A solid pharmaceutical composition comprising dolutegravir

Abstract

The present invention relates to a pharmaceutical composition comprising dolutegravir or a pharmaceutically acceptable salt and sodium stearyl fumarate as a lubricant wherein sodium stearyl fumarate is used in the specific d90 values to obtain an improved powder blend uniformity and tablet compressibility.

Description

[0001]DESCRIPTION A SOLID PHARMACEUTICAL COMPOSITION COMPRISING DOLUTEGRAVIR Field of Invention The present invention relates to a pharmaceutical composition comprising dolutegravir or a pharmaceutically acceptable salt and sodium stearyl fumarate as a lubricant wherein sodium stearyl fumarate is used in the specific d90 values to obtain an improved powder blend uniformity and tablet compressibility. Background of the Invention Human immunodeficiency virus (HIV) is an infection that causes illness on the body’s immune system, specifically the white blood cells called CD4 cells. These CD4 cells are destroyed by HIV, and the immune system is weakened against opportunistic infections, such as tuberculosis and fungal infections, severe bacterial infections and some cancers. Dolutegravir is an orally bioavailable integrase strand-transfer inhibitor (INSTI) and take effect therapeutically against human immunodeficiency virus type 1 (HIV-1) infection. Through oral use, dolutegravir binds to the active site of integrase, an HIV enzyme that catalyzes the transfer of viral genetic material into human chromosomes. This avoids integrase from binding to retroviral deoxyribonucleic acid (DNA), and blocks the strand transfer step, which is required for the HIV replication cycle. This prevents HIV-1 replication. Dolutegravir is approved for use in the majority of HIV-infected patients. It can be used to treat HIV-infected adults who have been never cured with HIV therapy (treatment-naive) and HIV- infected adults who have been previously cured with HIV therapy (treatment-experienced), including those who have been cured with other integrase strand transfer inhibitors. Dolutegravir and its preparation method was described in EP1874117. Dolutegravir has a chemical name as (4R,12aS) - N - (2,4-difluorobenzyl) - 7 – hydroxy – 4 -methyl-6, 8 - dioxo - 3,4,6,8,12,12a – hexahydro - 2H-pyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazine - 9 - carboxamide and its chemical structure is shown below. Dolutegravir has molecular weight of 419.4 g / mol. Dolutegravir Different forms have been observed for Dolutegravir. As reference for Dolutegravir sodium, crystalline form is described in EP3177629 and amorphous form is described in EP2742051. Furthermore, detailed description about various forms of Dolutegravir can be achieved also in EP3337479 patent application. As stated in EP1874117, the present compound can be administered orally or parenterally. In the case of oral use, Dolutegravir or pharmaceutically acceptable salt thereof can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In the case of parenteral use, Dolutegravir or pharmaceutically acceptable salt thereof can be used as an aqueous or oily suspension injectable, or a nasal drop. Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be preferentially used. As an anti-HIV drug, particularly, an oral agent is preferable. A preparation of EP1874117 is prepared by combining (e.g. mixing) a therapeutically effective amount of Dolutegravir or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent. EP1874117 has also stated that a dose of the present invention is different depending on an administration method, an age, a weight and condition of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05mg to 3000mg, preferably about 0.1 mg to 1000 mg may be administered per adult a day, if necessary, by dividing the dose. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05mg to 500mg is administered per adult a day. The brand name of Dolutegravir is Tivicay, which is an anti-retroviral medication used together with other medication, to treat HIV / AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is for oral use. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naive or treatment-experienced but have not previously taken other integrase strand transfer inhibitors. It is indicated in the European Union, in combination with other anti-retroviral medicinal preparations, for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above six years of age. The indication for dolutegravir in the US was updated in June 2020, to include children at least four weeks old and weighing at least 3 kg. In view of the foregoing, there is a need to improve powder flowability and tablet compression in compositions comprising dolutegravir or a pharmaceutically acceptable salt thereof in the state of the art and to produce tablets of a specifically desired quality and dissolution profile. The present invention provides a solution to these problems by providing novel compositions containing dolutegravir or a pharmaceutically acceptable salt thereof. These solutions will be described in detail. Brief Description of The Figures Figure 1: Dissolution Profiles of dolutegravir with low PSD value which is d (90) = 8 µm sodium stearyl Fumarate Figure 2: Dissolution Profiles of dolutegravir with optimal PSD value which is d (90) = 31 µm sodium stearyl Fumarate Summary of the Invention The present invention provides a solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and sodium stearyl fumarate as a lubricant, wherein the particle size distribution of the sodium stearyl fumarate is between 10 µm ≤ d (90) ≤50 µm. More preferably particle size distribution of sodium stearyl fumarate is between 20 µm ≤ d (90) ≤40 µm. The solid pharmaceutical composition for oral administration can be a tablet, a film coated tablet or a capsule. The solid pharmaceutical composition for oral administration can be a film coated tablet. The composition of the present invention comprises below: Table 1: Dolutegravir compositions Ingredients % weight Dolutegravir or its pharmaceutically acceptable salts5.00%-20.00%One or more disintegrants 4.00%-10.00% One or more diluents 35.00%-90.00% One or more binders 3.00%-7.00% Sodium stearyl fumarate 1.00%-2.50% One or more solvents q.s. Total 100.00% A process for preparing solid pharmaceutical composition of the present invention, said process comprises the steps below: a. Sieving dolutegravir or a pharmaceutically acceptable salts, a diluent, a disintegrant, a binder and a diluent, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a granulation solution, preferably purified water as a solvent, thereby forming the intra-granular phase, d. Wet sieving the mixture from step c, e. Drying the granules obtained in step d, f. Sieving the granules obtained in step e, g. Sieving the remaining amount of a disintegrant as a component of extra-granular phase, h. Mixing the sieved a disintegrant with the granules obtained in step f, i. Sieving sodium stearyl fumarate as a component of extra-granular phase, j. Mixing sieved sodium stearyl fumarate with the mix obtained in step h and completing the forming of extra-granular phase and obtaining the final mixture, k. Tablet compression and film coating of the tablet. A solid pharmaceutical composition of the present invention for use in the treatment of Human Immunodeficiency Virus (HIV) infections. Detailed Description of the Invention The aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the dolutegravir or pharmaceutically acceptable salt as defined hereinbefore and hereinafter. As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. 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 Dolutegravir or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable 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. The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, in The D90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips. 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 stearyl fumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred lubricant is sodium stearyl fumarate. Sodium Stearyl Fumarate is odorless, and tasteless powder that is soluble in water and alcohol. The particle size of sodium stearyl fumarate can be 10 µm ≤ d90 ≤50 µm. More specifically it can be 20 µm≤ d90 ≤40 µm. Even more specifically, the particle size herein may be 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, 30 µm, 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm or 40 µm. The inventors have found that the use of sodium stearyl fumarate as a lubricant in compositions containing dolutegravir or a pharmaceutically acceptable salt thereof, wherein the particle size of sodium stearyl fumarate is between 10 µm ≤ d90 ≤50 µm, improves powder blend uniformity and tablet compressibility. The inventors surprisingly have found that the use of sodium stearyl fumarate as a lubricant in compositions comprising dolutegravir or a pharmaceutically acceptable salt thereof, wherein the particle size of sodium stearyl fumarate is between 20 µm ≤ d90 ≤40 µm improves powder blend uniformity, tablet compressibility, dissolution and produces tablets with the desired properties. Disintegrants can also be used in the process. Disintegrants are used for disintegrating tablets into fine particles in gastric and intestinal fluid, so that the other components of the composition can be quickly dissolved and absorbed to have a desired effect. Most of these substances have good water absorption and expansion, so as to achieve the disintegration of tablets. Suitable disintegrants for this inventive formulation can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinized starch, 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 is sodium starch glycolate. Binders can also be used in the process. Binder excipients are formulated to act as an adhesive to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. They can also give volume to low active dose tablets. 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 is povidone (polyvinylpyrrolidone). Solvents can also be used in the process. Solvents are excipients used to enhance solubility, taste, anti-microbial effectiveness or stability, to reduce dose volume (such as oral, injections). Conversely, solvents can be used to optimize insolubility (if taste of an active pharmaceutical ingredient is an issue). Diluents or fillers or bulking agents can also be used in the process. Increases dosage form, volume, or weight of a pharmaceutical product with Spectrum's wide selection of diluent excipients. Because most dosages require only very small quantities of Active Pharmaceutical Ingredients (APIs), diluents often comprise a significant proportion of the dosage form. Suitable diluents according to the present invention are selected from the group including, but are not limited to, lactose, microcrystalline cellulose, starches, calcium phosphates, sucrose, maltodextrin, mannitol, sorbitol, and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred diluents are mannitol, microcrystalline cellulose or mixture thereof. Suitable solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water. In other embodiment the pharmaceutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is film-coated tablet form. Commonly available coating materials may be used for coating of tablets. In another embodiment, a pharmaceutical composition according to invention comprises: Table 2: Dolutegravir compositions Ingredients % weight Dolutegravir or its pharmaceutically acceptable salts5.00%-20.00%One or more disintegrants 4.00%-10.00% One or more diluents 35.00%-90.00% One or more binders 3.00%-7.00% One or more lubricants 1.00%-2.50% One or more solvents q.s. Total 100.00% Preferably, active ingredient in the present invention composition is dolutegravir or pharmaceutically acceptable salts. More preferably is dolutegravir sodium. Preferably lubricant in the present invention composition is sodium stearyl fumarate. The particle size of sodium stearyl fumarate can be 10 µm ≤ d90 ≤50 µm. More specifically it can be 20 µm≤ d90 ≤ 40 µm. In another preferred embodiment, the pharmaceutical composition according to invention: Table 3: Dolutegravir compositions Ingredients % weight Dolutegravir or its pharmaceutically acceptable salts5.00%-20.00%One or more disintegrants 4.00%-10.00% One or more diluents 35.00%-90.00% One or more binders 3.00%-7.00% Sodium stearyl fumarate 1.00%-2.50% One or more solvents q.s. Total 100.00% In other aspect of the invention the pharmaceutical compositions comprising dolutegravir or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, are prepared by a wet granulation process or a dry granulation process. Preferably, the pharmaceutical composition prepared by a wet granulation process. Preferably, the present invention relates to the pharmaceutical compositions comprising Dolutegravir or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has an intra-granular phase and an extra-granular phase. The process of the invention may also comprise the steps below: a. Sieving Dolutegravir or a pharmaceutically acceptable salts, a diluent, a disintegrant, a binder and a diluent, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a granulation solution, preferably purified water as a solvent, thereby forming the intra-granular phase, d. Wet sieving the mixture from step c, e. Drying the granules obtained in step d, f. Sieving the granules obtained in step e, g. Sieving the remaining amount of a disintegrant as a component of extra-granular phase, h. Mixing the sieved a disintegrant with the granules obtained in step f, i. Sieving sodium stearyl fumarate as a component of extra-granular phase, j. Mixing sieved sodium stearyl fumarate with the mix obtained in step h and completing the forming of extra-granular phase and obtaining the final mixture, k. Optionally tablet compression. l. Optionally Film coating of the tablet. In other aspect of present invention, a solid pharmaceutical composition for use in the treatment of Human Immunodeficiency Virus (HIV) infections. In another aspect of an invention pharmaceutical compositions comprising dolutegravir or a pharmaceutically acceptable salts and sodium stearyl fumarate as a lubricant for use in the treatment of HIV (Human Immunodeficiency Virus) infection. In-vitro Tests Dissolution results of dolutegravir compositions comprising low PSD sodium stearyl fumarate which is d (90) = 8 µm and optimal PSD sodium stearyl fumarate which is d (90) = 31 µm were compared. Table 4: Dissolution results of dolutegravir with low PSD value sodium stearyl Fumarate Time (min) Dissolution (%) 0 0 10 45 15 64 20 73 30 80 45 85 60 88 Table 4 shows the dolutegravir compositions comprising sodium stearyl fumarate with low PSD value which is d (90) = 8 µm. As can be seen, the dissolution of dolutegravir in compositions with sodium stearyl fumarate with low PSD values which is d (90) = 8 µm remained below 90% at the end of 1 hour. Table 5: Dissolution results of dolutegravir with optimal PSD value sodium stearyl Fumarate Time (min) Dissolution (%) 0 0 10 51 15 75 20 84 30 89 45 98 60 100 Table 5 shows the dolutegravir compositions comprising sodium stearyl fumarate (SSF) with optimal PSD value which is d (90) = 31 µm. As can be seen, the dissolution of dolutegravir in the compositions with sodium stearyl fumarate with optimal PSD value which is d (90) = 31 µm increased above 95% at 45 minutes and reached 100% by the end of the 1 hour. As can be seen from the above tables, the desired dissolution values could not be achieved with SSF with low PSD which is d (90) = 8 µm. The desired values were obtained with SSF with an optimal PSD value which is d (90) = 31 µm. The above-mentioned dolutegravir compositions and preparation process thereof were developed with sodium stearyl fumarate with particle sizes of 10 µm < (d90) < 50 µm, more specifically 20 µm < (d90) < 40 µm, even more specifically which is d (90) = 31 µm to produce film-coated tablet compositions with the desired dissolution values. As a result of the comparison of the data in table4 and table 5 above, the desired compositions were obtained with SSF with the optimal PSD value which is d (90) = 31 µm.

Claims

CLAIMS 1. A solid pharmaceutical composition comprising dolutegravir or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate as lubricant wherein the particle size distribution of the sodium stearyl fumarate is between 10 µm ≤ d (90) ≤50 µm.

2. The solid pharmaceutical composition according to claim 1, wherein the particle size distribution of the sodium stearyl fumarate is between 20 µm ≤ d (90) ≤40 µm.

3. The solid pharmaceutical composition according to claim 1 or 2, wherein the composition dosage form for oral administration is a tablet, film coated tablet or capsule.

4. The solid pharmaceutical composition according to claim 3, wherein the composition dosage form is film coated tablet.

5. The solid pharmaceutical composition preceding claims, wherein said composition comprises • 5.00%-20.00% by weight Dolutegravir or its pharmaceutically acceptable salts • 4.00%-10.00% by weight One or more disintegrants • 35.00%-90.00% by weight One or more diluents • 3.00%-7.00% by weight One or more binders • 1.00%-2.50% by weight Sodium stearyl fumarate • At least one solvent 6. A process for preparing solid pharmaceutical composition according to any one of preceding claims, comprising the steps of a. Sieving dolutegravir or a pharmaceutically acceptable salts, a diluent, a disintegrant, a binder and a diluent, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a granulation solution, preferably purified water as a solvent, thereby forming the intra-granular phase, d. Wet sieving the mixture from step c, e. Drying the granules obtained in step d, f. Sieving the granules obtained in step e, g. Sieving the remaining amount of a disintegrant as a component of extra-granular phase, h. Mixing the sieved a disintegrant with the granules obtained in step f,i. Sieving sodium stearyl fumarate as a component of extra-granular phase, j. Mixing sieved sodium stearyl fumarate with the mix obtained in step h and completing the forming of extra-granular phase and obtaining the final mixture, k. Tablet compression and film coating of the tablet.

7. A solid pharmaceutical composition according to claims 1 to 5, for use in the treatment of Human Immunodeficiency Virus (HIV) infections.

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