WO2021091498A1

WO2021091498A1 - Pharmaceutical compositions comprising tenofovir and emtricitabine

Info

Publication number: WO2021091498A1
Application number: PCT/TR2019/050926
Authority: WO
Inventors: Abdulhaluk SANCAK; Ayşe Figen ONUK GÖREN; Başak ACAR KARAKÖY; Hakan Gürpinar; Koray YILMAZ; Asiye SEZGİN; Gizem ALKAN
Original assignee: Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Priority date: 2019-11-06
Filing date: 2019-11-06
Publication date: 2021-05-14

Abstract

The present invention relates to the preperation of stable pharmaceutical compositions comprising tenofovir and emtricitabine; and also relevant excipients, having an improved manufacturing process and storage stability by using dry granulation method. Tenofovir Disoproxil Fumarate and Emtricitabine prepare as two different dry granules. The weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w) at total tablet composition.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING TENOFOVIR AND

EMTRICITABINE

Field of invention

The present invention relates to the preparation of pharmaceutical compositions comprising tenofovir and emtricitabine; and also relevant excipients, having an improved manufacturing process and storage stability by using dry granulation method.

Background of the invention

Human immunodeficiency vims (HIV) infection and related diseases are a major public health problem worldwide. Tenofovir and emtricitabine are used for the management of HIV infection.

The use of combinations of compounds can yield an equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy.

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI). In HIV infection, it blocks the activity of reverse transcriptase, an enzyme produced by HIV that allows it to infect cells and make more viruses.

Tenofovir Disoproxil Fumarate is a pro-drug which is a fumaric acid salt form of tenofovir, a nucleoside reverse transcriptase inhibitor analog of adenosine. Tenofovir disoproxil fumarate is a fumarate salt prepared from equimolar amounts of tenofovir disoproxil and fumaric acid. This drug is prescribed in combination with other drugs in the management of HIV infection as well as in Hepatitis B therapy.

Tenofovir Disoproxil Fumarate has a chemical name as [[(2R)-l-(6-aminopurin-9-yl)propan- 2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate; (E)-but-2-enedioic acid and its chemical structure is shown below.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of HIV infection in adults. Emtricitabine is a cytidine analogue. The chemical classification of emtricitabine is Nucleoside Analog. The drug works by inhibiting HIV reverse transcriptase, preventing transcription of HIV RNA to DNA.

Emtricitabine has a chemical name as 4-amino-5-fluoro-l-[(2R,5S)-2-(hydroxymethyl)-l,3- oxathiolan-5-yl]pyrimidin-2-one and its chemical structure is shown below.

Tenofovir Disoproxil Fumarate / Emtricitabine is available in the market as film-coated tablet compositions. It is administered orally in therapeutic dose of 245 mg / 200 mg and is indicated for the treatment of HIV infection in adults.

Tenofovir Disoproxil Fumarate / Emtricitabine is marketed under the trademark Truvada® in 245/200 mg dosage forms by GILEAD. It is used to prevent human immunodeficiency vims (HIV) from multiplying in human body. It is to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). Truvada® includes Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free).

Immediate release tablet of Emtricitabine and Tenofovir disproxil fumarate is formulated and evaluated by using different disintegrants. The main objective of the present study is to formulate and evaluate an immediate release tablet of Emtricitabine and Tenofovir disproxil fumarate using different disintegrants. This study was performed according to (Manikandan M., Kannan K.*, Selvamuthukumar S. and Manavalan R., Composition development and evaluation of Emtricitabine and Tenofovir Disproxil Fumarate Tablets, International Journal of Drug Development & Research. January-March 2012 | Vol. 4 | Issue 1)

EP 1890681 A2 relates to a pharmaceutical preparation of emtricitabine/tenofovir DF is provided by dry granulating a composition comprising a pharmaceutically acceptable excipient, tenofovir DF and emtricitabine.

EP3326619 A1 relates to a pharmaceutical composition comprises tenofovir / emtricitabine active ingredients and excipients that free of starches for treating HIV-1 and hepatitis B. Tablet composition is prepared by wet granulation. WO2015085976A1 relates to stable pharmaceutical composition for preparation of tablets by wet granulation, which comprises tenofovir disoproxil fumarate, or a combination of tenofovir disoproxil fumarate and another active substance, and a disintegrant. Using of a disintegrant from the group including crospovidone, maize starch, and hydroxypropylcellulose instead of sodium salt of Croscarmellose prevents the conversion of tenofovir disoproxil fumarate to tenofovir disoproxil hemifumarate.

WO2019059868A2 relates to an oral pharmaceutical composition comprising tenofovir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof and efavirenz or a pharmaceutically acceptable salt thereof in combination. Process is going on by wet granulation.

Summary of the invention

The present invention relates to preperation of pharmaceutical compositions comprising Tenofovir Disoproxil Fumarate and Emtricitabine in the treatment of HIV infection.

The present invention provides a pharmaceutical composition comprising Tenofovir

Disoproxil Fumarate and Emtricitabine for the treatment of HIV, wherein process including dry granulation method.

Disoproxil Fumarate, Emtricitabine, Croscarmellose Sodium and Magnesium Stearate, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0: 1 (w/w) at total tablet composition.

A synergistic effect is observed over the dissolution profile and bioavailability of the said composition when Croscarmellose sodium and magnesium stearate is used in a specific weight ratio wherein the weight ratio is between 1,2:1 to 2,0:1 (w/w), preferably it is 1,4:1 to 1,8:1 (w/w), more preferably it is 1,5:1 to 1,6:1 (w/w) at the total tablet composition.

Detailed description of the invention

The present invention relates to preperation of pharmaceutical compositions comprising tenofovir disoproxil fumarate and emtricitabine in the treatment HIV infection, the virus that can cause acquired immunodeficiency syndrome (AIDS).

Due to the water used in wet granulation and the temperature factors used in the drying process, the active substances tenofovir and emtricitabine are degraded due to hydrolysis.

The use of organic solvents (isopropyl alcohol, ethanol) in wet granulation increases potential environmental risks and costs in process. Therefore dry granulation method is preferred for the manufacturing method. Main object of the present invention is to provide a stable tablet composition of tenofovir DF and emtricitabine which using dry granulation method.

Instead of the wet granulation process containing water and heat, which is the main reason for the degradation (hydrolysis) of active substances, dry granulation method is used in this process. Dry granulation that is used in this process is faster than wet granulation according to process time.

Another object is to provide improved manufacturing processes which is simple, cost- effective and time saving for preparing the film coated tablet compositions of tenofovir disoproxil fumarate and emtricitabine. Dry granulation method has many advantages over wet granulation in this process. Because of using dry granulation method, it provides a very cost- effective composition in flow chart.

The present invention provides a novel composition of tenofovir disoproxil fumarate and emtricitabine as defined by the claims which overcomes the above described problems in prior art and have additive advantages over them.

A further object is to obtain bioequivalent and stable pharmaceutical composition comprising tenofovir disoproxil fumarate and emtricitabine and excipients during shelf life.

Another object of the present invention is to obtain combination compositions of tenofovir DF and emtricitabine with high stability and bioavalibility.

A further object of the present invention is to develop combination compositions of tenofovir DF and emtricitabine having an improved level of dissolution rate and solubility.

It is found when the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w) at total tablet composition, synergestic effect observed in Dissolution and Bioequivalence study results.

Another object of the present invention is to have two different stages: Dry granule- 1 and Dry granule-2. Tenofovir disoproxil fumarate is added in the stage of Dry granule- 1, and emtricitabine is added in the stage of Dry granule-2. These steps are obtained seperately, then Dry granule- 1 and Dry granule-2 are mixed. The mixing step is followed by the tablet compression, film coating and packaging steps.

The present invention provides a pharmaceutical composition comprising Tenofovir Disoproxil Fumarate, Emtricitabine, Croscarmellose Sodium and Magnesium Stearate for the treatment of HIV infection, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w), preferable between 1,4:1 to 1,8:1 (w/w), more preferable between 1,5:1 to 1,6:1 (w/w). The present invention also provides a tenofovir disoproxil fumarate and emtricitabine pharmaceutical composition comprising; a) tenofovir disoproxil fumarat granule prepared by dry granulation method as dry granule- 1, b) emtricitabine granule prepared by dry granulation method as dry granule-2, c) Croscarmellose sodium and magnesium stearate as excipients, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w), preferably 1,4:1 to 1,8:1 (w/w), more preferably 1,5:1 to 1,6:1 (w/w) at total tablet composition.

In one embodiment, the composition can further comprise at least one pharmaceutically acceptable excipient selected from the group consisting of disintegrants, diluents, binders, lubricants and glidants.

The composition can furher comprise Microcrystalline cellulose and Pregelatinized Starch as a disintegrant and/or binder.

The composition can further comprise Lactose Monohydrate as a diluent.

The composition can further comprise Colloidal Silicon Dioxide and Talc as a glidant.

The composition according to the present invention may be any solid oral dosage forms. The preferred dosage form according to the present invention is tablet, more preferable a film- coated tablet form.

Diluents may be water-soluble or water insoluble. Diluents can be selected from the group, but are not limited to, spray-dried(SD) or anhydrous lactose, lactose monohydrate, sucrose, dextrose, starch, pre-gelatinized starch, mannitol, maltitol, sorbitol, xylitol, dextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulfate, kaolin, precipitated calcium carbonate, maltodextrin and other materials known to one of ordinary skill in the art. The preferred diluents are lactose SD and/or lactose monohydrate and/or microcrystalline cellulose. A mixture of diluents may also be used.

Binders can be selected from the group, but are not limited to, methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, silicified microcrystalline cellulose, polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pre-gelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol, sucralose and other materials known to one of ordinary skill in the art. The preferred binder is pregelatinized starch. A mixture of binders may also be used. Disintegrants can be selected from the group, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethyl cellulose, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, Croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, cross- linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate, crystalline cellulose, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used. The preferred disintegrants are Croscarmellose sodium and lactose monohydrate. A mixture of disintegrants may also be used.

Lubricants can be selected from the group, but are not limited to, vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulphate, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art. The preferred lubricant is magnesium stearate. A mixture of lubricants may also be used.

Glidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. The preferred glidants are colloidal silicon dioxide and talk. A mixture of glidants may also be used.

Fillers can be selected from the group, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, com starch, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol and other materials known to one of ordinary skill in the art. The preferred filler is lactose monohydrate. A mixture of fillers may also be used.

"Film coating agent" can be selected from the group, but are not limited to, hydroxypropyl cellulose, hydroxymethyl cellulose, ethyl cellulose, talc, polyethylene glycol, titanium dioxide, lactose monohydrate, iron oxide yellow, triacetin and other materials known to one of ordinary skill in the art. A mixture of film coating agents may also be used. Dry granule- 1, which comprises tenofovir disoproxil fumarat granule, can be prepared by the steps; a. Sieving Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline cellulose, Lactose Monohydrate, Pregelatinized Starch, Talc and Colloidal Silicon Dioxide, b. Mixing this mixture, c. Sieving Magnesium stearate, d. Mixing this mixture, e. Slugging, f. Sieving all excipients,

Dry granule-2, which comprises emtricitabine granule, can be prepared by the steps; a. Sieving Emtricitabine, Croscarmellose Sodium, Microcrystalline cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide, b. Mixing this mixture, c. Sieving Magnesium stearate, d. Mixing this mixture, e. Slugging, f. Sieving all exipients,

Present invention also provides a process for preparing pharmaceutical compositions according to invention, comprising the steps of; a. Mixing dry granule- 1 and dry granule-2, b. Sieving Magnesium stearate, c. Mixing this mixtures, d. Tablet compression, e. Mixing, f. Film coating, g. Packaging. The present invention provides pharmaceutical compositions comprising tenofovir disoproxil fumarate and emtricitabine and relevant excipients, characterized by i) good stability, ii) to control / program the release of the active ingredient according to desired therapeutical needs, and iii) a simple and competitive manufacturing process.

The choice and function of the excipients in the composition was based on the need for excipients that have the smallest possible impact on the degradation of the drug substance in composition and the physical properties necessary for the manufacturing process.

In one embodiment, the process for preparing the tablet composition of Tenofovir Disoproxil Fumarate and Emtricitabine, can comprise the following steps; (Figure 1)

Dry granule- 1 a. Sieving: Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline cellulose, Lactose Monohydrate, Pregelatinized Starch, Talc and Colloidal Silicon Dioxide, b. Mixing c. Sieving magnesium stearate d. Mixing stage c and stage a components, d. slugging, e. Sieving

Dry granule-2 f. Sieving: Emtricitabine, Croscarmellose Sodium, Microcrystalline cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide, g. Mixing stage f components h. Sieving magnesium stearate i. Mixing stage f and stage h components, j. slugging, k. Sieving l. Mixing with Dry granule- 1 and Dry granule-2. m. Tablet compression n. Film coating o. Packaging

Compositions according to this invention can be used for the treatment of HIV. Present invention also provides a pharmaceutical composition for the treatment of HIV comprises: a. 20 to 40 % by weight of tenofovir disoproxil fumarate, b. 15 to 25 % by weight of emtricitabine, c. 0,5 to 5,0 % by weight of Croscarmellose sodium, d. 20 to 50 % by weight of microcrystalline cellulose, e. 5,0 to 15 % by weight of lactose monohydrate, f. 5,0 to 20 % by weight of pregelatinized starch, g. 0.1 to 1,0 % by weight of colloidal silicon dioxide, h. 0.1 to 10% by weight of talc, i. 0.1 to 5,0% by weight of magnesium stearate.

Table 1: Final composition of tenofovir DF / emtricitabine film coated tablet (245mg/200mg)

Opadry Light Blue Y-30-10671-A

_ _

Dissolution and Bioequivalence Studies

It is used pharmaceutical composition comprising Tenofovir Disoproxil Fumarate and Emtricitabine, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w). Dissolution and Pivotal Bioequivalence study results were satisfy by using in composition the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w). Invitro Studies for final composition

Invitro studies are below for pharmaceutical composition comprising Tenofovir Disoproxil Fumarate and Emtricitabine, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w). Final tablet composition is in Table 1.

Table 2: Comparative dissolution profile of Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablets (0.01 N HC1 medium / pH 4.5 sodium phosphate medium / pH 6.8 phosphate buffer medium) (Tenofovir Disoproxil)

The pharmaceutical composition of this present invention was tested for “Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet [Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND / Manufactured by: Gilead Sciences Inti Ltd.) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002 / Manufactured by: Pharmactive ilaç San. ve Tic. A.§.)]” dissolution rate measured in 900 mF at 50 rpm. Tenofovir Disoproxil dissolution rate of samples were calculated for 10, 15, 20, 30, 45, 60 minute periods in 0.01 N HC1 medium / pH 4.5 sodium phosphate medium / pH 6.8 phosphate buffer medium. (Figure 2, 3, 4)

Table 3: Comparative dissolution profiles of Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablets (0.01 N HC1 medium / pH 4.5 sodium acetate medium / pH 6.8 phosphate buffer medium) (Emtricitabin)

The pharmaceutical composition of this present invention was tested for “Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet [Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND / Manufactured by: Gilead Sciences Inti Ftd.) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002 / Manufactured by: Pharmactive Ilaç San. ve Tic. A.§.)]” dissolution rate measured in 900 mL at 50 rpm. Emtricitabin dissolution rate of samples were calculated for 10, 15, 20, 30, 45, 60 minute periods in 0.01 N HC1 medium / pH 4.5 sodium acetate medium / pH 6.8 phosphate buffer medium. (Figure 5, 6, 7)

Bioequivalence Studies (Pharmacokinetic)

Bioequivalence data for composition comprising Tenofovir and emtricitabine wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w), against the commercially available tablets "Truvada" is shown below in Tables 4, 5 and Figure 8-9.

We have found that pharmaceutical composition comprising active agent(s) Tenofovir and emtricitabine exhibits bioequivalence to the commercially available film coated tablet, Truvada; when administered to human subject, under the bioequivalence parameters of: (a) a 90% Confidence Interval (Cl) for AUC which is between 80% and 125%, and (b) a 90% Confidence Interval for Cmax, which is between 80% and 125%. Table 4: Pharmacokinetic results of Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Emtricitabin)

Table 5: Pharmacokinetic results of Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Tenofovir)

Brief description of the drawing:

Figure 1: Flowchart for pharmaceutical composition comprising Tenofovir DF / Emtricitabine film coated tablet

Figure 2: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: 0.01 N HC1, 900 mL, Rate: 50 rpm) (Tenofovir Disoproxil)

Figure 3: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: pH 4.5 Sodium Acetate buffer, 900 mL, Rate: 50 rpm) (Tenofovir Disoproxil)

Figure 4: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: pH 6.8 Phosphate buffer, 900 mL, Rate: 50 rpm) (Tenofovir Disoproxil)

Figure 5: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: 0.01 N HC1, 900 mL, Rate: 50 rpm) (Emtricitabin)

Figure 6: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: pH 4.5 Sodium Acetate buffer, 900 mL, Rate: 50 rpm) (Emtricitabin)

Figure 7: Comparative dissolution profile of Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND) and Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet (Batch No: 7423001, 7423002) (Dissolution Medium: pH 6.8 Phosphate buffer, 900 mL, Rate: 50 rpm) (Emtricitabin)

Figure 8: Average plasma concentration of emtricitabin Figure 9: Average plasma concentration of tenofovir

Claims

1. A tenofovir disoproxil fumarate and emtricitabine pharmaceutical composition comprising; a) tenofovir disoproxil fumarat granule prepared by dry granulation method as dry granule- 1, b) emtricitabine granule prepared by dry granulation method as dry granule-2, c) Croscarmellose sodium and magnesium stearate as excipients, wherein the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,2:1 to 2,0:1 (w/w) at total tablet composition.

2. A pharmaceutical composition according to claim 1, the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,4:1 to 1,8:1 (w/w).

3. A pharmaceutical composition according to claim 1, the weight ratio of Croscarmellose sodium and magnesium sterarate is between 1,5:1 to 1,6:1 (w/w).

4. A pharmaceutical composition according to claim 1 or 5, further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of disintegrants, diluents, binders, lubricants and glidants.

5. A pharmaceutical composition according to any preceding claims, wherein the composition comprises Microcrystalline cellulose and Pregelatinized Starch as disintegrant and/or binder.

6. A pharmaceutical composition according to any preceding claims, wherein the composition comprises Lactose Monohydrate as the diluent.

7. A pharmaceutical composition according to any preceding claims, wherein the composition comprises Colloidal Silicon Dioxide and Talc as the glidant.

8. A pharmaceutical composition according to claim 1, wherein the composition is a film coated tablet composition.

9. A pharmaceutical composition according to any preceding claims, wherein dry granule- 1 is prepared by the steps; a. Sieving Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline cellulose, Lactose Monohydrate, Pregelatinized Starch, Talc and Colloidal Silicon Dioxide, b. Mixing this mixture, c. Sieving Magnesium stearate, d. Mixing this mixture, e. Slugging, f. Sieving all excipients,

10. A pharmaceutical composition according to any preceding claims, wherein dry granule-2 is prepared by the steps; a. Sieving Emtricitabine, Croscarmellose Sodium, Microcrystalline cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide, b. Mixing this mixture, c. Sieving Magnesium stearate, d. Mixing this mixture, e. Slugging, f. Sieving all exipients,

11. A process for preparing a pharmaceutical composition according to any preceding claims, comprising the steps of; a. Mixing dry granule- 1 and dry granule-2, b. Sieving Magnesium stearate, c. Mixing this mixtures, d. Tablet compression, e. Mixing, f. Film coating, g. Packaging.

12. A pharmaceutical composition for the treatment of HIV according to any preceding claims; j. 20 to 40 % by weight of tenofovir disoproxil fumarate, k. 15 to 25 % by weight of emtricitabine, l. 0,5 to 5,0 % by weight of Croscarmellose sodium, m.20 to 50 % by weight of microcrystalline cellulose, n. 5,0 to 15 % by weight of lactose monohydrate, o. 5,0 to 20 % by weight of pregelatinized starch, p. 0.1 to 1,0 % by weight of colloidal silicon dioxide, q. 0.1 to 10% by weight of talc, r. 0.1 to 5,0% by weight of magnesium stearate.