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

SOLID DRUG COMPOSITION CONTAINING DOLUTEGRAVIR Technical Area The present invention uses dolutegravir or a pharmaceutically acceptable salt and lubricant. It relates to a pharmaceutical composition containing sodium stearyl fumarate; where sodium stearyl Fumarate is used to improve the homogeneity of the powder mixture and the compressibility of the tablet. It is used at specific d90 values. Previous Technique Human immunodeficiency virus (HIV) attacks the body's immune system, particularly CD4 cells. It is a virus that causes disease in white blood cells called CD4 cells. HIV It is destroyed by the immune system, and tuberculosis and fungal infections are severe. They become susceptible to opportunistic infections such as bacterial infections and some cancers. Dolutegravir is an integrase chain transfer inhibitor (INSTI) with oral bioavailability. It has a therapeutic effect against human immunodeficiency virus type 1 (HIV-1) infection. When taken orally, dolutegravir binds viral genetic material to human chromosomes. It binds to the active site of integrase, an HIV enzyme that catalyzes its transfer. This, It prevents integrase from binding to retroviral deoxyribonucleic acid (DNA) and HIV replication. It blocks the chain transfer step, which is necessary for the cycle. Thus, HIV-1 replication is prevented. It is prevented. Dolutegravir is approved for use in most patients infected with HIV. This drug is more HIV-infected individuals who have never received any HIV treatment before (and are new to treatment) In addition to adults, HIV-positive individuals who have previously received HIV treatment (treatment experience) It can be used in the treatment of infected adults; this includes other integrase chain transfer This includes those who have been treated with inhibitors. Dolutegravir and its preparation method are described in document EP1874117. Dolutegravir's... chemical name (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, chemically Its structure is shown below. Dolutegravirin has a molecular weight of 419.4 g / mol. Dolutegravir 1 Different forms of dolutegravir have been observed. For dolutegravir sodium, the reference form is: The crystalline form is described in document EP3177629, and the amorphous form in document EP2742051. This is explained. In addition, detailed descriptions of the various forms of Dolutegravir are provided. EP3337479 could also be filed as a patent application. As stated in document EP1874117, the present compound is administered orally or parenterally. It is applicable. For oral use, Dolutegravir or its pharmaceutically accepted equivalent. any form of readily available salt, for example, in tablets, powders, granules, capsules and similar solid agents. a dosage form; an aqueous agent; an oily suspension; or a liquid agent such as syrup It can also be used as a traditional preparation. In the case of parenteral use, Dolutegravir or its pharmaceutically acceptable salt, in an injectable aqueous or oily form It can be used as a suspension or nasal drops. During preparation, traditional methods are used. Excipients, binders, lubricants, aqueous solvents, oily solvents, Emulsifiers, suspending agents, preservatives, stabilizers, and similar additives may be used. As an anti-HIV drug, an oral agent is particularly preferred. A preparation according to EP1874117, a therapeutically effective amount of Dolutegravir or its pharmaceutically acceptable equivalent combining its salt with a pharmaceutically acceptable carrier or diluent (for example It is prepared by (mixing). Document EP1874117 also states that the dose subject to the present invention depends on the method of administration, the patient's It has been stated that this varies depending on age, weight, condition, and the type of illness; Generally, when administered orally, the dose is approximately 0.05 mg to 3000 mg per adult per day. Preferably administered in doses of approximately 0.1 mg to 1000 mg, with the dose divided if necessary. Also available parenterally. In this case, approximately 0.01 mg to 1000 mg per adult per day, preferably around 0.05 mg to 500 mg is administered. Dolutegravir's trade name is Tivicay; this drug is used with other drugs to treat HIV / AIDS. It is an antiretroviral drug used. It is also used as part of post-exposure prophylaxis. It can also be used to prevent HIV infection following possible exposure. Oral administration. It is taken. Tivicay is used for patients who have not previously received treatment or who have received treatment but have previously had another integrase chain reaction. Children who have not received transfer inhibitors, weigh at least 40 kilograms (kg), and are 12 years of age or older. It has also been approved for. In the European Union, it is used in combination with other antiretroviral drugs against Human Immunodeficiency Virus (HIV). It is indicated for the treatment of adults, adolescents, and children over six years of age infected with the virus. 2 In the US, the indication for dolutegravir is for children who are at least four weeks old and weigh at least 3 kg. Updated in June 2020 to include [other terms]. In light of the above, in the current technology, dolutegravir or its pharmaceutical equivalent... powder fluidity and tablet compaction in compositions containing an acceptable amount of salt improvement and especially the production of tablets with the desired quality and dissolution profile. There is a need for it. The present invention relates to dolutegravir or its pharmaceutical equivalent. It offers a solution to these problems by presenting new compositions containing a usable salt. Solutions will be explained in detail. Brief Description of the Figures Figure 1: Dolutegravirin with sodium stearyl fumarate having a low PSD value of d (90) = 8 µm. dissolution profiles Figure 2: Dolutegravirin with sodium stearyl fumarate having an optimal PSD value of d (90) = 31 µm. dissolution profiles Brief Description of the Invention The present invention relates to dolutegravir or a pharmaceutically acceptable salt thereof, and It presents a solid pharmaceutical composition containing sodium stearyl fumarate as a lubricant; Here, the particle size distribution of sodium stearyl fumarate is 10 µm ≤ d (90) ≤ 50 µm It is in the range. More preferably, the particle size distribution of sodium stearyl fumarate is 20 µm ≤ d (90) It is in the range of ≤ 40 µm. The solid pharmaceutical composition intended for oral administration may be a tablet, film-coated tablet, or capsule. The solid pharmaceutical composition intended for oral administration may be a film-coated tablet. The composition of the present invention includes the following: Table 1: Dolutegravir compounds Components by Weight (%) Dolutegravir or its pharmaceutically acceptable equivalent 5.00%-20.00% salts One or more distributors 4.00%-10.00% One or more diluents 35.00%-90.00% One or more binders 3.00%–7.00% 3 Sodium stearyl fumarate 1.00%–2.50% One or more solvent qs Total 100.00% The subject matter of the present invention is a process for the preparation of a solid pharmaceutical composition, The process in question includes the following steps: a. Dolutegravir or its pharmaceutically acceptable salts, a The elimination of a diluent, a dispersant, a binder, and a diluent, b. Mixing the ingredients from step a, c. The mixture from step b is granulated, preferably with purified water as a solvent. granulation with the solution and thus the formation of the intragranular phase, Wet sieving of the mixture in step d.c. Drying of the granules obtained in step e.d., f. Sieving of the granules obtained in step e, g. Elimination of any remaining dispersant as a component of the extra-granular phase, h. Mixing the sieved dispersant with the granules obtained in step f, i. Sieving of sodium stearyl fumarate as a component of the extragranular phase, j. Mixing the sifted sodium stearyl fumarate with the mixture obtained in step h and Completion of the formation of the non-granular phase and obtaining the final mixture, k. Pressing the tablet and film coating the tablet. For use in the treatment of Human Immunodeficiency Virus (HIV) infections, currently available The subject of the invention is a solid pharmaceutical compound. Detailed Description of the Invention The aspects and descriptions, in particular pharmaceutical compositions, methods and according to the present invention, Uses include dolutegravir or its pharmaceutical derivatives, as defined above and below. It refers to the salt that can be considered acceptable. As used here, "pharmaceutically acceptable salt" refers to a compound's biologically acceptable form. It refers to a compound salt that does not eliminate its activity and properties. Pharmaceutical salts, The compound described here can be obtained by reacting it with an acid or a base. 4 The excipients used in a formulation, their physicochemical and pharmacokinetic properties. It can have a negative effect. These excipients can interact with the active ingredient. This Therefore, when developing a formulation, the ingredients to be used, in addition to the active ingredient, are carefully considered. and should be chosen consciously. Preferably, the present invention refers to Dolutegravir or its pharmaceutically acceptable salts. or their esters and one or more pharmaceutically acceptable excipients This relates to the pharmaceutical composition containing excipients, solvents, diluents, lubricants, fillers, dispersants, binders, surfactants and in this field including, but not limited to, other substances known to an expert and mixtures thereof. They are selected from the non-existent group. The d90 value represents 90% of the dispersion measured using a laser diffractometer. For the purposes of the present invention, the d90 value is the number of particles relative to the distribution. It indicates the particle size that is below 90%. In other words, d90 is the percentage of the distribution. ninety percent of the particles have smaller sizes, while ten percent have larger particle sizes. definitions. Lubricants can also be used in this process. Lubricants help the tablet material adhere to the molds and punches. It is used to prevent adhesion to surfaces. This reduces wear and tear on tablet dispensing equipment. to reduce wear and tear and prevent tablet defects such as cracks or breaks It helps. According to the present invention, suitable lubricants include calcium stearate, magnesium stearate, and mineral oil. stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol in this field other substances known to an expert and mixtures thereof, but not limited to these. It is selected from a non-existent group. The preferred lubricant is sodium stearyl fumarate. Sodium stearyl fumarate is an odorless and tasteless powder that is soluble in water and alcohol. The particle size of sodium stearyl fumarate can range from 10 µm ≤ d90 ≤ 50 µm. Furthermore... Specifically, it could be in the range of 20 µm ≤ d90 ≤ 40 µm. Even more specifically, here... particle size 20 µm, 21 µm, 22 µm, 23 µm, 24 µm, 25 µm, 26 µm, 27 µm, 28 µm, 29 µm, µm can be 31 µm, 32 µm, 33 µm, 34 µm, 35 µm, 36 µm, 37 µm, 38 µm, 39 µm or 40 µm. The inventors have developed a drug containing dolutegravir or a pharmaceutically acceptable salt thereof. in compositions, when sodium stearyl fumarate is used as a lubricant — Here, the particle size of sodium stearyl fumarate is between 10 µm ≤ d90 ≤ 50 µm — powder. They found that the homogeneity of the mixture and the compressibility of the tablet had improved. The inventors have developed a drug containing dolutegravir or a pharmaceutically acceptable salt thereof. in compositions, when sodium stearyl fumarate is used as a lubricant – Here, the particle size of sodium stearyl fumarate is between 20 µm ≤ d90 ≤ 40 µm – powder. the homogeneity of the mixture and the compressibility of the tablet increased, and the solubility improved. And surprisingly, they found that tablets with the desired features were obtained. Dispersants can also be used in this process. Dispersants disperse the tablets into gastric and intestinal fluids, breaking them down easily. It is used to disperse the particles; thus, the other components of the composition can be quickly dispersed. They dissolve and are absorbed, achieving the desired effect. Many of these substances cause the tablets to disintegrate. It has good water absorption and expansion properties to ensure durability. Suitable dispersants for this innovative formulation are alginic acid and colloidal silicon dioxide. Croscarmellose sodium, crospovidon, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polyacrilin potassium, starch, pregelatinized starch, sodium including alginate, hydroxypropyl starch, and other materials known to someone with expertise in this field. It can be selected from among the groups mentioned above, but is not limited to them. A combination of dispersants can also be used. The preferred dispersant is sodium starch glycolate. Binders can also be used in this process. Binding aids include powders, granules, and by literally “binding” the other dry components together, the product gains the necessary mechanical properties. It is formulated to provide resistance. Additionally, it is available in tablets with a low dose of active ingredient. They can add volume. According to the present invention, suitable binders include microcrystalline cellulose, starches, lactose, and mannitol. sugar alcohols, polyvinylpyrrolidone, polyethylene glycol, isomalt, hypromellose (hydroxypropyl polymers such as methylcellulose and other materials known to someone specializing in this field It is selected from a group that includes, but is not limited to, mixtures of these. Preferred The binder is povidone (polyvinylpyrrolidone). Solvents can also be used in this process. Solvents are evaluated based on their solubility, taste, and antimicrobial activity. or to increase stability and reduce dose volume (e.g., oral medications, injections) These are the auxiliary substances used. In contrast, solvents are also used to optimize insolubility. It can be used (if the taste of the active pharmaceutical ingredient is a problem). Thinners, fillers, or bulking agents may also be used in this process. With Spectrum's wide range of diluent excipients, the dosage of a pharmaceutical product can be adjusted. You can increase its form, volume, or weight. Most dosages only require a very small amount of the active ingredient. 6 Since Pharmaceutical Ingredients (APIs) must be used, diluents are usually added to the dosage form. It constitutes a significant part of it. Suitable diluents according to the present invention include lactose, microcrystalline cellulose, starches, and calcium. phosphates, sucrose, maltodextrin, mannitol, sorbitol, and others known to an expert in this field. The preference is selected from a group that includes, but is not limited to, substances and their mixtures. The diluents used are mannitol, microcrystalline cellulose, or a mixture thereof. Suitable solvents include ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, and distilled alcohol. from a group such as water and other substances known to someone knowledgeable in this field, and mixtures thereof. These are some options, but not limited to them. The preferred solvent is purified water. In another configuration, the pharmaceutical composition, according to the present invention, is in the form of a tablet, capsule, caplet, or film. coated tablets, enteric tablets, controlled-release tablets, and any similar solid oral dosage form This could be in the form of a film-coated tablet. According to the present invention, the preferred dosage form is the film-coated tablet. Commonly available coating materials for coating tablets. available. In another configuration, a pharmaceutical composition according to the invention includes the following: Table 2: Dolutegravir compounds Components by Weight (%) Dolutegravir or its pharmaceutically acceptable equivalent 5.00%-20.00% salts One or more distributors 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 solvent qs Total 100.00% Preferably, the active substance dolutegravir in the composition of the present invention or a pharmaceutically equivalent substance. These are acceptable salts. Dolutegravir sodium is more preferable. 7 Preferably, according to the present invention, the lubricant in the composition is sodium stearyl fumarate. Sodium The particle size of stearyl fumarate can be 10 µm ≤ d90 ≤ 50 µm. More specifically, 20 µm ≤ d90 ≤ 40 µm is possible. In another preferred configuration, the pharmaceutical composition according to the invention is: Table 3: Dolutegravir compounds Components by Weight (%) Dolutegravir or its pharmaceutically acceptable equivalent 5.00%-20.00% salts One or more distributors 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 solvent qs Total 100.00% Another aspect of the invention is dolutegravir or its pharmaceutically acceptable salts. or containing one or more pharmaceutically acceptable excipients with their esters Pharmaceutical compounds are prepared by either the wet granulation process or the dry granulation process. Ideally, the pharmaceutical compound is prepared by the wet granulation process. Preferably, the present invention applies to dolutegravir or its pharmaceutically acceptable salts. also contains esters and one or more pharmaceutically acceptable excipients. This relates to pharmaceutical compositions; where the composition has an intragranular phase and an extragranular phase. According to the invention, the process may also include the following steps: a. Dolutegravir or its pharmaceutically acceptable salts, a diluent, Elimination of a dispersant, a binder, and a diluent, b. Mixing the ingredients from step a, c. The mixture in step b is granulated using preferably purified water as a solvent. granulation with solution and thus formation of the intragranular phase, Wet sieving of the mixture in step d.c. Drying of the granules obtained in step e.d., 8 f. Sieving of the granules obtained in step e, g. a residual amount of decomposition agent as a component of the extragranular phase elimination, h. Mixing the screened aggregate with the granules obtained in step f, i. Sieving of sodium stearyl fumarate as a component of the extragranular phase, j. Mixing the sifted sodium stearyl fumarate with the mixture obtained in step h and Completion of the formation of the extragranular phase and obtaining the final mixture, k. Tablet pressing is optional. l. Optional screen protector application for the tablet. Another aspect of the current invention is the treatment of Human Immunodeficiency Virus (HIV) infections. A solid pharmaceutical compound designed for use in the treatment of heart disease. Another aspect of the invention is that pharmaceutical compounds can be used to treat HIV (Human Immunodeficiency Virus). Dolutegravir or pharmaceutically accepted drugs are used to treat the infection. It contains available salts and sodium stearyl fumarate as a lubricant. In vitro tests Sodium stearyl fumarate with low PSD, d(90) = 8 µm, and d(90) = 31 µm. dissolution of dolutegravir compounds containing sodium stearyl fumarate with optimal PSD The results were compared. Table 4: Solubility of dolutegravir with sodium stearyl fumarate having a low PSD value. results Time (min) Dissolution (%) 0 0 45 64 73 80 45 85 60 88 Table 4, sodium stearyl fumarate with low PSD value of d (90) = 8 µm It shows the dolutegravir compositions. As can be seen, the low PSD with d (90) = 8 µm. 9 The dissolution of dolutegravir in compounds containing sodium stearyl fumarate with a certain value takes 1 hour. Ultimately, it remained below 90%. Table 5: Solubility of dolutegravir with sodium stearyl fumarate having optimum PSD value. results Time (min) Dissolution (%) 0 0 51 75 84 89 45 98 60 100 Table 5 shows sodium stearyl fumarate (SSF) with an optimal PSD value of d (90) = 31 µm. It shows the dolutegravir compositions. As can be seen, the optimal PSD is d (90) = 31 µm. The dissolution of dolutegravir in compositions containing sodium stearyl fumarate with a valence of 45. It exceeded 95% per minute and reached 100% after 1 hour. As can be seen from the tables above, we have a low PSD value of d (90) = 8 µm. The desired dissolution values ​​could not be achieved with SSF. The desired values ​​are d (90) = 31 µm. It was obtained with SSF having the optimal PSD value. The dolutegravir compounds mentioned above and their preparation process provide the desired dissolution. To produce film-coated tablet compositions with particle sizes < 10 µm (d90) < 50 µm, more specifically 20 µm < (d90) < 40 µm and even more specifically d (90) It was developed using sodium stearyl fumarate with a concentration of 31 µm. See Table 4 and Table above. Comparing the data in 5, we have the optimal PSD value of d (90) = 31 µm. The desired compositions were obtained with SSF.

Claims

1. A solid pharmaceutical compound, characterized by its composition being dolutegravir or a pharmaceutically accepted equivalent thereto. It contains sodium stearyl fumarate as a usable salt and lubricant, and sodium The particle size distribution of stearyl fumarate is in the range of 10 µm ≤ d (90) ≤ 50 µm.

2. According to claim 1, it is a solid pharmaceutical compound, characterized by the fact that it is a particle of sodium stearyl fumarate. The size distribution is between 20 µm ≤ d (90) ≤ 40 µm.

3. A solid pharmaceutical composition according to claim 1 or 2, characterized by its intended use for oral administration. The dosage form is tablet, film-coated tablet, or capsule.

4. According to claim 3, it is a solid pharmaceutical composition, characterized by the fact that the dosage form of the composition is film-coated. It is a tablet.

5. It is a solid pharmaceutical compound according to the previous requirements, and its characteristic is that the said compound;  5.00%–20.00% by weight of Dolutegravir or pharmaceutically acceptable salts,  4.00%–10.00% by weight of one or more distributors,  35.00–90.00% by weight of one or more diluents,  3.00–7.00% by weight of one or more binders,  1.00–2.50% by weight Sodium stearyl fumarate,  It must contain at least one solvent.

6. Preparation of solid pharmaceutical composition according to any of the previous requirements. It is a method, and its characteristic is; a. Dolutegravir or its pharmaceutically acceptable salts, a a diluent, a decomposition aid, a binder, and a diluent elimination, Mixing the ingredients in step ba, The mixture in step cb is a granulation, preferably containing purified water as a solvent. granulation with solution and thus formation of the intragranular phase, Wet sieving of the mixture at step dc, Drying of the granules obtained in the first step, Sieving of granules obtained in the fe step, g. Sieving of the remaining dispersant as a component of the extragranular phase, h. Mixing the sieved dispersant with the granules obtained in step f, i. Sieving of sodium stearyl fumarate as a component of the extragranular phase, 11 j. Mixing the sifted sodium stearyl fumarate with the mixture obtained in step h and The final mixture is obtained upon completion of the formation of the extragranular phase. being done, k. This includes the steps of pressing the tablet and film coating the tablet.

7. Request 1 for use in the treatment of Human Immunodeficiency Virus (HIV) infections. A solid pharmaceutical compound according to any of 5. 12