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CA-3184960-C - SOLID ORAL FORMULATION OF UTIDELONE

CA3184960CCA 3184960 CCA3184960 CCA 3184960CCA-3184960-C

Abstract

An oral pharmaceutical formulation using 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazole-4-yl)-ethenyl]]-oxacyclohex (utidelone) as an active ingredient, suitable for oral administration. The pharmaceutical formulation is a solid formulation such as tablets and capasules, and the pharmaceutical dosage form has good stability, in vitro dissolution behavior, and bioavailability.

Inventors

  • Li Tang
  • Chuan Zhang
  • Rongguo Qiu

Assignees

  • BEIJING BIOSTAR PHARMACEUTICALS CO., LTD.
  • CHENGDU BIOSTAR PHARMACEUTICALS, LTD.

Dates

Publication Date
20260505
Application Date
20210902
Priority Date
20200902

Claims (9)

  1. 23 CLAIMS 1. A solid oral formulation comprising Utidelone or a pharmaceutically acceptable salt, solvate or ester thereof as an active ingredient, and a pharmaceutically acceptable excipient, wherein the formulation is a micropellet capsule encapsulating micropellets, or a tablet prepared by micropellet compression, wherein the micropellets are pellet cores coated with a coating layer comprising the active ingredient and said pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises a hydrophilic pharmaceutical excipient, a sustained-release pharmaceutical excipient, and optionally a surfactant, and wherein the ratio of the active ingredient to the pharmaceutically acceptable excipient is in the range of 1:1 to 1:30 by weight.
  2. 2. The solid oral formulation according to claim 1, wherein the ratio of the active ingredient to the pharmaceutically acceptable excipient is in the range of 1:5 to 1:20.
  3. 3. The solid oral formulation according to any one of claims 1-2, wherein the hydrophilic pharmaceutical excipient is selected from at least one of povidone, hypromellose, mannitol, lactose, sucrose, poloxamer and polyvinyl alcohol; the sustained-release pharmaceutical excipient is selected from at least one of povidone, hypromellose, polyethylene glycol, ethyl cellulose, polyvinyl acetal diethylamine acetate, hypromellose acetate succinate, acetate methacrylate copolymer, cellulose acetate, methyl cellulose, polyacrylic resin, polyvinyl phthalate, cellulose phthalate, and hypromellose phthalate; and the surfactant is selected from at least one of polysorbate, polyoxyl castor oil, sodium lauryl sulfate, cholate, fatty acid glyceride, sorbitan, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, and poloxamer.
  4. 4. The solid oral formulation according to claim 3, wherein the hydrophilic pharmaceutical excipient is selected from at least one of low viscosity hypromellose, povidone and poloxamer; the sustained-release pharmaceutical excipient is selected from at least one of high viscosity hypromellose, high viscosity polyethylene glycol, 24 ethyl cellulose and cellulose acetate; and the surfactant is selected from at least one of polyoxyl castor oil, polysorbate and poloxamer.
  5. 5. The solid oral formulation according to any one of claims 1-4, wherein the micropellet capsule or tablet comprises 2%-10% (w/w) of the active ingredient based on the weight of the micropellet or the weight of the tablet.
  6. 6. The solid oral formulation according to claim 5, wherein the micropellet capsule or tablet further comprises 30%-70% (w/w) of pharmaceutically acceptable excipients and 20%~60% (w/w) pellet core based on the weight of the micropellet or tablet.
  7. 7. The solid oral formulation according to any one of claims 1-6, which is a micropellet capsule comprising Utidelone as an active ingredient, and polyoxyethylene (40) hydrogenated castor oil, low-viscosity hypromellose and high viscosity hypromellose as pharmaceutically acceptable excipients.
  8. 8. The solid oral formulation according to any one of claims 1-7, wherein the active ingredient Utidelone is present in an amorphous or molecular form.
  9. 9. The solid oral formulation according to any one of claims 1-8 for use in treatment of a cancer selected from breast cancer, lung cancer, digestive tract tumors, lymphoid tumors, prostate cancer, brain cancer, gynecological tumors, liver cancer, head and neck tumors, ovarian cancer, colon cancer and stomach cancer.

Description

Solid Oral Formulation of Utidelone Technical Field The present application belongs to pharmaceutical field, and specifically relates to a solid oral formulation ofUtidelone and the preparation method and use thereof. Background Art Utidelone is a class of epothilone derivatives belonging to macrolides and secondary metabolites produced by the genetically modified Sorangium Cellulosum. Studies have shown that epothilones have the same pharmacological mechanism as paclitaxel, which exerts anti-tumor effect by inhibiting the depolymerization of tubulin. The chemical name of Utidelone is: 4,8- dihydroxy-5,5, 7,9, 13-pentamethyl-16-[ 1-methyl-2-(2-methyl-thiazole-4-yl)-vinyl]hexadecoxetane- 13-en-2,6-one lactone with the chemical structure as shown below: s -{ N Utidelone injection (brand name: ttfHi™), strength 5 ml: 50 mg, intravenous infusion for about 1.5 hours, dose 30-40 mg/m2/day, administered once a day for 5 consecutive days, 21 days as a treatment cycle, until disease progression or intolerable toxicity. Utidelone injection needs to be diluted with normal saline for injection (the final concentration of Utidelone is 0.2mg/ml to 0.5mg/ml) before use. It is used to treat patients with advanced breast cancer, lung cancer, gastric cancer, liver cancer and other solid tumors. Utidelone is easily soluble in ethanol, methanol, ethyl acetate, and chloroform, but insoluble in water. The saturated solubility in water is less than lμg/ml, so it is difficult to develop into an oral formulation with suitable bioavailability. At present, the marketed epothilone antitumor drugs such as Utidelone injection and Ixabepilone injection etc., all of which use non-aqueous solvents CA 03184960 2023-1-4 such as ethanol and polyoxyl castor oil as solvents, are diluted with sodium chloride injection for administration by intravenous infusion. Since polyoxyl castor oil is a strong allergenic substance, antiallergic treatment must be given before intravenous administration, which reduces the compliance of this type of drug in clinical use, increases the adverse reactions of patients, and limits its clinical application. Solid oral formulations of epothilone compounds are rare, and pharmaceutical formulations for intravenous injection are usually used for oral administration, such as those described in patent CN 1011123 73. Epothilone compounds are prone to ring-opening degradation in solution state and crystallize out due to poor solubility in the body, therefore the pharmaceutical formulations containing epothilone compounds in the form of solution for oral administration usually have poor stability, high irritation, and low bioavailability, are thus not pharmaceutically feasible. Therefore, it is an industry consensus to develop an oral formulation with high bioavailability and high drug stability. Summary In order to solve the above-mentioned problems, the present application provides an oral formulation using Utidelone as an active ingredient and a preparation method thereof. The oral formulation of the present application has high bioavailability and good physical and chemical stability, making it possible to administer such an active ingredient orally, improving medication compliance, and eliminating the strong allergic reaction caused by administering polyoxyl castor oil via injection. The oral formulations of the present application not only effectively improves the solubility of Utidelone, but also solves the in vivo and in vitro stability of Utidelone, significantly improves the bioavailability of the formulation, and establishes a process for preparing the drug suitable for industrialized large-scale production. The oral formulations of Utidelone of the present application may be in the form of solid formulation such as capsules, tablets or granules, for example, micropellet capsules. The dissolution and bioavailability of the solid oral formulations of the present application have been shown good bioavailability by the data. According to one aspect, the present application provides a solid oral formulation containing CA 03184960 2023-1-4 2 an active ingredient of epothilone, such as Utidelone. In general, poorly soluble drugs may improve its solubility by reducing the particle size of API, preparing solid dispersions with hydrophilic carriers, and adding surfactants, etc. thereby improving the bioavailability of the drugs. Due to the extremely poor water solubility ofUtidelone, it is difficult to obtain an ideal dissolution of the drug by the above mentioned general means such as reducing the particle size of the drug and adding surfactants. Therefore, it is very challenging and creative to obtain oral formulations with good physical and chemical stability and enhanced solubility and oral bioavailability of Utidelone. The oral solid formulation containing Utidelone of the present application contains API (ie, active ingredient: Utidelone or a pharmaceutically acceptable salt, solvate or ester thereof) and pharmaceuti