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CN-121985946-A - Enzalutamide oral solid pharmaceutical preparation

CN121985946ACN 121985946 ACN121985946 ACN 121985946ACN-121985946-A

Abstract

The invention relates to a novel oral solid pharmaceutical preparation which comprises enzalutamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable auxiliary materials. In addition, the invention also provides a preparation method of the improved enzalutamide oral solid preparation.

Inventors

  • Damesh Mahendrabai Shah
  • Aladdin Manapa Batigo
  • Abu Hajit Ashok Rang Upahai
  • Samir Babral Panchal

Assignees

  • BDR制药国际私人有限公司

Dates

Publication Date
20260505
Application Date
20240918
Priority Date
20230918

Claims (10)

  1. 1. A solid oral composition comprising enzalutamide and one or more matrix polymers in a ratio of 1:1 to 1:10.
  2. 2. The solid oral composition of claim 1, comprising: a) 10% to 50% w/w enzalutamide; b) 1% to 95% w/w of a polymer or mixture thereof; c) 1% to 55% w/w of a diluent; d) 5% to 30% w/w of a disintegrant; e) 0.5% to 3% w/w of a lubricant or mixture thereof; f) 0.4% to 5% w/w glidant; g) 0.5% to 10% (w/w) of a flow director; h) 1% to 3% (w/w) of a coating agent; i) A solvent or a mixture thereof, and optionally other excipients.
  3. 3. The solid oral composition of claim 1, wherein the total amount of enzalutamide in the composition is from 25mg to 250mg.
  4. 4. The solid oral composition of claim 1, comprising a premix enzalutamide and a polymer mixture, wherein the polymer is selected from the group consisting of non-cellulosic polymers selected from the group consisting of polylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), polyglutamic acid (PGA), poly-I-glutamic acid, polylactic acid, poly (N-isopropylacrylamide), poly (2-hydroxyethyl methacrylate), polyamidoamine, polyvinyl acetate phthalate (PVAP), cross-linked polyvinylpyrrolidone, and mixtures thereof, the cellulose polymer is selected from cyclodextrin such as hydroxypropyl cyclodextrin, CAAdP-cellulose adipate propionate, CAPhth-cellulose acetate phthalate, CASub-cellulose acetate suberate, CAAdp-cellulose acetate adipate, CA seb-cellulose acetate sebacate, CHC-5-carboxyamyl hydroxypropyl cellulose, CMC-carboxymethyl cellulose, CMCAB carboxymethyl cellulose acetate butyrate, EC-ethyl cellulose, HEC hydroxyethyl cellulose, HPC-hydroxypropyl cellulose, HPC-Pen 106-AA-H-hydroxypropyl pent-4-enyl cellulose, HPMC-hydroxypropyl methyl cellulose, HPMCAS-hydroxypropyl methyl cellulose acetyl succinate, HPMCP-hydroxypropyl methylcellulose phthalate (hydroxypropyl methylcellulose phthalate) or mixtures thereof.
  5. 5. The solid oral composition according to claim 1, wherein the diluent is selected from microcrystalline cellulose and sodium carboxymethyl cellulose or a mixture thereof, preferably 0.5 to 3% by weight of the total pharmaceutical composition.
  6. 6. Solid oral composition according to claim 1, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, low substituted hydroxypropylcellulose, or mixtures thereof, preferably from 0.5 to 3% by weight of the total pharmaceutical composition.
  7. 7. The solid oral composition according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate and talc or mixtures thereof, preferably from 0.5 to 3% by weight of the total pharmaceutical composition.
  8. 8. The solid oral composition according to claim 1, wherein the glidant and the flow directing agent are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate and silicon dioxide, preferably at 0.5 to 1.5% by weight of the total pharmaceutical composition.
  9. 9. The solid oral composition of claim 1, wherein the solvent is selected from the group consisting of acetone, acetone and methylene chloride, methanol and methylene chloride, acetone and water, acetone and methanol, acetone and ethanol, methylene chloride and ethanol, or ethanol and water, or mixtures thereof.
  10. 10. A method of preparing an enzalutamide solid oral composition comprising spray drying techniques or hot melt granulation or inclusion complexes.

Description

Enzalutamide oral solid pharmaceutical preparation Technical Field The invention relates to a novel oral solid pharmaceutical preparation, which comprises enzalutamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable auxiliary materials. In addition, the invention also provides a preparation method of the improved enzalutamide oral solid preparation. Background Enzalutamide is a non-steroidal antiandrogen (NSAA) drug used to treat metastatic castration-resistant prostate cancer patients. The structure of enzalutamide is shown below: prostate cancer is a common cancer in men, particularly in the united states and europe. It has been reported that prostate cancer grows slowly and, if found at an early stage, can be cured by radical excision of the prostate. However, if not found early, prostate cancer can develop and lead to invasive prostate cancer, and cancer cells can metastasize to other parts of the body, affecting vital organs such as lymph nodes, lungs, bones, and gastrointestinal tract. Enzalutamide was first disclosed in U.S. Pat. No. 77O9517 and sold under the trade name XTANDI, XTANDI is a liquid-filled soft capsule for oral administration. The recommended dosage of enzalutamide is 160 mg, and 4 capsules of 40 mg are taken daily. Each capsule contains enzalutamide dissolved in Labrasol in ALF, which is reported to contain Xin Jixian polyethylene glycol-8 glyceride (caprylic capric polyethylene glycol glyceride). The blood concentration of enzalutamide reached a steady state after 28 days under daily dosing regimen. The possible treatment of the disease depends on various individual conditions, such as age, general health, extent of spread of cancer and possible metastasis. Thus, the decision whether to treat localized prostate cancer for cure purposes is a result of the tradeoff between expected benefit and risk for the patient, including patient survival and maintenance of a certain quality of life. According to the United states food and drug administration, XTANDI is a liquid-filled soft capsule for oral administration containing enzalutamide. The dosage form is reported to be useful in treating metastatic castration resistant prostate cancer patients. WO2015/022349 discloses a formulation containing enzalutamide in dissolved form. In addition, the present invention uses a solvent having an HLB value that is responsible for forming the water-in-oil emulsion. In a preferred embodiment, the dosage form is a capsule, preferably a soft gelatin capsule. WO2014/043208 requires the provision of a solid dispersion tablet composition comprising particles consisting of a co-precipitate on a substrate, wherein the co-precipitate comprises amorphous enzalutamide and a cellulose concentration-enhancing polymer. The cellulose concentrate enhancing polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP). Only when the solubility of enzalutamide in HPMCAS-M solid dispersion was 25%, it was comparable to the soft capsules containing Labrasol ALF solution. WO2019/008426 discloses novel formulations of enzalutamide and methods for their preparation, preferably in the form of hard gelatin capsules containing pharmaceutically acceptable excipients. In the granulating stage, the solution containing Labrasol cube ALF and enzalutamide is sprayed on anhydrous lactose for surface adsorption. The enzalutamide hard gelatin capsule formulation obtained in this way shows excellent stability in terms of dissolution data and product stability. The current XTANDI cubic dosage is 160 mg, and the oral administration is carried out once a day, four capsules are taken each time, and each capsule contains 40 mg of active pharmaceutical ingredient. It is reported that XTANDI is not affected by food intake. The dissolution requires the use of a solvent Labrasol cube ALF. Labrasol cube is a critical auxiliary material for dissolving the enzalutamide, so that the size of Xtandi cube capsules depends on the amount of Labrasol cube required for dissolving the enzalutamide, and the capsule size is larger. Larger capsule sizes and larger numbers of capsules can lead to dysphagia. Furthermore, the dissolution of the active ingredient under acidic conditions, especially in simulated gastric fluid conditions, of the formulation containing enzalutamide described above appears to be incomplete. In particular, the active ingredient does not remain dissolved, but rather appears to precipitate. In the prior art, the IIG limit of Labrasol ALF is not within the daily dosage range recommended by the U.S. food and drug administration. The invention discloses a tablet formulation of enzalutamide. The dissolution of the invention was observed at pH7.5 without the need for surfactants. In addition, labrasol cube ALF is not used in the invention, so that the problems are solved. Thus, toxic events and side effects associated with Labrasol-A