Solid oral preparation of testosterone undecanoate and preparation method thereof

Abstract

The invention provides a testosterone undecanoate oral solid particle capable of being quickly released, the solubility of testosterone undecanoate in an aqueous solvent is greatly improved by using a special adsorbent and a preparation method, and the dissolution rate exceeds 40% under the condition of not containing a lipophilic solubilizer or a lipophilic surfactant. And more unexpectedly, the dissolution speed is extremely high, and complete dissolution can be realized within 5 minutes. The preparation method disclosed by the invention is simple, low in cost and relatively low in API loss.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field and relates to an oral solid preparation of testosterone undecanoate and a preparation method thereof. Technical Background

[0002] Testosterone preparations are the most effective hormone replacement therapy for treating male sexual dysfunction, including male hypogonadism, anorchia, cryptorchidism, and male menopause and other related diseases in the medical market at home and abroad. The commonly used exogenous androgens are testosterone propionate (TP) and testosterone undecanoate (TU). Testosterone undecanoate is the only oral testosterone on the market in China. Compared with most testosterone drugs that use injections or topical gel formulations, the oral formulation has greatly improved safety and convenience.

[0003] Testosterone undecanoate is insoluble in water, and its oral absolute bioavailability is only about 7%. Due to the solubility problem, the research on oral preparations of testosterone undecanoate is mainly based on oil-soluble soft capsules. The currently commercially available testosterone undecanoate soft capsules are made by dissolving testosterone undecanoate in oleic acid for oral administration. Although the bioavailability is improved, long-term use is prone to gastrointestinal reactions, and due to the limitations of the dosage form itself, it is not convenient to store and store for a long time. At the same time, the soft capsule dosage form does not have the characteristics of tablets or granules that can be divided into doses for medication.

[0004] Solid dispersion refers to a dispersion system formed by uniformly dispersing a drug in one or more solid carriers in a highly dispersed state such as molecular form, amorphous form, microcrystalline form through a process. For poorly soluble drugs, the solid dispersion prepared using a water-soluble carrier can not only maintain the highly dispersed state of the drug, but also has good wettability to the drug. This is of great significance in improving drug solubility, accelerating drug dissolution, and thus improving the bioavailability of the drug. CN106727409A discloses the preparation of testosterone undecanoate using a method of solid dispersion (SD), but the prescription of the patent still uses an oil-soluble carrier and a surfactant for solubilization, and simultaneously the preparation process of its preparation requires continuous heating of an organic solvent, there is a safety risk, and the spray drying process using the melt after heating is complicated, and the industrial production difficulty is high.

[0005] At present, there are few studies on non-oil-soluble testosterone undecanoate oral preparations. US10245273B2 discloses a non-oil-soluble prescription system, but it increases the solubility of testosterone undecanoate by nano-forming. The nano-forming process is complex, technically difficult, and costly. At the same time, nano-forming testosterone undecanoate poses a safety hazard to relevant experimenters or production personnel during the research and development process and the production process.

[0006] In order to make testosterone undecanoate better for clinical application, it is necessary to develop new solid oral dosage forms, such as tablets, granules, and capsules, to produce solid preparations that are milder, easier to store and carry, and more convenient and flexible to use. Summary of the invention

[0007] The invention provides a fast-released testosterone undecanoate oral solid granule, which greatly improves the solubility of testosterone undecanoate in an aqueous solvent by using a special prescription process, and the solubility exceeds 40% in the absence of a lipophilic solubilizer or a lipophilic surfactant. More unexpectedly, the dissolution rate is extremely fast, and the dissolution can be nearly complete in 5 minutes. The preparation method of the invention is simple, low in cost, and less in API loss, and can be prepared into dosage forms such as granules, tablets, and capsules.

[0008] In one embodiment provided by the present invention, the testosterone undecanoate oral solid particles comprise testosterone undecanoate, an adsorbent and a carrier.

[0009] In one embodiment provided herein, the particles are free of lipophilic solubilizers or surfactants.

[0010] In one embodiment provided by the present invention, the ratio of testosterone undecanoate to adsorbent is 1:1-1:100, preferably 1:10-1:60, and more preferably 1:20-1:50, in parts by weight.

[0011] In one embodiment provided by the present invention, the ratio of testosterone undecanoate to adsorbent is 1:44 by weight.

[0012] In one embodiment provided by the present invention, the ratio of testosterone undecanoate to adsorbent is 1:22 by weight.

[0013] In one embodiment provided by the present invention, the adsorbent is lactose or maltodextrin, preferably lactose, and more preferably lactose G200.

[0014] In one embodiment provided by the present invention, the weight ratio of testosterone undecanoate to the carrier is 5:1-1:5, preferably 1:2-2:1, and more preferably 1:1.

[0015] In one embodiment provided by the present invention, the carrier is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, povidone, polyethylene glycol, ethyl cellulose, pregelatinized starch, sodium carboxymethyl starch, etc., preferably hydroxypropyl methylcellulose, and more preferably hydroxypropyl methylcellulose E6 LV.

[0016] In one embodiment provided by the present invention, the solid particles of testosterone undecanoate may further comprise other pharmaceutically acceptable excipients, wherein the other excipients are selected from binders, plasticizers, sustained-release materials, fillers, disintegrants, glidants, enteric materials, etc., preferably comprising disintegrants.

[0017] In one embodiment provided by the present invention, the disintegrant is selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, etc., preferably cross-linked polyvinylpyrrolidone.

[0018] In one embodiment provided by the present invention, the solid particles of testosterone undecanoate include the following components in a weight ratio:

[0019]

[0020] or

[0021]

[0022] In one embodiment provided by the present invention, testosterone undecanoate does not need to be subjected to special treatment methods such as micronization or nano-crystallization, and its d90 particle size can be 80 microns to 120 microns, preferably 100 microns.

[0023] In one embodiment provided by the present invention, the solid particles of testosterone undecanoate are prepared by a solid dispersion process.

[0024] In one embodiment provided by the present invention, the method for preparing solid particles of testosterone undecanoate is as follows:

[0025] (1) Add testosterone undecanoate to 95% ethanol and stir until completely dissolved. Slowly add hydroxypropyl methylcellulose under medium-speed stirring and continue stirring until fully swollen, and use the drug-containing solution for later use;

[0026] (2) Place lactose in a wet mixer, turn on the stirring paddle at 500 rpm, add the prepared drug-containing solution, take out the wet granules after the addition is complete, and perform wet granulation of 20-40 mesh;

[0027] (3) The granulated particles are placed in a fluidized bed for drying at an air inlet temperature of 50±3°C and a drying end point LOD of less than 3%. After drying, the particles are sized to 20-40 mesh and mixed with a corresponding proportion of cross-linked polyvinylpyrrolidone to obtain solid dispersion particles.

[0028] In one embodiment provided by the present invention, the solid particles of testosterone undecanoate can be used directly as particles, or can be prepared into other oral solid preparations such as tablets or capsules by conventional methods, or can be prepared into sustained-release or enteric-coated solid oral preparations by coating conventional sustained-release coatings or enteric-coated films, including sustained-release granules, sustained-release tablets, sustained-release capsules, enteric-coated granules, enteric-coated tablets, enteric-coated capsules and other solid oral preparations.

[0029] Implementation

[0030] Example 1

[0031] The solid preparation of testosterone undecanoate is granulated using a solid dispersion process, and its formulation composition and specific preparation method are as follows:

[0032] Testosterone Undecanoate 5mg Lactose G200 220mg Hydroxypropyl methylcellulose E6 LV 5mg Crospovidone 28mg

[0033] Testosterone undecanoate is added to 95% ethanol, stirred until completely dissolved, and then hydroxypropyl methylcellulose is slowly added under stirring, and stirring is continued to fully swell, and the solution is used as a drug-containing solution for standby use; lactose is placed in a wet mixer, the stirring paddle is turned on at 500 rpm, and the prepared drug-containing solution is added at a uniform speed. After the addition is completed, the wet particles are taken out and wet granulated with 20 mesh to 40 mesh; the granulated particles are placed in a fluidized bed for drying, the air inlet temperature is 50±3°C, and the drying end point LOD is less than 3%. After drying, the particles are dry granulated with 20 mesh to 40 mesh, and a corresponding proportion of cross-linked polyvinylpyrrolidone is mixed externally to obtain solid dispersion particles.

[0034] Example 2

[0035] Testosterone undecanoate solid preparation, the amount of lactose in Example 1 is halved, the specific prescription is as follows:

[0036] Testosterone Undecanoate 5mg Lactose G200 110mg Hydroxypropyl methylcellulose E6 LV 5mg Crospovidone 28mg

[0037] The preparation method is the same as that of Example 1

[0038] Example 3

[0039] Testosterone undecanoate solid preparation, the lactose in Example 2 is replaced by maltodextrin, the specific formula is as follows

[0040] Testosterone Undecanoate 5mg Maltodextrin 110mg Hydroxypropyl methylcellulose E6 LV 5mg Crospovidone 28mg

[0041] The preparation method is the same as that of Example 1

[0042] Comparative Example 1

[0043] Testosterone undecanoate solid preparation is granulated using a self-emulsifying process. The specific formula and preparation method are as follows:

[0044] Testosterone Undecanoate 5mg Microcrystalline cellulose 102 260mg Medium Chain Triglycerides 25mg Caprylic / capric macrogol glycerides 30mg Diethylene glycol monoethyl ether 10mg

[0045] Add testosterone undecanoate to medium-chain triglycerides and stir at medium speed until completely dissolved; then add caprylic acid capric acid macrogol glyceride and diethylene glycol monoethyl ether to the solution and stir at medium speed until the solution is uniform, clear and transparent. Then slowly pour the solution into microcrystalline cellulose and stir slowly until the microcrystalline cellulose completely and evenly absorbs the solution to form self-emulsifying particles.

[0046] Comparative Example 2

[0047] Testosterone undecanoate solid preparation, the microcrystalline cellulose in comparative example 1 is replaced with maltodextrin, the specific formula is as follows

[0048] Testosterone Undecanoate 5mg Maltodextrin 260mg Medium Chain Triglycerides 25mg Caprylic / capric macrogol glycerides 30mg Diethylene glycol monoethyl ether 10mg

[0049] Preparation method is the same as that of Comparative Example 1

[0050] Comparative Example 3

[0051] Testosterone undecanoate solid preparation, using wet granulation process, the specific formula and preparation method are as follows:

[0052] Testosterone Undecanoate 5mg Lactose G200 37.3mg Microcrystalline Cellulose 101 37.3mg Povidone K30 2mg

[0053] Put testosterone undecanoate, lactose and microcrystalline cellulose into a wet granulator, turn on the stirring paddle at 500rpm to mix evenly. Add povidone to purified water, stir at medium speed until clear and transparent, and use it as a binder solution for later use. Turn on the stirring paddle of the wet granulator at 500rpm, slowly add the binder solution into the wet granulator, and after all the binders are added, turn on the cutting paddle for granulation, and the cutting paddle is 1000rpm. Take out the wet granules and perform 20 mesh wet granulation; put the granulated granules into a fluidized bed for drying, the inlet air temperature is 50±3℃, and the drying end point LOD is less than 3%. After drying, perform 20 mesh dry granulation on the granules to obtain wet granulated granules.

[0054] Dissolution results

[0055] It is determined according to the dissolution and release test method (Method 2, General Rules 0931, Part 4, 2020 Edition of the Chinese Pharmacopoeia).

[0056] Dissolution conditions: 900 ml of pH 6.8 phosphate buffer (6.8 g of potassium dihydrogen phosphate and 0.9 g of sodium hydroxide are weighed, dissolved in water to 1000 ml, and the pH value is adjusted to 6.8 with phosphoric acid or sodium hydroxide solution) is used as the dissolution medium, the rotation speed is 75 revolutions per minute, and the operation is carried out according to the law. 1.5 ml of the dissolution solution is taken after 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes, and the dissolution medium of the same temperature and volume is immediately replenished. After the dissolution is completed, the rotation speed is adjusted to 200 revolutions per minute, and the operation is carried out according to the law. 1.5 ml of the dissolution solution is taken after 30 minutes.

[0057] Test solution: Take the dissolution solution after 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes respectively.

[0058] Reference solution: Take an appropriate amount of testosterone undecanoate API, add an appropriate amount of methanol, sonicate to dissolve, and quantitatively dilute to make a solution containing approximately 5.6 μg per 1 ml.

[0059] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; the mobile phase was acetonitrile-isopropanol-water (43:43:14); and the detection wavelength was 240 nm.

[0060] Dissolution test results

[0061] Dissolution time Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 5min 48％ 41％ 23％ 4％ 7％ 0.1％ 10min 49％ 44％ 25％ 4％ 7％ 0.2％ 15min 49％ 43％ 25％ 4％ 7％ 0.2％ 30min 49％ 44％ 24％ 4％ 7％ 0.3％ 45min 48％ 42％ 25％ 4％ 7％ 0.3％ 60min 46％ 43％ 24％ 4％ 7％ 0.4％

Claims

1. A testosterone undecanoate oral granule, characterized in that, The particles contain testosterone undecanoate, an adsorbent and a carrier.

2. testosterone undecanoate oral granules as claimed in claim 1, wherein the granules do not contain a lipophilic solubilizing agent or a surfactant.

3. as the testosterone undecanoate oral granules described in any one of claim 1-2, in parts by weight, the ratio of testosterone undecanoate to adsorbent is 1:1-1:100, preferably 1:10-1:60, more preferably 1:20-1:

50.

4. as claimed in any one of claims 1-3 testosterone undecanoate oral granules, in parts by weight, the ratio of testosterone undecanoate to adsorbent is 1:44 or 1:

22.

5. as claimed in any one of claims 1 to 4, the testosterone undecanoate oral granules, the adsorbent is lactose or maltodextrin, preferably lactose, more preferably lactose G200.

6. as claimed in any one of claims 1-5 testosterone undecanoate oral granules, the weight ratio of described testosterone undecanoate and carrier is 5:1-1:5, preferably 1:2-2:1, more preferably 1:

1.

7. The testosterone undecanoate oral granules according to any one of claims 1 to 6, wherein the carrier is selected from one or more of hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, povidone, polyethylene glycol, ethyl cellulose, pregelatinized starch, and sodium carboxymethyl starch, preferably hypromellose, more preferably hypromellose E6 LV.

8. as any one of claim 1-7 testosterone undecanoate oral granules, the testosterone undecanoate solid particles also comprise other pharmaceutically acceptable adjuvants, the other adjuvants are selected from binders, plasticizers, sustained-release materials, fillers, disintegrants, glidants, enteric materials etc., preferably comprising disintegrants.

9. The testosterone undecanoate oral granules according to any one of claims 1 to 8, wherein the disintegrant is selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, etc., preferably cross-linked polyvinylpyrrolidone.

10. The testosterone undecanoate oral granules according to any one of claims 1 to 9, wherein the testosterone undecanoate solid granules comprise the following components in a weight ratio: or 11. as any one of claims 1-10 described testosterone undecanoate oral granules, the d90 particle size of testosterone undecanoate is 80-120 micron, preferably 100 micron.

12. The testosterone undecanoate oral granules according to any one of claims 1 to 11, wherein the granules are prepared by a solid dispersion process.

13. The testosterone undecanoate oral granules according to any one of claims 1 to 12, wherein the preparation method comprises: (1) Add testosterone undecanoate to 95% ethanol and stir until completely dissolved. Slowly add hydroxypropyl methylcellulose while stirring and continue stirring until fully swollen, and use this as a drug-containing solution for later use; (2) placing lactose in a wet mixer, turning on the stirring paddle, adding the prepared drug-containing solution, and after the addition is complete, taking out the wet granules and performing wet granulation; (3) The granules are placed in a fluidized bed for drying. After drying, the granules are dry granulated and mixed with a corresponding proportion of cross-linked polyvinylpyrrolidone to obtain solid dispersion granules.

14. The testosterone undecanoate oral granules according to any one of claims 1 to 13, wherein the granules are further coated with one or more layers of functional coatings.

15. An oral preparation of testosterone undecanoate, characterized in that: The oral preparation comprises the testosterone undecanoate oral granules according to any one of claims 1 to 14 and pharmaceutically acceptable excipients.

16. The testosterone undecanoate oral preparation according to claim 15, wherein the preparation is in the form of granules, tablets or capsules.

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