HK40069916B - Solid oral formulation of utidelone - Google Patents

Description

Utilideron solid oral dosage form

Technical Field

This application pertains to the pharmaceutical field, specifically relating to solid oral dosage forms of utidelon, their preparation methods, and uses.

Background Technology

Utidelon is an epothilone derivative, a macrolide compound, and a secondary metabolite produced by the genetically modified myxobacterium *Cyclocarya pallida*. Studies have shown that epothilone antibiotics have the same pharmacological mechanism of action as paclitaxel, exerting their antitumor effect by inhibiting the depolymerization of tubulin. The chemical name of utidelon is 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazolyl-4-yl)-vinyl]-hexadecoxetane-13-ene-2,6-one lactone, and its chemical structure is shown below.

Utidelon injection (trade name: Utidelon ^™ ), 5ml:50mg, is administered via intravenous infusion over approximately 1.5 hours, at a dose of 30-40mg/ ^m² /day, once daily for 5 consecutive days, with a 21-day treatment cycle. Treatment continues until disease progression or intolerable toxicity. Utidelon injection must be diluted with physiological saline for injection (final concentration 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.

Utidelon is readily soluble in ethanol, methanol, ethyl acetate, and chloroform, but poorly soluble in water, with a saturated solubility of less than 1 μg/ml, making it difficult to develop into an oral formulation with suitable bioavailability. Currently marketed epothilone-type antitumor drugs, such as utidelon injection and ixaprone injection, use non-aqueous solvents such as ethanol and polyoxyethylene castor oil as solvents. Before clinical use, they are diluted with sodium chloride injection and administered via intravenous drip. Because polyoxyethylene castor oil is a strong sensitizer, anti-allergy treatment must be given before intravenous administration, reducing patient compliance, increasing adverse reactions, and limiting its clinical applicability.

Solid oral formulations of epothilone compounds are relatively rare. Instead, intravenous drug formulations are often combined for oral administration, as illustrated in patent CN 101112373. Because epothilone compounds are prone to ring-opening degradation in solution and crystallize out in vivo due to poor solubility, solution-based oral formulations of epothilone compounds typically suffer from poor stability, high oral irritation, and low bioavailability, making them generally not pharmaceutically feasible. Therefore, developing an oral formulation with high bioavailability and high drug stability is a consensus in the industry.

Summary of the Invention

To address the aforementioned issues, this application provides an oral formulation with utedelon as the active ingredient and a method for preparing the same. The oral formulation of this application exhibits high bioavailability and good physical and chemical stability, enabling oral administration of this active ingredient, improving medication compliance, and eliminating the severe allergic reactions caused by injectable polyoxyethylene castor oil.

The oral formulation of this application effectively improves the solubility of utidelon while solving the in vivo and in vitro stability of utidelon, significantly improving the bioavailability of the drug formulation, and creating a drug formulation preparation process suitable for large-scale industrial production.

The oral formulation of utidelon of this application can be prepared into solid dosage forms such as capsules, tablets, or granules, for example, microcapsules. Data show that the dissolution and bioavailability of the solid oral formulation of this application have good bioavailability.

According to one aspect, this application provides a solid oral dosage form containing an epoetomycin-type active ingredient, such as utedelone, suitable for oral administration.

Typically, poorly soluble drugs can have their solubility improved by reducing API particle size, preparing solid dispersions using hydrophilic carrier materials, or adding surfactants, thereby enhancing their bioavailability. However, due to the particularly poor water solubility of utidelon, it is difficult to achieve ideal drug dissolution through a single method such as reducing drug particle size or adding surfactants within pharmaceutically permissible limits. Therefore, obtaining oral formulations with physical and chemical stability while enhancing utidelon solubility and oral bioavailability is extremely challenging and requires considerable creativity.

The oral solid dosage form containing utidelon of this application comprises an active pharmaceutical ingredient (i.e., the active ingredient: utidelon or a pharmaceutically acceptable salt, solvate, or ester thereof) and pharmaceutical excipients. The oral dosage form includes: 1) utidelon or a pharmaceutically acceptable salt, solvate, or ester thereof; 2) at least one hydrophilic pharmaceutical excipient; 3) at least one sustained-release pharmaceutical excipient; and 4) optionally at least one surfactant component.

This application applies not only to utedelon but also to other epokine derivatives of the same class as utedelon.

According to some embodiments, the solid oral dosage form of this application, such as microcapsules, includes: 1) utedelon or a pharmaceutically acceptable salt, solvate or ester thereof; 2) at least one hydrophilic pharmaceutical excipient; 3) at least one sustained-release pharmaceutical excipient; and 4) at least one surfactant excipient.

In the oral formulation of this application, the ratio of utidelon to pharmaceutical excipients is in the range of 1:1 to 1:30, preferably 1:5 to 1:20.

The microcapsules of this application comprise a core and a pharmaceutical composition coating layer and/or a pharmaceutical coating layer encapsulating the core. The core may be, for example, a spherical or elliptical pharmaceutical excipient with a particle size of 100-1000 μm. The support material used for tablets and cores is generally referred to as the core material, and may include, for example, sucrose, starch, lactose, microcrystalline cellulose, mannitol, and biodegradable polymers.

The microcapsules or tablets contain approximately 2%-10% (w/w) of utidelon; approximately 30%-70% (w/w) of pharmaceutical excipients; and approximately 20%-60% (w/w) of core material, the weight percentages being calculated based on the total weight of the microcapsules or tablets. Preferably, each capsule may contain 5-30 mg of utidelon, and each tablet may contain approximately 5-20 mg of utidelon.

The oral formulation of this application uses a core material selected from sucrose, starch, microcrystalline cellulose, or other pharmaceutically acceptable core materials, preferably sucrose core materials. The core material diameter is 0.2 mm to 1.5 mm, preferably 0.4 mm to 1.0 mm. The particle size of the drug-coated microspheres is 0.5-1.5 mm.

The hydrophilic pharmaceutical excipients in the oral formulations (such as microcapsules) of this application are selected from one or a mixture of several of the following: povidone, hydroxypropyl methylcellulose, mannitol, lactose, sucrose, poloxamer, polyvinyl alcohol, etc., such as low-viscosity hydroxypropyl methylcellulose, povidone, and poloxamer.

The sustained-release pharmaceutical excipients in the oral formulations (such as microcapsules) of this application are selected from one or a mixture of several of the following: povidone, hydroxypropyl methylcellulose, polyethylene glycol, ethylcellulose, polyvinyl acetate diethylamine acetate, hydroxypropyl methylcellulose acetate succinate, methacrylate acetate copolymer, cellulose acetate, methylcellulose, polyacrylic acid resin, polyvinyl phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate, etc., such as high-viscosity hydroxypropyl methylcellulose, high-viscosity polyethylene glycol, ethylcellulose, and cellulose acetate.

The surfactant excipients in the oral formulations (such as microcapsules) of this application are selected from one or a mixture of several of the following: polysorbate, polyoxyethylene castor oil, sodium lauryl sulfate, bile salts, fatty acid glycerides, sorbitan, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, and poloxamer. Polyoxyethylene castor oil is preferred, and polysorbate and poloxamer are secondary choices.

According to one embodiment, this application provides a solid oral dosage form, such as microcapsules, which uses utedelon as the active ingredient, and uses polyoxyethylene (40) hydrogenated castor oil, low-viscosity hydroxypropyl methylcellulose (such as E50), and high-viscosity hydroxypropyl methylcellulose (such as K100) as pharmaceutical excipients, with sucrose as the core.

According to another aspect, this application provides a method for preparing oral formulations. For example, the method for preparing microcapsules containing utidelon involves dissolving utidelon and corresponding excipients in a solvent, coating the utidelon into a pellet core using a coating process to prepare microcapsules, and finally encapsulating them in capsules to prepare capsules or compressing them into tablets. This preparation method solves the problem of poor bioavailability caused by the poor water solubility of utidelon and the tendency of drug formulations prepared by solid dispersion technology to undergo defects such as in vitro and in vivo recrystallization. Furthermore, the oral formulation of this application does not require strict control of the particle size and crystal form of the active pharmaceutical ingredient to ensure the stability of the formulation process; it has advantages such as low dust generation during production and the ability to achieve fully enclosed preparation, thereby reducing occupational hazards; and the utidelon in the obtained oral solid dosage form exists in an amorphous or molecular form.

The above-mentioned oral formulations of utidelon and their preparation processes have at least the following characteristics:

1) Oral formulations contain at least one hydrophilic pharmaceutical excipient to improve drug solubility.

2) Oral formulations may contain pharmaceutical excipients with sustained-release function to inhibit the release rate of drugs in solid dispersions prepared with hydrophilic pharmaceutical excipients, thereby reducing the supersaturation concentration of drugs in vivo and inhibiting the recrystallization process of drugs in vivo.

3) Oral formulations may contain one or more surfactants to further inhibit the recrystallization process of drugs in vivo and in vitro, and at the same time play a certain plasticizing role in the microcapsule preparation process, increasing the toughness of the finished microcapsules.

4) During the preparation process, Utidelon must first be dissolved in an organic solvent or a mixture of organic solvents or a mixture of organic solvent and water.

5) During the preparation process, Utidelon, which is dissolved in an organic solvent or a mixture of organic solvents or a mixture of organic solvents and water, needs to be co-dried with hydrophilic pharmaceutical excipients and/or sustained-release pharmaceutical excipients and/or surfactants to prepare a solid dispersion with high solubility or a microsphere with both high solubility and sustained-release properties.

The organic solvents mentioned above are selected from pharmaceutically acceptable organic solvents such as ethanol, methanol, ethyl acetate, acetone, dichloromethane, and chloroform, for example, ethanol, methanol, ethyl acetate, or acetone, or mixtures of two or more of the above solvents in any proportion.

The aforementioned co-drying preparation processes mainly include fluidized bed coating, spray drying, vacuum drying, and other drying processes such as heating and freezing.

The oral formulations of this application, which are suitable for human patients (or animals), include solid dosage forms such as soft and hard capsules, tablets, granules, multigranules, or microcapsules such as microcapsules.

Depending on the commercially available unit dosage form, the daily dose and frequency can be administered, and the daily dose of the oral formulation of this application can be obtained by administering half a unit, a single unit, or more unit dosage forms.

According to another aspect, this application is for the treatment of cancer in humans or animals. As stated herein, cancer refers to all forms of cancer, wherein the tumors referred to are solid tumors, especially breast cancer, lung tumors, digestive tract tumors, lymphomas, prostate cancer, brain cancer, gynecological tumors, liver cancer, head and neck tumors, such as breast cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, and stomach cancer;

Terminology Definition

Pharmaceutical excipients: Pharmaceutical excipients refer to the excipients and additives used in the production of drugs and the preparation of prescriptions. They are substances, other than the active ingredients, that have undergone reasonable safety assessments and are included in the drug formulation.

Pellet core: Pellet core is an essential masterbatch for preparing and producing skeleton-type micro pellets.

Hydrophilic pharmaceutical excipients: These are pharmaceutical excipients that have a strong affinity for water, can attract water molecules, or are easily soluble in water.

Sustained-release pharmaceutical excipients: Materials that enable the slow release of drugs to prolong the duration of drug action, such as microcapsules that can hold drugs and release them slowly.

Low-viscosity hydroxypropyl methylcellulose: refers to hydroxypropyl methylcellulose with a viscosity <80 mPa·s. Such as E5, E3, E15, E50, K3 and other grades of hydroxypropyl methylcellulose.

High-viscosity hydroxypropyl methylcellulose: refers to hydroxypropyl methylcellulose with a viscosity ≥ 80 mPa·s. Such as K100LV, K100M, K100LVP, K4M, E4M, E4MP, K100MP and other grades of hydroxypropyl methylcellulose.

High viscosity polyethylene glycol: refers to polyethylene glycol with a molecular weight >1000, such as polyethylene glycol of grades PEG1000, PEG2000, PEG4000, PEG8000, etc.

This application has the following advantages;

1. The oral formulation of this application has high bioavailability, even reaching over 55%.

2. The preparation process of this application does not require strict control over the particle size and crystal form of the active pharmaceutical ingredient as is required in conventional oral solid dosage form preparation processes. After dissolving the active ingredient in an easily soluble organic solvent, it is coated onto the core of pharmaceutical blank microcapsules using a coating process. After drying, the utedelon in the resulting microcapsules exists in an amorphous and molecular form within the microcapsules or powder, and exhibits a certain degree of stability.

3. The oral formulation of this application can be prepared using an integrated molding process. During the preparation process, a closed operation is basically adopted, which can effectively avoid occupational exposure hazards caused by cytotoxic compounds.

4. The total yield of the oral formulation of this application reaches over 90% during preparation, which is far higher than the total yield of conventional oral solid dosage forms.

5. The active ingredient, utidelon, in the solid oral dosage form of this application exists in an amorphous or molecular form, rather than a crystalline form.

Attached Figure Description

Figure 1: Dissolution curve of the oral formulation of Example 1;

Figure 2: Dissolution curve of the oral formulation of Example 2;

Figure 3: Dissolution curve of the oral formulation of Example 3;

Figure 4: Dissolution curve of the oral formulation of Example 4;

Figure 5A: Dissolution curve of the oral formulation of Example 5-A;

Figure 5B: Dissolution profile of the oral formulation of Example 5-B;

Figure 6: Area under the plasma concentration-time curve of utidelon injection;

Figure 7: Area under the plasma concentration-time curve of Utidelon capsules in Example 1;

Figure 8: Area under the plasma concentration-time curve of utidelon injection;

Figure 9: Area under the plasma concentration-time curve of Utidelon capsules in Example 5-A;

Figure 10: X-ray diffraction pattern of utidyl crystalline form;

Figure 11: X-ray diffraction pattern of utidylcholine in amorphous form;

Figure 12: X-ray diffraction pattern of the pharmaceutical excipients (without active ingredients) used in the preparation of Utidelon capsules in Example 5-A;

Figure 13A: X-ray diffraction pattern of the contents of the utidylcholine capsules prepared in Example 5-A (stored at room temperature);

Figure 13B: HPLC chromatogram of the contents of the utidylcholine capsules prepared in Example 5-A (stored at room temperature).

Detailed Implementation

The present application is further described below with reference to specific embodiments. However, the present application is not limited to the following embodiments. For those skilled in the art, appropriate optimizations and modifications can be made without departing from the principle of the present application. These improvements and modifications are also considered to be within the scope of protection of the present application.

Material:

The formulations of the following examples use utidelon manufactured by Chengdu Huahao Zhongtian Pharmaceutical Co., Ltd. All excipients meet national standards or the 2020 edition of the Chinese Pharmacopoeia. Specifically, polyoxyethylene (40) hydrogenated castor oil is manufactured by BASF China Ltd., hydroxypropyl methylcellulose E50 is manufactured by Rohm and Haas, hydroxypropyl methylcellulose K100 is manufactured by Rohm and Haas, the core (sucrose) is manufactured by Shanghai Carvac Coating Co., Ltd., and the hydroxypropyl methylcellulose empty capsules are manufactured by Suzhou Capsule Co., Ltd. However, the excipients used in the oral solid dosage forms of the following examples are not limited to those of the same manufacturer.

Example 1: Utidelon oral solid dosage form formulation

Dissolve the prescribed amounts of eutidelon, polyoxyethylene (40) hydrogenated castor oil, and povidone K30 in an anhydrous ethanol solution in a beaker. Add the prescribed amount of purified water and mix well; or dissolve the prescribed amount of hydroxypropyl methylcellulose E5 in the prescribed amount of purified water while stirring. Slowly add the hydroxypropyl methylcellulose E5 aqueous solution to the anhydrous ethanol solution and continue stirring for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine, coat with the drug, dry thoroughly after coating, discharge the material, and fill the resulting microgranules into capsules. Each capsule can be filled with 10-30 mg of eutidelon.

Dissolution test:

The sample tested was a capsule containing 20 mg of utidelon. Dissolution and release were determined according to Method I of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia. The test capsule was added to a rotating basket, the rotation speed was 100 rpm, and the dissolution medium was 900 ml of pH 6.8 phosphate buffer. The release rate was determined using high-performance liquid chromatography (HPLC). A C18 column was used, the mobile phase was acetonitrile-water (65:35), the column temperature was 30℃, and the detection wavelength was 250 nm. The dissolution curve is shown in Figure 1.

While using a hydrophilic carrier material as the solid dispersion carrier to prepare a solid dispersion with utidelon significantly improves drug solubility, the dissolved drug is prone to recrystallization in vivo, thereby reducing bioavailability. In this embodiment, the bioavailability in beagle dogs was 29%.

Example 2

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyoxyethylene (40) hydrogenated castor oil 30g Hydroxypropyl methylcellulose E5 155g Sugar-filled pellets 100g Ethyl cellulose 11g Polyethylene glycol 400 1.5g Anhydrous ethanol 2800g Purified water 1200g

Take the prescribed amounts of thiamethoxam and polyoxyethylene (40) hydrogenated castor oil and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol. Add the prescribed amount of hydroxypropyl methylcellulose E5 to the prescribed amount of purified water while stirring until dissolved. Slowly add the hydroxypropyl methylcellulose E5 aqueous solution to the anhydrous ethanol solution and continue stirring for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine, coat with the drug, and dry thoroughly after coating to obtain drug-containing microgranules.

Dissolve 11g of ethyl cellulose and 1.5g of polyethylene glycol 400 in 175ml of anhydrous ethanol in a beaker, then dilute with water to 250ml to obtain a controlled-release coating solution. Place the drug-containing microspheres in a fluidized bed and top with the controlled-release coating solution. The coating weight increases by approximately 4%. After coating, age at 40°C for at least 2 hours to obtain utedellon sustained-release microspheres. Fill the utedellon sustained-release microspheres into capsules.

Dissolution test:

The sample tested was a capsule containing 20 mg of utidelon. Dissolution and release were determined according to Method I of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia. The test capsule was added to a rotating basket, the rotation speed was 100 rpm, and the dissolution medium was 900 ml of pH 6.8 phosphate buffer. The release rate was determined using high-performance liquid chromatography (HPLC). A C18 column was used, the mobile phase was acetonitrile-water (65:35), the column temperature was 30℃, and the detection wavelength was 250 nm. The dissolution curve is shown in Figure 2.

Example 3

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyoxyethylene (40) hydrogenated castor oil 30g Hydroxypropyl methylcellulose E50 80g Hydroxypropyl methylcellulose K100 25g Sugar-filled pellets 100g Anhydrous ethanol 3000g Purified water 1400g

Dissolve the prescribed amounts of thiamethoxam and polyoxyethylene (40) hydrogenated castor oil in an anhydrous ethanol in a beaker. Dissolve the prescribed amounts of hydroxypropyl methylcellulose E50 and K100 in purified water while stirring. Slowly add the hydroxypropyl methylcellulose aqueous solution to the anhydrous ethanol solution and stir continuously for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine, coat with the medicine, dry thoroughly after coating, discharge the material, and fill the resulting micro-pellets into capsules.

Dissolution test:

The sample tested was a capsule containing 20 mg of utidelon. Dissolution and release were determined according to Method I of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia. The test capsule was added to a rotating basket, the rotation speed was 100 rpm, and the dissolution medium was 900 ml of pH 6.8 phosphate buffer. The release rate was determined using high-performance liquid chromatography (HPLC). A C18 column was used, the mobile phase was acetonitrile-water (65:35), the column temperature was 30℃, and the detection wavelength was 250 nm. The dissolution curve is shown in Figure 3.

Example 4

Utilidelon oral solid dosage form prescription

Dissolve the prescribed amounts of thiamethoxam, polyoxyethylene (40) hydrogenated castor oil, and ethyl cellulose in anhydrous ethanol in a beaker. Dissolve the prescribed amount of hydroxypropyl methylcellulose E50 in purified water while stirring. Slowly add the hydroxypropyl methylcellulose solution to the anhydrous ethanol solution and stir continuously for about 1 hour to ensure thorough mixing. Add the pellet core to a multi-functional granulation and coating machine, coat with the medicine, dry thoroughly after coating, discharge the material, and fill the resulting micro-pellets into capsules.

Dissolution test:

The sample tested was a capsule containing 20 mg of utidelon. Dissolution and release were determined according to Method I of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia. The test capsule was added to a rotating basket, the rotation speed was 100 rpm, and the dissolution medium was 900 ml of pH 6.8 phosphate buffer. The release rate was determined using high-performance liquid chromatography (HPLC). A C18 column was used, the mobile phase was acetonitrile-water (65:35), the column temperature was 30℃, and the detection wavelength was 250 nm. The dissolution curve is shown in Figure 4.

Example 5-A

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyoxyethylene (40) hydrogenated castor oil 30g Hydroxypropyl methylcellulose E50 60g Hydroxypropyl methylcellulose K100 45g Sugar-filled pellets 100g Anhydrous ethanol* 3000g Purified water* 1400g Hydroxypropyl methylcellulose empty capsules As needed

*: Solvents used in the process and eventually removed.

Dissolve the prescribed amounts of Utidelon and polyoxyethylene (40) hydrogenated castor oil in an anhydrous ethanol solution in a beaker. Dissolve the prescribed amounts of hydroxypropyl methylcellulose E50 and K100 in purified water while stirring. Slowly add the hydroxypropyl methylcellulose aqueous solution to the anhydrous ethanol solution and stir continuously for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet cores to a multi-functional granulation and coating machine, coat with the medicine, dry thoroughly after coating, discharge the material, and fill the resulting micro-pellets into capsules to obtain Utidelon capsules.

Dissolution test:

The sample tested was a capsule containing 20 mg of utidelon. Dissolution and release were determined according to Method I of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia. The test capsule was added to a blue solvent at 100 rpm, and the dissolution media were 900 ml of pH 6.8 phosphate buffer, 0.1 mol/L hydrochloric acid, purified water, and pH 4.5 acetate buffer. The release rate was determined using high-performance liquid chromatography (HPLC) with a C18 column, a mobile phase of acetonitrile-water (65:35), a column temperature of 30℃, and a detection wavelength of 250 nm. The dissolution curve is shown in Figure 5A. The in vitro dissolution characteristics of the prepared sample met the expected targets. Under different conditions, approximately 57% dissolved at 30 minutes and approximately 99% dissolved at 60 minutes, with no burst release or incomplete release.

Example 5-B

The preparation method and dissolution test method of the microcapsule in this embodiment are the same as those in Example 5-A.

name Prescription quantity Utidelon 15g Polyoxyethylene (40) hydrogenated castor oil 30g Hydroxypropyl methylcellulose E50 80g Hydroxypropyl methylcellulose K100 30g Sugar-filled pellets 100g Anhydrous ethanol* 2500g Purified water* 2000g Hydroxypropyl methylcellulose empty capsules As needed

The dissolution curves are shown in Figure 5B, which demonstrate good batch uniformity of release from multiple batches of the prepared capsules (as shown in Figure 5B).

Example 6

Utilidelon oral solid dosage form prescription;

Dissolve the prescribed amounts of uredelonone and polyoxyethylene (40) hydrogenated castor oil in an anhydrous ethanol in a beaker. Dissolve the prescribed amounts of hydroxypropyl methylcellulose E50 and K100 in purified water while stirring. Slowly add the hydroxypropyl methylcellulose aqueous solution to the anhydrous ethanol and stir continuously for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine, coat with the drug, and dry thoroughly after coating. Discharge the product to obtain drug-containing microcapsules. Mix the drug-containing microcapsules with the prescribed amounts of povidone K30, lactose, and talc, compress into tablets to obtain uredelonone tablets.

Example 7

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyoxyethylene (40) hydrogenated castor oil 10g Povidone K30 120g lactose 100g Hydroxypropyl methylcellulose K100M 150g talcum powder 5g Anhydrous ethanol 600g

Take the prescribed amounts of utidylcholine, polyoxyethylene (40) hydrogenated castor oil, and povidone K30 and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol and mix well to obtain a drug solution. Spray dry the drug solution using a multi-functional granulation and coating machine to obtain utidylcholine solid dispersion. Granulate the utidylcholine solid dispersion with the prescribed amounts of lactose, hydroxypropyl methylcellulose K100M, and talc using a dry granulation method, and then compress it into tablets to obtain utidylcholine tablets.

Example 8

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyethylene glycol 6000 155g Twain 80 30g Sugar-filled pellets 100g Anhydrous ethanol 1500g Purified water 500g

Take the prescribed amount of utedelon, polyoxyethylene (40) hydrogenated castor oil, Tween 80, and polyethylene glycol 6000 and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol, then add the prescribed amount of purified water and mix well. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine, coat with the medicine, dry thoroughly after coating, discharge the material, and fill the resulting micro-pellets into capsules.

Example 9

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polosham 407 65g Polyethylene glycol 8000 85g Sugar-filled pellets 100g Anhydrous ethanol 1500g Purified water 500g

Take the prescribed amounts of Utidelon, Poloxamer 407, and polyethylene glycol 8000 and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol, then add the prescribed amount of purified water and mix well. Add the prescribed amount of pellet core to a multi-functional granulation and coating machine for coating. After coating, dry thoroughly and discharge the material. Fill the resulting micro-pellets into capsules.

Example 10

Utilidelon oral solid dosage form prescription

Take the prescribed amount of utidylcholine, polyoxyethylene (40) hydrogenated castor oil, and polyethylene glycol 6000 and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol, mix well, and spray dry in a multi-functional granulation and coating machine to obtain utidylcholine solid dispersion.

Utidelon solid dispersion and the prescribed amounts of lactose, silica, and povidone K90 were granulated by a dry granulation machine and then compressed into tablets to obtain Utidelon tablets.

Example 11

Utilidelon oral solid dosage form prescription

name Prescription quantity Utidelon 15g Polyethylene glycol 4000 150g Polosham 407 30g Glyceryl behenate 30g Polyvinylpyrrolidone 5g sucrose 100g Micronized silica 100g Anhydrous ethanol 1500g

Take the prescribed amounts of utidylcholine, poloxamer 407, and polyethylene glycol 4000 and place them in a beaker. Dissolve them in the prescribed amount of anhydrous ethanol, mix well, and spray dry in a multi-functional granulation and coating machine to obtain utidylcholine solid dispersion.

Utidelon solid dispersion and the prescribed amounts of lactose, silica, behenicol glyceryl ester, and polyvinylpyrrolidone are granulated using a dry granulator and then compressed into tablets to obtain Utidelon tablets.

Example 12

Utilidelon oral solid dosage form prescription

Dissolve the prescribed amounts of utidelon, polysorbate, and cellulose acetate in an anhydrous ethanol solution in a beaker. Dissolve the prescribed amounts of lactose in purified water while stirring. Slowly add the purified water solution to the anhydrous ethanol solution and stir continuously for about 1 hour to ensure thorough mixing. Add the prescribed amount of pellet cores to a multi-functional granulation and coating machine, coat with the medication, and dry thoroughly after coating. Discharge the material and fill the resulting microgranules into capsules to obtain utidelon capsules.

Example 13: Bioavailability Test

1. Bioavailability of the utidylcholine capsules prepared using Example 1

Test method:

Four Beagle dogs were divided into two groups. In the first experiment, each dog in one group received an oral dose of 1 mg/kg of utedelone microgranules. In the other group, each dog received an intravenous infusion of 1 mg/kg of utedelone injection. Blood samples were collected intravenously before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. After centrifugation to separate the plasma, the concentration of utedelone in the plasma was determined by LC-MS/MS. The experimental results are shown in Figure 6.

The pharmacokinetic data of Utidelon injection and Utidelon capsules (Example 1) are shown in the table below;

Table 1: _PK / _PD data for Utilidelon Injection

Table 2: P _K / P _D data for Utilideron capsules (Example 1)

The oral formulation of Example 1 has an average relative bioavailability of approximately 29%.

Using the same testing methods, the average relative bioavailability of the utidelon formulations prepared in Examples 2, 3, and 4 was measured to be between 30% and 50%.

2. Bioavailability test of the utidelon formulations prepared using Examples 5 and 6

Test methods;

Six Beagle dogs were divided into two groups of three. In the first group, each dog was orally administered 1.5 mg/kg of utedelone capsules (Example 5-A). In the second group, utedelone injection was administered intravenously at a rate of 1 mg/kg per dog. Blood samples were collected intravenously before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. After centrifugation to separate the plasma, the concentration of utedelone in the plasma was determined by LC-MS/MS. The results for the injection are shown in Figure 8. The results for the capsules are shown in Figure 9.

The pharmacokinetic data of Utidelon injection and Utidelon capsules (Example 5-A) are shown in Table 3 below.

Table 3: Mean values of pharmacokinetic parameters after a single intravenous administration of utidelon injection and oral administration of utidelon capsules in beagle dogs

The relative bioavailability of utedellon capsules after a single oral administration ranged from 53.1% to 103.8%, with an average relative bioavailability of 78.5%.

Using the same testing method as in Example 5-A, the average relative bioavailability of the utidelon tablets prepared in Example 6 was found to be over 55%.

Example 14: Stability

The results of related substances testing of Utidelon capsules (Examples 1 and 5) after one month of storage under accelerated testing conditions of 40°C and 75% RH showed that the degradation impurities in the product were within the range specified by ICH Q3, indicating that the oral Utidelon formulation of the present invention has good stability.

After one month of storage under accelerated testing conditions of 40°C and 75% RH, X-ray diffraction analysis of the Utidelon capsules (Examples 1 and 5) showed that Utidelon existed in an amorphous or molecular form.

Example 15: Preparation of Utidelon amorphous products

Method 1:

Dissolve 1g of utidylcholine in 5ml of any two or three of the following solvents: dichloromethane, chloroform, or a mixture of dichloromethane, chloroform, and ethyl acetate. Evaporate to dryness under reduced pressure at 30℃～80℃ and -0.05Mpa to obtain the final product.

Method 2:

Dissolve 1g of utidylcholine in 5ml of any two or three of the following solvents: dichloromethane, chloroform, or a mixture of dichloromethane, chloroform, and ethyl acetate. Then, spray dry the solution using a fluidized bed with a material and inlet air temperature ≥30℃.

Method 3: Dissolve 1g of utedellon in 10ml of methanol or ethanol, and evaporate to dryness under reduced pressure using a rotary evaporator.

The X-ray diffraction pattern of the utidyl-1 amorphous material is shown in Figure 11.

Utidelon in capsules obtained through the process technology of this patent embodiment exists in an amorphous or molecular form.

Claims (9)

1. A solid oral pharmaceutical preparation, characterized in that the oral preparation is a microcapsule comprising the following microcapsules; or the oral preparation is a tablet made from the following microcapsules; wherein the microcapsule comprises a core and a coating layer encapsulating the core, wherein the coating layer comprises an active ingredient and pharmaceutical excipients, the active ingredient being utedelone, a pharmaceutically acceptable salt thereof, and the pharmaceutical excipients comprising hydrophilic pharmaceutical excipients, sustained-release pharmaceutical excipients, and optionally surfactants, wherein the utedelone exists in an amorphous or molecular form. 2. The solid oral dosage form according to claim 1, wherein the weight percentage of the active ingredient to the pharmaceutical excipient is 1:1 to 1:30. 3. The solid oral dosage form according to claim 2, wherein the weight percentage of the active ingredient to the pharmaceutical excipient is 1:5 to 1:20. 4. The solid oral dosage form according to any one of claims 1-3, characterized in that the hydrophilic pharmaceutical excipient is selected from at least one of povidone, hydroxypropyl methylcellulose, mannitol, lactose, sucrose, poloxamer, and polyvinyl alcohol; the sustained-release pharmaceutical excipient is selected from at least one of povidone, hydroxypropyl methylcellulose, polyethylene glycol, ethyl cellulose, polyvinyl acetate diethylamine acetate, hydroxypropyl methylcellulose acetate succinate, methacrylate acetate copolymer, cellulose acetate, methylcellulose, polyacrylic acid resin, polyvinyl phthalate, cellulose phthalate, and hydroxypropyl methylcellulose phthalate; and the surfactant is selected from at least one of polysorbate, polyoxyethylene castor oil, sodium lauryl sulfate, bile salts, fatty acid glycerides, sorbitan, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, and poloxamer. 5. The solid oral dosage form according to claim 4, characterized in that the hydrophilic pharmaceutical excipient is selected from at least one of low-viscosity hydroxypropyl methylcellulose, povidone, and poloxamer; the sustained-release pharmaceutical excipient is selected from at least one of high-viscosity hydroxypropyl methylcellulose, high-viscosity polyethylene glycol, ethyl cellulose, and cellulose acetate; and the surfactant is selected from at least one of polyoxyethylene castor oil, polysorbate, and poloxamer. 6. The solid oral dosage form according to claim 1, wherein the microcapsule or tablet contains 2%-10% (w/w) of active ingredient based on the weight of the microcapsule or tablet. 7. The solid oral dosage form according to claim 1, characterized in that, based on the weight of the microcapsule or tablet, 30%-70% (w/w) is pharmaceutical excipient and 20%-60% (w/w) is core material. 8. The solid oral preparation according to any one of claims 1-7 is a microcapsule, with utedelone as the active ingredient and polyoxyethylene (40) hydrogenated castor oil, low-viscosity hydroxypropyl methylcellulose and high-viscosity hydroxypropyl methylcellulose as pharmaceutical excipients. 9. The solid oral dosage form according to claim 8, wherein the microcapsules are sucrose-based.