Pharmaceutical composition of tenofovir alafenamide monofumarate with improved impurity

Abstract

The present invention relates to a dry granulation process for preparing a solid pharmaceutical composition comprising Tenofovir alafenamide or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, and its use in the treatment of for the treatment of chronic hepatitis B (CHB). The pharmaceutical composition comprises at least a disintegrant as pharmaceutical acceptable excipient for increasing the stability of the Tenofovir alafenamide and tablet coating material comprising hypromellose and hydroxypropyl cellulose, thus surprisingly improved impurity values and also improved dissolution profile has been obtained.

Description

[0001] PHARMACEUTICAL COMPOSITION OF TENOFOVIR ALAFENAMIDE MONOFUMARATE WITH IMPROVED IMPURITY

[0002] Field of the Invention

[0003] The present invention relates to a dry granulation process for preparing a solid pharmaceutical composition comprising Tenofovir alafenamide or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, and its use in the treatment of for the treatment of chronic hepatitis B (CHB). The pharmaceutical composition comprises at least a disintegrant as pharmaceutical acceptable excipient for increasing the stability of the Tenofovir alafenamide and tablet coating material comprising hypromellose and hydroxypropyl cellulose, thus surprisingly improved impurity values and also improved dissolution profile has been obtained.

[0004] Background of the Invention

[0005] Hepatitis B is an infection of the liver caused by the hepatitis B virus. The infection can be acute (short and severe) or chronic (long term).

[0006] Tenofovir alafenamide (TAF) is indicated for adult patients with chronic hepatitis B virus (HBV) infection with compensated liver disease at an oral dose of 25 mg / day.

[0007] TAF is a more stable prodrug in the plasma than tenofovir disoproxil fumarate (TDF), leading to decreased plasma exposure of tenofovir.

[0008] Tenofovir alafenamide, sold under the brand name Vemlidy, is a hepatitis B virus (HBV) nucleotide reverse transcriptase inhibitor medication for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease. According to Gilead documents, hemifumarate form is used in Vemlidy product.

[0009] Tenofovir alafenamide is a prodrug of tenofovir. It was developed by Gilead Sciences for use in the treatment of HIV / AIDS and chronic hepatitis B, and is applied in the form of tenofovir alafenamide fumarate (TAF). Closely related to the commonly used reverse-transcriptase inhibitor tenofovir disoproxil fumarate (TDF), TAF has greater antiviral activity and better distribution into lymphoid tissues than that agent.

[0010] Scheme 1. Tenofovir alafenamide Scheme 2. Tenofovir alafenamide monofumarate

[0011] Tenofovir alafenamide has a chemical name as propan-2-yl (25)-2-[[[(2J?)-l-(6-aminopurin-9- yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate and its chemical structure is shown in the Scheme 1.

[0012] Tenofovir alafenamide monofumarate has a chemical name as (E)-but-2-enedioic acid; propan -2-yl (25)-2-[[[(27?)- 1 -(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl] amino

[0013] ] propanoate and its chemical structure is shown in the Scheme 2.

[0014] Scheme 3. Tenofovir alafenamide hemifumarate

[0015] Tenofovir alafenamide hemifumarate has a chemical name as propan-2-yl N-[(S)-({[(2R)-l-(6 -amino-9H-purin-9-yl)propan-2-yl]-oxy}methyl)(phenoxy)phosphoryl]-l-alaninate, (2E)-but-2 -enedioate and its chemical structure is shown in the Scheme 3. Besides providing important contributions of Vemlidy as a medicament for the treatment of chronic hepatitis B virus (HBV) infection, there is a requirement to develop a simple, reproducible and cost-effective manufacturing process and a stable pharmaceutical composition comprising Tenofovir alafenamide with an improved flowability, content uniformity and processability, while at the same time ensuring that the desired properties such as impurity, dissolution, stability, bioavailability are maintained and are comparable with respect to the Reference Product Vemlidy. Film coating is a modern and widely spread process for coating oral solid products in the pharmaceutical. The process of film coating involves the spraying of a thin, but uniform polymer-based formulations onto the surface of solids including tablets and the others.

[0016] Film coating material can use in pharmceutical products for aesthetical, protectional and functional purpose. The film coating process can increase the shelf life of tablets and improve the appearance and identification of the product, as well as improve tablet strength and mask tastes and odors associated with the API.

[0017] Typical coating formula may include pharmaceutical polymer, plasticizer, polyhydric alcohols (such as propylene glycol or polyethylene glycol (PEG) or glycerol), colorants and pigments, glidants, flavors, viscosity modifiers.

[0018] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0019] The pharmaceutical composition may include active ingredient, and also relevant excipients, wherein the excipients are selected from the group including such as solvents, diluents, lubricants, fillers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof.

[0020] Summary of the Invention

[0021] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises at least a disintegrant as pharmaceutical acceptable excipient and tablet coating material comprising hypromellose and hydroxypropyl cellulose for increasing the stability of the final product.

[0022] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises low moisture pregelatinized maize starch as disintegrant in intragranular phase and tablet coating material comprising hypromellose and hydroxypropyl cellulose as for increasing the stability of the final product.

[0023] The present invention relates to a pharmaceutical composition comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein low moisture pregelatinized maize starch as disintegrant and tablet coating material are used. The present invention relates to a pharmaceutical composition comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein low moisture pregelatinized maize starch as disintegrant and tablet coating material comprising hypromellose and hydroxypropyl cellulose are used.

[0024] For preparing the film coated tablet compositions of this invention, an improved process by dry granulation method have been used. The inventive composition comprises at least a disintegrant in intragranular phase for increasing the stability of the Tenofovir alafenamide monofumarate and tablet coating material comprising hypromellose and hydroxypropyl cellulose, thus surprisingly improved impurity values and also improved dissolution profile has been obtained.

[0025] Detailed Description of the Invention

[0026] The present invention provides a pharmaceutical composition comprising tenofovir alafenamide or pharmaceutically acceptable salts or esters thereof, for the the treatment of Hepatit B, wherein process including dry granulation method.

[0027] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises low moisture pregelatinized maize starch as disintegrant in intragranular phase and tablet coating material comprising hypromellose and hydroxypropyl cellulose as.

[0028] According to this invention, tenofovir alafenamide can be used as fumarate form, chemical name is 9-[(R)-2-[[(S)-[[(S)-l-5 (isopropoxycarbonyl) ethyl]arruno] phenoxyphosphinyl] methoxy] propyl] adenine fumarate (1 : 1), also it is called GS-7340-2.

[0029] The present invention relates to tenofovir alafenamide monofumarate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 5.3, about 9.8, about 10.4, about 15.9 and about 16.6.

[0030] One embodiment for tenofovir alafenamide monofumarate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of 5.28, 9.77, 10.35, 15.83 and 16.60.

[0031] One embodiment for tenofovir alafenamide monofumarate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of 5.29, 9.75, 10.37 and 10.38, 15.84 and 16.60.

[0032] One embodiment for tenofovir alafenamide monofumarate exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of 5.28, 9.77, 10.38, 15.88 and 16.61. The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises a disintegrant and film coating materials.

[0033] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises a disintegrant such as Starch 1500 and film coating materials.

[0034] Disintegrants can be used in the manufacturing process for pharmaceutical products. Disintegrants are used to promote the break-up of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the drug substance.

[0035] In this invention, it is obtained pharmaceutical compositions comprising tenofovir alafenamide, wherein the composition comprises a low moisture pregelatinized maize starch as a disintegrant.

[0036] In this invention, it is obtained pharmaceutical compositions comprising tenofovir alafenamide, wherein the composition comprises a low moisture pregelatinized maize starch as a disintegrant such as Starch 1500.

[0037] Starch 1500 is a commercial product and it can be called “Starch 1500 LM Partially Pregelatinized Maize Starch (Low Moisture)”

[0038] In this invention, low moisture pregelatinized maize starch used in the formula helps to stabilise the active substance and due to its moisture-attracting properties, slows down the impurity and thus the rate of degradation.

[0039] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises low moisture pregelatinized maize starch as disintegrant such as Starch 1500 LM and film coating materials.

[0040] The present invention relates to the preparation of pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, wherein the composition comprises low moisture pregelatinized maize starch as disintegrant such as Starch 1500 LM in intragranular phase and film coating materials.

[0041] One of the critical point for this invetion is film coating material. There are many kinds of coating material can be used for pharmaceutical tablet compositions. Three types of materials are used in our studies; PVA coating (is used in reference product - Vemlidy), water- based / moisture barrier AMB coating and (alcohol based) hypromellose, hydroxypropyl cellulose coating.

[0042] PVA coating is used in reference product. In one embodiment, ingredients of this coating material; polyvinyl alcohol, talc, polyethylene glycol / macrogol, titanium dioxide and colorant. It is a commercial product and it can be named as Opadry II Complete Film Coating System.

[0043] In one embodiment, ingredients of water-based / moisture barrier coating are polyvinyl alcohol, talc, glyceryl mono and di capryl ocaprate and sodium lauryl sulfate. It is a commercial product and it can be named as Opadry AMB II High Performance Moisture Barrier Film Coating.

[0044] In one embodiment, tablet coating material comprising hypromellose and hydroxypropyl cellulose is used in our tablet compositions.

[0045] In one embodiment, ingredients of tablet coating material comprising hypromellose and hydroxypropyl cellulose, further there may be other ingredients such as talc, titanium dioxide and colorants in this coating. There is a commercial product and named as Opadry Complete Film Coating System.

[0046] Granulation is an effective way to form granular materials from a powdered or solid substance. Generally, there are two types of granulation methods: dry granulation and wet granulation.

[0047] As the name implies, dry granulation is a process performed without adding any liquids. This method is done for ingredients that are sensitive to moisture and heat. Since no liquid binder is used, the process won't change the chemical composition. So, the dry granulation method is the preferred option for compacting chemical raw materials into granules.

[0048] In this invention, dry granulation is used for manufacturing method.

[0049] The present invention relates to a dry granulation process for preparing a pharmaceutical composition comprising Tenofovir alafenamide or pharmaceutically acceptable salts thereof, and also relevant excipients, for use in the treatment of chronic hepatitis B virus (HBV) infection.

[0050] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. Preferably, the present invention relates to the pharmaceutical composition comprising Tenofovir alafenamide monofumarate, and also relevant excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fillers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof.

[0051] In this invention, low moisture pregelatinized maize starch as disintegrant can be used in the process to help to stabilise the active substance and due to its moisture-attracting properties, slows down the impurity and thus the rate of degradation.

[0052] Suitable disintegrants for this inventive formulation can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, pregelatinized maize starch, low moisture pregelatinized maize starch cross-linked polyvinylpyrrolidones, sodium alginate, 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 disintegrant in this invention is low moisture pregelatinized maize starch as a disintegrant such as Starch 1500 and also croscarmellose sodium.

[0053] Suitable binders according to the present invention are selected from the group including, but are not limited to, microcrystalline cellulose, starches, lactose, sugar alcohols like mannitol, polymers like polyvinylpyrrolidone, polyethylene glycol, isomalt, hypromellose (hydroxypropyl methylcellulose) and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred binder for the inventive composition is low moisture pregelatinized maize starch, which is also used as disintegrant in this inventive pharmaceutical composition.

[0054] Suitable lubricants according to the present invention are selected from a group including, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred lubricant is magnesium stearate.

[0055] Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, lactose, lactose monohydrate, lactose anhydrous, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. The preferred fillers for this invention are lactose anhydrous and Avicel PH / microcrystalline cellulose.

[0056] The present invention relates to the preparation of pharmaceutical composition comprising Tenofovir alafenamide monofumarate, and one or more pharmaceutically acceptable excipients, wherein preferably low moisture pregelatinized maize starch and also croscarmellose sodium are used as disintegrant, magnesium stearate can be used as lubricant, lactose anhydrous and Avicel PH / microcrystalline cellulose are used as filler.

[0057] Preferably, the present invention relates to the pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase, prepared by a dry granulation process.

[0058] Preferably, the pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein Tenofovir alafenamide monofumarate as active ingredient, fillers, a certain amount of lubricant, binder if any and some of disintegrants are in the intra-granular phase.

[0059] Preferably, the pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein Tenofovir alafenamide monofumarate as active ingredient, fillers, a certain amount of lubricant, binder if any and low moisture pregelatinized maize starch as disintegrant are in the intra-granular phase.

[0060] Preferably, the pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein Tenofovir alafenamide monofumarate as active ingredient, Lactose anhydrous and MCC as filler, a certain amount of lubricant such as Magnesium stearate and low moisture pregelatinized maize starch as a disintegrant are in the intra-granular phase.

[0061] Preferably, the pharmaceutical compositions comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, wherein remaining amount of lubricant and disintegrants are in the extra-granular phase.

[0062] An aim of the present invention to solve the problems of the prior art and is to provide an improved pharmaceutical composition comprising Tenofovir alafenamide or pharmaceutically acceptable salts thereof, obtaining concurrently comparable and satisfactory impurity and stability values and dissolution rates. Surprisingly, it is found that improved impurity values and an appropriate dissolution profile can be obtained, when low moisture pregelatinized maize starch is used as disintegrant in the intragranular phase, absorbing the moisture and improving the stability of the active ingredient.

[0063] Additionally in case using tablet coating material comprising hypromellose and hydroxypropyl cellulose, it has been observed that the impurity values to be even better.

[0064] The present invention introduces a solid pharmaceutical composition comprising Tenofovir alafenamide monofumarate, wherein the composition comprises at least one disintegrant such as low moisture pregelatinized maize for increasing the stability of the Tenofovir alafenamide monofumarate and also tablet coating material comprising hypromellose and hydroxypropyl cellulose, thus surprisingly improved impurity values and also improved dissolution profile has been obtained.

[0065] The pharmaceutical composition according to the present invention has suitable physical and chemical properties with the active ingredient and also with excipients present in the composition. According to these properties, the composition is stable and reproducible as a result, without any unwanted interaction with the active ingredient, and it provides the requirements for desired functionality and cost effective preparation, as well as improved dissolution profile.

[0066] The embodiment examples for inventive pharmaceutical film-coated tablet composition are given as detailed in Table 1 and Table 2 below. These examples are not limiting the scope of the present invention and is to be considered according to the foregoing detailed description. Any other modifications of the composition or production methods are possible if they are implemented in line with maintaining the stability of the composition and the dissolution profile of the active substance.

[0067] Example 1 is related to the case of using low moisture pregelatinized maize as disintegrant and Example 2 is related to the case of without using low moisture pregelatinized maize. The process flows related to the Examples are also given below each table.

[0068] Example 1 is related to the case of using low moisture pregelatinized maize starch as disintegrant. The process flows related to the Examples are also given below each table. Example 1

[0069] Table 1: Composition of Tenofovir alafenamide monofumarate (200 mg) - Film Coated Tablet (Using Low moisture pregelatinized maize) Process flow for Preparing of Example 1 is summarized as below: a) Sieving Tenofovir alafenamide monofumarate, lactose anhydrous, MCC, croscarmellose sodium ve low moisture pregelatinized maize, b) Mixing the substances from step a at a certain speed in a specific time interval, c) Sieving magnesium stearate, adding to the mix from step b and mixing at a certain speed in a specific time interval, d) Compaction the mix from step c, e) Sieving the compact substance from step d and keeping mixing at a certain speed in a specific time interval, f) Sieving croscarmellose sodium, adding it to the mix from step e to prepare the extragranular phase and mixing at a certain speed in a specific time interval, g) Sieving magnesium stearatethe dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h and mixing at a certain speed in a specific time interval to prepare a homogenous final mix, j) Tablet compressing and film coating, k) Bottle filling and packaging.

[0070] Example 2 is related to the case of without low moisture pregelatinized maize. The process flows related to the Examples are also given below each table.

[0071] Example 2

[0072] Table 2: Composition of Tenofovir alafenamide monofumarate (200 mg) - Film Coated Tablet

[0073] (Without Low moisture pregelatinized maize) Process flow for Preparing of Example 2 is summarized as below: a) Sieving Tenofovir alafenamide monofumarate, lactose anhydrous, MCC, and croscarmellose sodium, b) Mixing the substances from “step a” at a certain speed in a specific time interval, c) Sieving croscarmellose sodium, adding it to the mix from “step b” to prepare the extragranular phase and mixing at a certain speed in a specific time interval, d) Sieving magnesium stearate, adding to the mix from “step c” and mixing at a certain speed in a specific time interval, e) Compaction the mix from step d, f) Sieving the compact substance from “step e” and keeping mixing at a certain speed in a specific time interval, g) film coating, h) Bottle filling and packaging.

[0074] Impurity Test Values

[0075] Impurity Test Values without low moisture pregelatinized maize as a disintegrant

[0076] Table 3: Impurity Test Values for tenofovir alafenamide monofumarate composition used water-based / moisture barrier coating material without low moisture pregelatinized maize as disintegration agent. (lstmonth - 2ndmonth - 3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH)

[0077] The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 3)

[0078] Third month impurity value for tenofovir alafenamide monofumarate composition used water- based / moisture barrier coating material without low moisture pregelatinized maize as disintegration agent is %1.05 at 40 °C. Table 4: Impurity Test Values for tenofovir alafenamide monofumarate composition used PVA coating material without low moisture pregelatinized maize as disintegration agent. (lstmonth - 2ndmonth - 3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH) The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 4)

[0079] Third month impurity value for tenofovir alafenamide monofumarate composition used PVA coating material without low moisture pregelatinized maize as disintegration agent is %1.20 at 40 °C.

[0080] Table 5 : Impurity Test Values for tenofovir alafenamide monofumarate composition with tablet coating material comprising hypromellose and hydroxypropyl cellulose material without low moisture pregelatinized maize as disintegration agent. (lstmonth - 2ndmonth - 3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH)

[0081] The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 5) Third month impurity value for tenofovir alafenamide monofumarate composition with tablet coating material comprising hypromellose and hydroxypropyl cellulose material without low moisture pregelatinized maize as a disintegration agent is %0.60 at 40 °C.

[0082] Table 6: Impurity Test Values for tenofovir alafenamide monofumarate composition used water-based / moisture barrier coating material, PVA coating and also tablet coating material comprising hypromellose and hydroxypropyl cellulose without low moisture pregelatinized maize starch as a disintegration agent. (3rdweek, 55°C ± 2°C / %85 RH ± %5 RH)

[0083] The inventors found during drug development that the pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in third week at 55°C. (Table 6)

[0084] In addition, the above-mentioned problems cannot be effectively solved by the conventional methods of controlling the temperature, pH value, co-solvent, preparation time and other factors in the process steps.

[0085] In particular, the content of the total impurities of tenofovir alafenamide monofumarate in the pharmaceutical composition can be unexpectedly controlled. If we compared to three different coating, it can be seen that hypromellose, hydroxypropyl cellulose can reduce impurity values. Impurity Test Values with low moisture pregelatinized maize starch as a disintegrant

[0086] Table 7: Impurity Test Values for tenofovir alafenamide monofumarate composition used water-based / moisture barrier coating material with low moisture pregelatinized maize starch as disintegration agent. (lstmonth - 2ndmonth - S^month, 40°C ± 2°C / %75 RH ± %5 RH)

[0087] The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 7)

[0088] Impurity values for Tenofovir alafenamide monofumarate composition used water- based / moisture barrier coating material with low moisture pregelatinized maize starch as disintegration agent in intragranular phase are given in table 7.

[0089] Third month impurity value for tenofovir alafenamide monofumarate composition used water- based / moisture barrier coating material with low moisture pregelatinized maize starch as disintegration agent is %1.25 at 40 °C. Table 8: Impurity Test Values for tenofovir alafenamide monofumarate composition used PVA coating material with low moisture pregelatinized maize starch as disintegration agent.

[0090] (lstmonth - 2ndmonth - 3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH) The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 8)

[0091] Impurity values for Tenofovir alafenamide monofumarate composition used PVA coating material with low moisture pregelatinized maize starch as disintegration agent in intragranular phase are given in table 8.

[0092] Third month impurity value for tenofovir alafenamide monofumarate composition used PVA coating material with low moisture pregelatinized maize starch as disintegration agent is %1.40 at 40 °C.

[0093] Table 9: Impurity Test Values for tenofovir alafenamide monofumarate composition used tablet coating material comprising hypromellose and hydroxypropyl cellulose with low moisture pregelatinized maize starch as a disintegration agent. (1stmonth - 2ndmonth - 3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH)

[0094] The pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in first-second-third months at 40°C. (Table 9)

[0095] Impurity values for Tenofovir alafenamide monofumarate composition used tablet coating material comprising hypromellose and hydroxypropyl cellulose with low moisture pregelatinized maize starch as disintegration agent in intragranular phase are given in table 9.

[0096] Third month impurity value for tenofovir alafenamide monofumarate composition used tablet coating material comprising hypromellose and hydroxypropyl cellulose with low moisture pregelatinized maize starch as a disintegration agent is %0.64 at 40 °C. Table 10: Impurity Test Values for tenofovir alafenamide monofumarate composition used water-based / moisture barrier, PVA coating material and also tablet coating material comprising hypromellose and hydroxypropyl cellulose with low moisture pregelatinized maize starch as a disintegration agent. (3rdmonth, 40°C ± 2°C / %75 RH ± %5 RH)

[0097] The pharmaceutical compositions containing the active ingredient of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in third month at 40°C. (Table 10)

[0098] Impurity values for Tenofovir alafenamide monofumarate composition used low moisture pregelatinized maize starch as disintegration agent in intragranular phase are given in table 10.

[0099] In particular, the content of the total impurities of tenofovir alafenamide monofumarate in the pharmaceutical composition can be unexpectedly controlled. If we compared to three different coating, it can be seen that tablet coating material comprising hypromellose and hydroxypropyl cellulose can reduce impurity values.

[0100] Table 10 provides additional support that composition comprising tenofovir alafenamide monofumarate with tablet coating material comprising hypromellose and hydroxypropyl cellulose is more stable than other compositions with different coating, as evidenced by the low levels of impurity. Table 11 : Impurity Test Values for tenofovir alafenamide monofumarate composition used water-based / moisture barrier, PVA coating material and tablet coating material comprising hypromellose and hydroxypropyl cellulose as disintegration agent. (3rdweek, 55°C ± 2°C / %85 RH ± %5 RH)

[0101] The inventors found during drug development that the pharmaceutical compositions containing the active ingredients of tenofovir alafenamide monofumarate has impurities: impurity 1, impurity 2, impurity 3, isomer 6&1, each other impurity and total impurity in third week at 55°C. (Table 11)

[0102] Impurity values for Tenofovir alafenamide monofumarate composition used low moisture pregelatinized maize starch as disintegration agent in intragranular phase are given in table 11.

[0103] In addition, the above-mentioned problems cannot be effectively solved by the conventional methods of controlling the temperature, pH value, co-solvent, preparation time and other factors in the process steps.

[0104] In particular, the content of the total impurities of tenofovir alafenamide monofumarate in the pharmaceutical composition can be unexpectedly controlled. If we compared to three different coating, it can be seen that tablet coating material comprising hypromellose and hydroxypropyl cellulose can reduce impurity values.

Claims

CLAIMS1. A pharmaceutical composition comprising Tenofovir alafenamide monofumarate, and at lease one pharmaceutically acceptable excipients, characterized in comprising low moisture pregelatinized maize starch as disintegrant in intragranular phase and tablet coating material comprising hypromellose and hydroxypropyl cellulose.

2. A pharmaceutical composition according to Claim 1, characterized in further comprising croscarmellose sodium as disintegrant.

3. A pharmaceutical composition according to any one of the preceeding claims, characterized in further comprising lactose anhydrous and microcrystalline cellulose as filler.

4. A pharmaceutical composition according to any one of the preceeding claims, characterized in further comprising magnesium stearate as lubricant.

5. A pharmaceutical composition according to any one of the preceeding claims, wherein ttablet coating material comprises hypromellose, hydroxypropyl cellulose, talc, titnium dioxide and colorants.

6. Process for manufacturing of pharmaceutical composition of Claim 1 characterized in comprising steps of: a) Sieving Tenofovir alafenamide monofumarate, lactose anhydrous, MCC, croscarmellose sodium ve low moisture pregelatinized maize starch, b) Mixing the substances from step a at a certain speed in a specific time interval, c) Sieving magnesium stearate, adding to the mix from step b and mixing at a certain speed in a specific time interval, d) Compaction the mix from step c, e) Sieving the compact substance from step d and keeping mixing at a certain speed in a specific time interval, f) Sieving croscarmellose sodium, adding it to the mix from step e to prepare the extragranular phase and mixing at a certain speed in a specific time interval, g) Sieving magnesium stearatethe dried granules from step f, h) Sieving the colloidal anhydrous silica and mixing it with granules from step g homogenously, i) Sieving the magnesium stearate and adding it to the mix from step h and mixing at a certain speed in a specific time interval to prepare a homogenous final mix,j) Tablet compressing and film coating, k) Bottle filling and packaging.

7. A pharmaceutical composition according to any one of Claims 1-5, for use in the treatment of chronic hepatitis B virus (HBV) infection.

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