablets prepared according to example 1 to 5 were presented in Table 1.

Table 1 :

EXAMPLE 6-7:

Extended release compositions of Nevirapine prepared by wet granulation process: Example-6 Example-7

S.No Ingredients g/ unit

Intragranular ingredients

1 Nevirapine anhydrous 400.00 400.00

2 Lactose Monohydrate 400.00 410.00

3 Microcrystalline cellulose 140.00 130.00

Granulation

4 Povidone USP ( ollidon 90F) 50.00 -

5 Povidone USP (Kollidon K30F) - ^■ 50.00

6 Purified water q.s. q.s.

Extra granular ingredients

7 Magnesium Stearate USP/NF 10.00 10.00

Total Tablet weight 1000.00 1000.00

Brief manufacturing process: Same as given for example 1. Dissolution study:

Dissolution Medium pH 6.8 buffer with 2% SLS

Volume 900 ml

Apparatus USP I (Basket)

Speed 100 rpm

The dissolution results of nevirapine tablets prepared according to example 6 to 7 were presented in Table 2.

Table 2:

EXAMPLE 8:

Extended release compositions of Nevirapine prepared by direct compression process:

3 Microcrystalline cellulose 140.00

4 Povidone (Kollidon K90F) 43.00

5 Magnesium stearate 10.00

Total Tablet weight 1000.00

Brief manufacturing process:

The composition of example-8 was made by direct compression method, which includes blending together all the excipients followed by compressing in to tablets.

EXAMPLE 9:

Extended release compositions of Nevirapine prepared by extrusion-spheronization:

Brief manufacturing process:

i) Povidone was dissolved in required quantity of purified water to form binder solution,

ii) intra granular ingredients were dry mixed, followed by wet massing with binder solution of step (i) using rapid mixer granulator,

iii) the wet mass of 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

v) spherical granules of step (iv) were lubricated with extra granular ingredients and finally compressed into tablets or filled into capsules.

EXAMPLE 10:

Extended release compositions of Nevirapine prepared by dry granulation process:

3 Macrocrystalline cellulose 407.00

4 Povidone (Kollidon K90F) 43.00

Extra granular ingredients

5 Magnesium stearate 10.00

Total Tablet weight 1000.00

Brief manufacturing process: i) Intragranular ingredients were sifted and blended together,

ii) the blend of step no (i) was slugged/ compacted and the resulted slugs/ compacts were milled using multimill or cone mill,

iii) milled granules of step (ii) were sifted through mesh # 30 completely, iv) extra granular magnesium stearate was sifted through mesh # 60,

v) materials of step (iii), and (iv) were blended together and finally compressed into tablets,

vi) compressed tablets were optionally coated with Opadry^® II Pink.

ii) the blend of step no (i) was loaded in a rapid mixer granulator and granulated using purified water over a period of 2 minutes,

iv) 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,

vi) lubricated materials of step (v) were blended together and finally compressed into tablets or filled into capsules.

Dissolution study:

Dissolution Medium pH 6.8 buffer with 2% SLS

Volume 900 ml

Apparatus USP I (Basket)

Speed 100 rpm

The dissolution results of nevirapine tablets prepared according to the example 1 1 is presented in Table 3.

Table 3:

Claims

WE CLAIM:

1. An extended release solid oral pharmaceutical composition comprising: i) nevirapine or its pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof, ii) a release control polymer/ material selected from pregelatinized starch having average particle diameter 20 to 40μ, ammonio methacrylate copolymer (Type- B), ethyl cellulose, povidone and combinations thereof and iii) one or more pharmaceutically acceptable excipients.

2. The composition according to claim 1 , wherein said nevirapine having particle size

3. The composition according to claim 1 , wherein said release control polymer/ material is present in the core and/ or coated on to the core.

4. The composition according to claim 1 , wherein said pharmaceutically acceptable excipient selected from a diluent, a binder, a lubricant and a combination thereof.

5. The solid oral composition according to claim 1 , which is a tablet, granules or a capsule.

6. The composition according to claim 1 , wherein the composition is prepared by wet granulation^ dry granulation, direct compression or extrusion and spheronization.

7. The composition according to claim 1 , wherein the composition is prepared by wet granulation process.

8. An extended release tablet composition comprising: i) 30-50% w/w of nevirapine, ii) 25 to 35% w/w of pregelatinized starch having average particle diameter 20 to 40μ and iii) one or more pharmaceutically acceptable excipients.

9. An extended release tablet composition comprising: i) 30-50% w/w of nevirapine, ii) l to 8% w/w of povidone having viscosity of more than about 300 mPas and iii) one or more pharmaceutically acceptable excipients.

10. An extended release tablet composition comprising: i) 30-50% w/w of nevirapine, ii) 1 to 15% w/w of ammonio methacrylate copolymer (Type-B) and iii) one or more pharmaceutically acceptable excipients.

1 1. An extended release tablet composition comprising: i) 30-50% w/w of nevirapine, ii) 1 to 8% w/w of ethyl cellulose and iii) one or more pharmaceutically acceptable excipients.

12. The composition according to claim 8 to 1 1, wherein said pharmaceutically acceptable excipient selected from a diluent, a binder, a lubricant and a combination thereof.

13. The method of treating HIV-1 infection in adults comprising administering a composition containing a therapeutically effective amount of nevirapine according to any of the claims 1 and 8 to 11.