DESC:STABLE PHARMACEUTICAL COMPOSITIONS OF TENOFOVIR DISOPROXIL FUMARATE, EMTRICITABINE AND RILPIVIRINE HYDROCHLORIDE AND PROCESS OF
PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing a stable solid oral composition containing Tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

BACKGROUND OF THE INVENTION

Tenofovir disoproxil fumarate (prodrug of Tenofovir) is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2­[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52 and its structural formula is

Tenofovir disoproxil fumarate is available in the market from Gilead Sciences Inc. under the name VIREAD®, in four strengths, 150mg, 200 mg, 250mg and 300 mg of Tenofovir disoproxil fumarate, and formulated as tablets for oral administration.

Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg/mL in water at 25 °C. The log P for Emtricitabine is -0.43 and the pKa is 2.65. The chemical name of Emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24 and its structural formula is

EMTRIVA® is available as capsules or as an oral solution in market from Gilead.

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6­dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride. Its molecular formula is C22H18N6 • HCl and its molecular weight is 402.88 and its structural formula is

Rilpivirine Hydrochloride is available in the market from Janssen Prods under the name EDURANT®, having strengths, 25mg of Rilpivirine base, and formulated as tablets for oral administration.

The triple combination of Tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride is available in the market from Gilead sciences Inc. under the name COMPLERA® , (Containing 300 mg of tenofovir disoproxil fumarate, 200 mg of emtricitabine and 25 mg base rilpivirine) and inactive ingredients: pregelatinized starch, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone, polysorbate 20 and formulated as tablets for oral administration

WO2005021001 discloses a co-wet granulation process for preparing a single layer tablet that comprises rilpivirine hydrochloride, emtricitabine, and tenofovir disoproxil fumarate wherein all three active ingredients are combined in a single granulation process with water in formulation and unstable.

US2013243857 discloses a bilayer tablet comprising a first layer and second layer wherein; a) the first layer comprises rilpivirine hydrochloride, is substantially free of tenofovir disoproxil fumarate; b) the second layer comprises tenofovir disoproxil fumarate and is substantially free of rilpivirine hydrochloride ; c) the tablet further comprises emtricitabine. US2013243857 further discloses the chemical stability of tenofovir disoproxil fumarate is affected in the presence of rilpivirine hydrochloride in the formulation provided by the co-wet granulation process discussed in WO 2005/021001 is not ideal for human clinical use.

WO2006135933 discloses a bilayer tablet wherein the first layer comprises emtricitabine and tenofovir DF and second layer comprises efavirenz.

Article published on XVIII International AIDS Conference (July 18-23, 2010; Mathias A et al) discloses bioequivalence of the Co-Formulation of Emtricitabine/Rilpivirine/Tenofovir disoproxil.

The above prior art disclose compositions of various combinations of antiretroviral agents prepared as single and/or double layered tablets. However, still there is a need to develop stable single layer dosage form comprising tenofovir disoproxil fumarate, emtricitabine and rilpivirine hydrochloride which avoids the common problems associated with bilayered tablets like layer separation, insufficient hardness, inaccurate individual layer weight control, cross contamination between the layers, reduced yield etc.

Thus, the Inventors of present invention have surprisingly found that an improved process for preparation of a stable single layer tablet comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine Hydrochloride; wherein tenofovir disoproxil fumarate and rilpivirine hydrochloride are not physically separated in composition.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a stable solid oral pharmaceutical composition comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

In one embodiment, the present invention relates to a stable single layer tablet dosage form comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

In one embodiment, the present invention relates to a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride, prepared by a process comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine and one or more pharmaceutically acceptable excipients with solvent or with a binder solution,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extra granular rilpivirine hydrochloride one or more pharmaceutically acceptable excipients ,
(e) lubricating the blend obtained of step (d) with lubricant and compressing into single layer tablet and optionally coating,
wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

In further embodiment the present invention provides a process for the preparation of a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine, diluents, disintegrant and binder with solvent ,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extragranular rilpivirine hydrochloride, diluents and disintegrant,
(e) lubricating the blend obtained of step (d) with lubricant and compressing into single layer tablet and optionally coating,
wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

In further embodiment the present invention provides a process for the preparation of a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride, comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine, lactose monohydrate, Microcrystalline cellulose, croscarmellose sodium and pregelatinized starch with water,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extragranular rilpivirine hydrochloride, Microcrystalline cellulose and croscarmellose sodium ,
(e) lubricating the blend obtained of step (d) with magnesium stearate and compressing into single layer tablet and optionally coating,
wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable solid oral pharmaceutical composition comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

In another embodiment, the present invention relates to a stable single layer tablet dosage form comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein the single layer tablet of present invention is stable according to USP specification limit for controlling impurities 5-FLUA and MONOESTER on stability in the composition.

The term "Pharmaceutical composition” of present invention can be present in a form of single layered tablet, caplet, mini tablet, tablet in capsule, granules in capsule, pellets, dry powder, pellets.

The term "single layer" according to the invention refers to “the active ingredients and excipients are distributed in one single phase, wherein the active ingredients can not be separated from each other, once mixed and compressed into tablets.

The term "stable" according to the invention refers that the single layer tablet dosage form meets the requirement of USP specification limit for controlling impurities 5-FLUA and MONOESTER under storage condition at 40°C and 75% RH and packed with HDPE bottle and 3 gm silica gel canister for minimum period of three month and/or till shelf life up to 24 months.

The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Throughout this specification and the appended claims it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such as "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

Pharmaceutically acceptable excipients include but not limited to diluents, disintegrants, binder, lubricants, granulating fluids.

A diluent according to present invention include powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate; sugars such as dextrose, lactose anhydrous, lactose monohydrate or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof; most preferably, diluent is lactose monohydrate & microcrystalline cellulose. Pharmaceutical composition comprises diluent in the amount of 1-30% w/w of the total composition.

A disintegrant according to present invention include calcium carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium (croscarmellose sodium), cross-linked carboxymethyl cellulose calcium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, pregelatinized starch; low substituted hydroxypropyl cellulose; and mixtures thereof, more preferably disintegrant is croscarmellose sodium. Pharmaceutical composition comprises disintegrant in the amount of 1– 15% w/w of the total composition.

A binder according to present invention include polyvinyl alcohol, starch, pregelatinized starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof; more preferably binder is pregelatinized starch. Pharmaceutical composition comprises binder in the amount of 0.01-5% w/w of the total composition.

A lubricant according to present invention include talc, metallic stearate such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate or mixtures thereof; more preferably lubricant is magnesium stearate. Pharmaceutical composition comprises lubricant in the amount of 0.1-5% w/w of the total composition.

Suitable granulating fluids include, for example alcohol, water, isopropyl alcohol, ethanol, or mixtures thereof; more preferably granulating fluid is water.

According to aspect of this invention, provided a process for the preparation of a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride, prepared by a process comprising steps of:
(1) Sifting:
(a) Sifting dispensed quantity of pharmaceutically acceptable excipients through S.S sieve of suitable mesh usually between 10-50 mesh preferably between 20-40 mesh on vibratory sifter and collect in suitable container (s).
(b) Sifting dispensed quantity of Tenofovir disoproxil, Emtricitabine through S.S sieve of suitable mesh usually between 10-50 mesh preferably between 20-40 mesh on vibratory sifter and collect in suitable container (s).
(2) Granulation:
(a) Dry mixing: loading of material of step (1) in rapid mixer granulator and mixing dry material.
(b) Binder addition: Adding measured quantity of purified water to obtained dry mixture of step (a) in rapid mixer granulator.
(c) Wet mixing: Mixing the obtained wet material of step (b) in rapid mixer granulator for 3 minutes with defined speed of Impeller and chopper.
(3) Wet milling: Wet milling the obtained mass of Step 2 (a, b, c) using suitable size reduction equipment at known parameters.
(4) Drying: Drying the granules of step (3) in suitable dryer usually fluidized bed dryer at suitable temperature till desire LOD is achieved.
(5) Sizing: Pass the dried granules of Step (f) through suitable instrument usually Quadro Comill fitted screen of suitable mesh size screen usually between 0.1 to 1.5 mm preferably between 0.1 to 0.9 mm.
(6) Blending:
(a) Sifting dispensed quantity of Rilpivirine hydrochloride and pharmaceutically acceptable excipients through S.S sieve of suitable mesh usually between 10-50 mesh preferably between 20-40 mesh on vibratory sifter and collect in suitable container (s).
(b) Blending the obtained materials of step (5) and step 6 (a) in a suitable container for 10 minutes.
(7) Lubrication: lubricating the obtained material of step (6) with sifted pharmaceutically acceptable lubricant usually magnesium stearate and mix further for five minutes.
(8) Compression: Compressing the lubricated blend of step (7) in to tablets.

Tablets of present invention may be coated optionally with suitable coating polymers and/or with other pharmaceutically acceptable coating additives.

The coating additives used to coat the tablets may comprise at least one polymer and/or one plasticizer, a surfactant or/and a colorant.

Accordingly, polymers usable in the film coating are cellulose ethers, particularly, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and mixtures thereof or, alternatively, acrylics, such as methacrylate and methyl methacrylate copolymers or vinyls such as polyvinyl alcohol. Examples of plasticizers usable in the film coating formulation are triethyl citrate, triacetin, propylene glycol, glycerol, macrogol, and mixtures thereof. Examples of colorants usable in the film coating formulation are titanium dioxide, yellow and red iron oxides and the like.

In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims.

EXAMPLE 1:
Composition Mg/tab. %w/w
Intragranular ingredients
Emtricitabine 200.00 22.84
Tenofovir Disoproxil fumarate 300.00 34.27
Lactose monohydrate 80.00 9.14
Microcrystalline cellulose 80.75 9.22
Croscarmellose sodium 28.00 3.20
Pregelatinized starch 34.00 3.88
Purified water# q.s. -
Extragranular ingredients
Croscarmellose sodium 42.00 4.80
Rilpivirine hydrochloride 27.50 3.14
Microcrystalline cellulose 50.25 5.74
Magnesium stearate 7.50 0.86
Total core tablet 850.00 97.09
Film Coating
Opadry purple 25.50 2.91
Total Coated tablet weight 875.50 100.00%

# does not remain in final product except in traces.

Process:
1. Sifting:
(a) Dispensed quantity of lactose monohydrate, microcrystalline cellulose, croscarmellose, pre-gelatinized starch were sifted through 40 mesh S.S sieve on vibratory sifter and collected in a suitable container.
(b) Dispensed quantity of tenofovir disoproxil fumarate and emtricitabine were sifted through 20 mesh S.S sieve on vibratory sifter and collected in a suitable container.
2. Granulation:
(a) Dry mixing: The material of step (1) was loaded in rapid mixer granulator and mixed for 5 minutes.
(b) Binder addition: The rapid mixer granulator was operated with defined speed of impeller and chopper and measured quantity of purified water was added to the dry mixture of step (a) in rapid mixer granulator for three minutes.
(c) Wet mixing: The rapid mixer granulator was operated with impeller and chopper at fast speed and the obtained wet material of step (b) was mixed for one minute.
(3) Wet milling: The obtained mass of step 2 (a, b, c) was wet milled using quadro comill with 6.35 mm S.S screen at 1770 rpm.
(4) Drying: The obtained granules of step (3) were dried in fluidized bed processor at 50°C till desire LOD (1.5-2.0 % w/w) achieved.
(5) Sizing: The dried granules of Step (4) were passed through quadro comill fitted with 0.813 mm (G) S.S screen.
(6) Blending:
(a) Dispensed quantity of rilpivirine, croscarmellose sodium, microcrystalline cellulose and magnesium stearate were sifted through 40 mesh S.S sieve on vibratory sifter and collected in suitable container.
(b)The obtained materials of step (5) and step 6 (a) was blended in a suitable container for 10 minutes.
(7) Lubrication: The obtained material of step (6) was lubricated with magnesium stearate (sifted through a mesh 60 S.S screen) and mixed for five minutes.
(8) Compression: The lubricated blend of step (7) was compressed to obtain tablets.
(9) Coating: The obtained tablets of step (8) were coated with a film coating material

Compositions of Example 1 were packed in HDPE bottle with 3g silica gel canister for 3 month at 40°C/75% RH to determine the comparative chemical stability of single layer tablet formulation made by prior art process disclosed in WO2005021001 and improved process used in present invention (Ex-1) to control the impurity (5-FLUA) of emtricitabine and Monoester impurity of tenofovir disoproxil fumarate on the stability of the product. Results are summarized in Table 2.

Table 2: Stability data of Single layer tablet of compositions of example 1 and composition made by prior-art process disclosed in WO2005021001

Impurities HDPE Bottle with 3g silica gel carnister Pack for 3 Months at 40°C/75% RH
(Formulation made by prior-art process ) HDPE Bottle with 3g silica gel carnister Pack for 3 Months at 40°C/75% RH
(Present invention-Example-1 made by improved process)
5-FLUA
(NMT 1.5%) 2.12 0.14
MONOESTER
(NMT 3.0 %) 5.82 1.04

It was observed that compositions of present invention made by improved process provided excellent stability as compare to prior-art co-formulation process for controlling impurities 5-FLUA and MONOESTER on stability in the composition.
,CLAIMS:We Claim:

1.A stable solid oral pharmaceutical composition comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein Tenofovir disoproxil fumarate and Rilpivirine hydrochloride are not physically separated in composition.

2. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is a single layer tablet.

3. A stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride, prepared by a process comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine and one or more pharmaceutically acceptable excipients with solvent or with a binder solution,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extra granular rilpivirine hydrochloride one or more pharmaceutically acceptable excipients ,
(e) lubricating the blend obtained of step (d) with lubricant and compressing into single layer tablet and optionally coating.

4. A process for the preparation of a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine, diluents, disintegrant and binder with solvent ,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extragranular rilpivirine hydrochloride, diluents and disintegrant,
(e) lubricating the blend obtained of step (d) with lubricant and compressing into single layer tablet and optionally coating.

5. A process for the preparation of a stable solid oral pharmaceutical composition comprising tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride, comprising steps of:
(a) granulating Tenofovir disoproxil fumarate, emtricitabine, lactose monohydrate, Microcrystalline cellulose, croscarmellose sodium and pregelatinized starch with water,
(b) drying the wet granules, and
(c) sieving the dried granules to obtain uniform granules of Tenofovir disoproxil fumarate and emtricitabine
(d) blending the granules of step (c) with extragranular rilpivirine hydrochloride, Microcrystalline cellulose and croscarmellose sodium ,
(e) lubricating the blend obtained of step (d) with magnesium stearate and compressing into single layer tablet and optionally coating.

6. A stable single layer tablet dosage form comprising: a) tenofovir disoproxil fumarate, Emtricitabine and Rilpivirine hydrochloride; b) one or more pharmaceutically acceptable carriers or excipients, wherein the single layer tablet is stable according to USP specification limit for controlling impurities 5-FLUA and MONOESTER on stability in the composition.