A kind of allylgestaltenone sustained-release medicine and preparation method thereof
Drug-loaded nanoparticles were prepared by reacting allyl progesterone with terminal carboxylic polylactic acid-hydroxyacetic acid, and combined with modified chitosan to make allyl progesterone sustained-release tablets, which solved the problems of inconvenience and poor stability of the existing allyl progesterone oral solution, and achieved the improvement of sustained-release effect and bioavailability.
Patent Information
- Application Number
- CN202510066277.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-16
- Publication Date
- 2025-04-11
- Estimated Expiration
- 2045-01-16
AI Technical Summary
The existing oral allyl progesterone oral solution administration methods are time-consuming and labor-intensive. The animal's direct irrigation compliance is poor, the dosage is inaccurate, and the stability is poor in acidic, light and thermal environments, resulting in low bioavailability and increased drug cost.
Drug-loaded nanoparticles were prepared by reacting allyl progesterone with terminal carboxylic polylactic acid-hydroxyacetic acid, and hydrophilic drug-loaded nanoparticles were prepared by reacting activation and modified chitosan. Combining hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose and lactose, a sustained-release tablet was prepared by direct tableting method.
The sustained release effect of allyl progesterone is achieved, its bioavailability is improved, the frequency of administration and labor cost is reduced, and the dispersion and release rate of the agent in the stomach environment is enhanced.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of polymer materials, in particular to an allylgestaltenone sustained-release medicament and a preparation method thereof. Background Art
[0002] Allylprogesterone belongs to the 19-nortestosterone compound, a synthetic fat-soluble steroidal progestin, also known as tetraenolone. Similar to other steroid drugs, it binds to the progesterone receptors of the hypothalamus and pituitary gland after entering the human body, producing negative feedback regulation, which can inhibit the pituitary gland from secreting gonadotropin-releasing hormone, thereby blocking the secretion of follicle-stimulating hormone and luteinizing hormone to prevent follicle development and estrus, thereby achieving regulation of the animal estrus cycle. Allylprogesterone has been used very maturely abroad to induce synchronous estrus in gilts and mares. At present, the legal allylprogesterone approved by my country is used in the form of oral solution in animal husbandry production, but the oral solution of allylprogesterone currently available at home and abroad is time-consuming and laborious to administer, and the animals have poor compliance when directly administered, and sprinkling it on the animal feed pile is also prone to inaccurate dosage. Moreover, under acidic conditions and light and heat environments, allylgestaltenes has poor stability and is easily damaged to a certain extent, resulting in problems such as low bioavailability, increased dosage, and increased drug costs, which has become the biggest limiting factor for its promotion and application in veterinary clinical practice.
[0003] Making allylgestalone into sustained-release tablets can continuously release the drug, prolong its half-life, maintain blood drug concentration, improve its bioavailability, and reduce the frequency of administration and labor costs. At present, the polylactic acid glycolic acid microsphere sustained-release system is preferentially suitable for the preparation of hydrophobic drugs, which can achieve the purpose of maintaining the effective concentration of drugs in the body for a long time. Summary of the invention
[0004] The purpose of the present invention is to provide a method for preparing an allergy-progesterone sustained-release medicament to solve the problems existing in the prior art.
[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:
[0006] The invention discloses an allylprogesterone sustained-release agent, which comprises the following steps: reacting allylprogesterone with carboxyl-terminated polylactic acid-glycolic acid to obtain drug-loaded nanoparticles; reacting chitosan with 3,4-dihydroxyphenylpropionic acid and then with carbodiimide solution to obtain modified chitosan; activating the drug-loaded nanoparticles with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide and then reacting with modified chitosan solution to obtain hydrophilic drug-loaded nanoparticles; and compressing the hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose and lactose into tablets by direct tableting.
[0007] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0008] (1) Allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane were mixed, stirred at 200-300 r / min for 1.5-2.5 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonicated at 750-850 r / min for 10-20 min using an ultrasonic homogenizer, centrifuged to separate the precipitate, washed with anhydrous ethanol and deionized water for 3-5 times, respectively, and freeze-dried to obtain drug-loaded nanoparticles;
[0009] (2) Mix chitosan and 1% acetic acid solution at a mass ratio of 1:500, stir at 200-300 r / min at room temperature until chitosan is completely dissolved, adjust the pH to 4-6 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, add 0.13-0.17 times the mass of chitosan 3,4-dihydroxyphenylpropionic acid, increase the speed to 800-1000 r / min, continue stirring for 1-2 h, and The pH value was adjusted to 4-6 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, and a carbodiimide solution of 0.2-0.22 times the mass of chitosan was added at 2-3 drops / second. After the addition was completed, the reaction was carried out at 500-600 r / min for 4-5 hours at room temperature, and then the pH value was adjusted to 5.0. After dialysis with pure water for 2 days, it was dialyzed with phosphate buffer solution for 4-5 hours, and then dialyzed with pure water for 1 day, and then freeze-dried to obtain modified chitosan;
[0010] (3) The drug-loaded nanoparticles were dispersed in 2-(N-morpholino)ethanesulfonic acid buffer at a pH of 5.0, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride at a mass of 0.05-0.1 times the mass of the drug-loaded nanoparticles and N-hydroxysuccinimide at a mass of 0.05-0.1 times the mass of the drug-loaded nanoparticles were added, and the mixture was stirred at 200-300 r / min for 1.5-2.5 h at room temperature, and a modified chitosan solution at a mass of 400-500 times the mass of the drug-loaded nanoparticles was added, and the stirring was continued for 40-50 h. The precipitate was separated by centrifugation, and the precipitate was washed 3-5 times with anhydrous ethanol and deionized water respectively, and freeze-dried to obtain hydrophilic drug-loaded nanoparticles;
[0011] (4) The hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed and compressed into 3.2 mm tablets by direct compression to prepare the progestogen sustained-release agent.
[0012] As an optimization, the mass ratio of allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane in step (1) is 1: (0.2-0.4): (30-40).
[0013] As an optimization, the carboxyl-terminated polylactic acid-glycolic acid in step (1) is a carboxyl-terminated polylactic acid-glycolic acid with an average molecular weight of 5000.
[0014] As an optimization, the chitosan described in step (2) is chitosan with a deacetylation degree of 85%.
[0015] As an optimization, the preparation method of the carbodiimide solution in step (2) is: mixing carbodiimide and deionized water in a mass ratio of 1: (25-35).
[0016] As an optimization, the preparation method of the phosphate buffer solution in step (2) is as follows: 8.0 g of sodium chloride, 0.2 g of potassium chloride, 1.44 g of disodium hydrogen phosphate, and 0.24 g of potassium dihydrogen phosphate are dissolved in 800 mL of pure water, the pH of the solution is adjusted to 7.4 with hydrochloric acid, and finally deionized water is added to make the volume to 1 L.
[0017] As an optimization, the mass ratio of the drug-loaded nanoparticles in step (3) to the 2-(N-morpholino)ethanesulfonic acid buffer with a pH of 5.0 is 1:50.
[0018] As an optimization, the mass ratio of the hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose in step (4) is 1:7:0.5:1:1.5.
[0019] As an optimization, the sustained-release formulation of progesterone is used as estrus medication for sows.
[0020] Compared with the prior art, the beneficial effects achieved by the present invention are:
[0021] When preparing the allylprogesterone sustained-release agent, the present invention comprises the following steps: reacting allylprogesterone with carboxyl-terminated polylactic acid-glycolic acid to obtain drug-loaded nanoparticles; reacting chitosan with 3,4-dihydroxyphenylpropionic acid and then reacting the reacted chitosan with a carbodiimide solution to obtain modified chitosan; activating the drug-loaded nanoparticles with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide and then reacting the reacted chitosan with a modified chitosan solution to obtain hydrophilic drug-loaded nanoparticles; and compressing the hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose and lactose into tablets by a direct tableting method to obtain the allylprogesterone sustained-release agent.
[0022] First, allylprogesterone is reacted with terminal carboxyl polylactic acid-glycolic acid to prepare drug-loaded nanoparticles. The terminal carboxyl polylactic acid-glycolic acid has good hydrophobicity and can effectively coat the equally hydrophobic allylprogesterone to achieve a good sustained-release effect. The terminal carboxyl polylactic acid-glycolic acid has good biocompatibility and biodegradability, and can be self-degraded and metabolized in animals without causing metabolic harm to the animals.
[0023] Secondly, the drug-loaded nanoparticles are activated by 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide and then reacted with a modified chitosan solution to obtain hydrophilic drug-loaded nanoparticles, which can effectively improve the hydrophilicity of the allylprogesterone sustained-release layer, thereby effectively improving its dispersibility in the gastric environment, thereby effectively improving the release rate of the allylprogesterone sustained-release agent, and chitosan, as a biomass material, can also be self-degraded and metabolized in the body, and will not cause metabolic harm to animals. DETAILED DESCRIPTION
[0024] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.
[0025] Embodiment 1:
[0026] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0027] (1) Allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane were mixed at a mass ratio of 1:0.2:30, stirred at 200 r / min for 1.5 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonically homogenized at 750 r / min for 10 min, centrifuged to separate the precipitate, washed three times with anhydrous ethanol and deionized water, respectively, and freeze-dried to obtain drug-loaded nanoparticles;
[0028] (2) Carbodiimide and deionized water were mixed at a mass ratio of 1:25 to prepare a carbodiimide solution; 8.0 g sodium chloride, 0.2 g potassium chloride, 1.44 g disodium hydrogen phosphate, and 0.24 g potassium dihydrogen phosphate were dissolved in 800 mL pure water, the pH of the solution was adjusted to 7.4 with hydrochloric acid, and finally deionized water was added to make the volume to 1 L to prepare a phosphate buffer solution; chitosan and 1% acetic acid solution were mixed at a mass ratio of 1:500, and stirred at 200 r / min at room temperature until the chitosan was completely dissolved, and 1 mol / L sodium hydroxide solution and 1 mol / L The pH value of the mixture was adjusted to 4 with hydrochloric acid solution, 0.13 times the mass of chitosan 3,4-dihydroxyphenylpropionic acid was added, the rotation speed was increased to 800 r / min, stirring was continued for 1 hour, and the pH value was adjusted to 4 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, 0.2 times the mass of chitosan carbodiimide solution was added dropwise at 2 drops / second, after the addition was completed, the mixture was reacted at 500 r / min at room temperature for 4 hours, and then the pH value was adjusted to 5.0, and the mixture was dialyzed with pure water for 2 days, then dialyzed with phosphate buffered saline for 4 hours, and then dialyzed with pure water for 1 day, and freeze-dried to obtain modified chitosan;
[0029] (3) Disperse the drug-loaded nanoparticles and 2-(N-morpholino)ethanesulfonic acid buffer solution with a pH of 5.0 at a mass ratio of 1:50, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.05 times the mass of the drug-loaded nanoparticles) and N-hydroxysuccinimide (0.05 times the mass of the drug-loaded nanoparticles), stir at 200 r / min for 1.5 h at room temperature, add 400 times the mass of the drug-loaded nanoparticles modified chitosan solution, continue stirring for 40 h, separate the precipitate by centrifugation, wash the precipitate with anhydrous ethanol and deionized water for 3 times, respectively, and freeze-dry to obtain hydrophilic drug-loaded nanoparticles;
[0030] (4) The hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed at a mass ratio of 1:7:0.5:1:1.5, and the mixture was compressed into 3.2 mm tablets by direct tableting to obtain a progestogen sustained-release preparation.
[0031] Embodiment 2:
[0032] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0033] (1) Allylgestaltenes, carboxyl-terminated polylactic-glycolic acid, and dichloromethane were mixed at a mass ratio of 1:0.3:35, stirred at 250 r / min for 2 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonically homogenized at 800 r / min for 15 min, centrifuged to separate the precipitate, washed 4 times with anhydrous ethanol and deionized water, respectively, and freeze-dried to obtain drug-loaded nanoparticles;
[0034] (2) Carbodiimide and deionized water were mixed at a mass ratio of 1:30 to prepare a carbodiimide solution; 8.0 g sodium chloride, 0.2 g potassium chloride, 1.44 g disodium hydrogen phosphate, and 0.24 g potassium dihydrogen phosphate were dissolved in 800 mL pure water, and the pH of the solution was adjusted to 7.4 with hydrochloric acid. Finally, deionized water was added to make the volume to 1 L to prepare a phosphate buffer solution; chitosan and 1% acetic acid solution were mixed at a mass ratio of 1:500, and stirred at 250 r / min at room temperature until the chitosan was completely dissolved. 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution were used to adjust the pH of the solution to 7.4. The pH was set to 5, 3,4-dihydroxyphenylpropionic acid (0.15 times the mass of chitosan) was added, the speed was increased to 900 r / min, stirring was continued for 1.5 h, and the pH was adjusted to 5 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, and a carbodiimide solution (0.21 times the mass of chitosan) was added dropwise at 2.5 drops / second. After the addition was completed, the reaction was carried out at 550 r / min at room temperature for 4.5 h, and then the pH was adjusted to 5.0. After dialysis with pure water for 2 days, it was dialyzed with phosphate buffered saline for 4.5 h, and then dialyzed with pure water for 1 day, and the modified chitosan was obtained after freeze-drying;
[0035] (3) Disperse the drug-loaded nanoparticles and 2-(N-morpholino)ethanesulfonic acid buffer solution with a pH of 5.0 at a mass ratio of 1:50, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.075 times the mass of the drug-loaded nanoparticles) and N-hydroxysuccinimide (0.075 times the mass of the drug-loaded nanoparticles), stir at 250 r / min for 2 h at room temperature, add modified chitosan solution (450 times the mass of the drug-loaded nanoparticles), continue stirring for 45 h, separate the precipitate by centrifugation, wash the precipitate with anhydrous ethanol and deionized water for 4 times, respectively, and freeze-dry to obtain hydrophilic drug-loaded nanoparticles;
[0036] (4) The hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed at a mass ratio of 1:7:0.5:1:1.5, and the mixture was compressed into 3.2 mm tablets by direct tableting to obtain a progestogen sustained-release preparation.
[0037] Embodiment 3:
[0038] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0039] (1) Allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane were mixed at a mass ratio of 1:0.4:40, stirred at 300 r / min for 2.5 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonically homogenized at 850 r / min for 20 min, centrifuged to separate the precipitate, washed 5 times with anhydrous ethanol and deionized water respectively, and freeze-dried to obtain drug-loaded nanoparticles;
[0040] (2) Carbodiimide and deionized water were mixed at a mass ratio of 1:35 to prepare a carbodiimide solution; 8.0 g of sodium chloride, 0.2 g of potassium chloride, 1.44 g of disodium hydrogen phosphate, and 0.24 g of potassium dihydrogen phosphate were dissolved in 800 mL of pure water, and the pH of the solution was adjusted to 7.4 with hydrochloric acid. Finally, deionized water was added to make the volume to 1 L to prepare a phosphate buffer solution; chitosan and 1% acetic acid solution were mixed at a mass ratio of 1:500, and stirred at 300 r / min at room temperature until the chitosan was completely dissolved. 1 mol / L sodium hydroxide solution and 1 mol / L salt were added. The pH of the solution was adjusted to 6, 3,4-dihydroxyphenylpropionic acid (0.17 times the mass of chitosan) was added, the speed was increased to 1000 r / min, stirring was continued for 2 hours, and the pH was adjusted to 6 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, and a carbodiimide solution (0.22 times the mass of chitosan) was added at 3 drops / second. After the addition was completed, the reaction was carried out at 600 r / min at room temperature for 5 hours, and then the pH was adjusted to 5.0. After dialyzing with pure water for 2 days, dialyzing with phosphate buffered saline for 5 hours, and then dialyzing with pure water for 1 day, the modified chitosan was obtained after freeze-drying;
[0041] (3) Disperse the drug-loaded nanoparticles and 2-(N-morpholino)ethanesulfonic acid buffer solution with a pH of 5.0 at a mass ratio of 1:50, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.1 times the mass of the drug-loaded nanoparticles) and N-hydroxysuccinimide (0.1 times the mass of the drug-loaded nanoparticles), stir at 300 r / min for 2.5 h at room temperature, add 500 times the mass of the drug-loaded nanoparticles modified chitosan solution, continue stirring for 50 h, centrifuge to separate the precipitate, wash the precipitate with anhydrous ethanol and deionized water for 5 times, respectively, and freeze-dry to obtain hydrophilic drug-loaded nanoparticles;
[0042] (4) The hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed at a mass ratio of 1:7:0.5:1:1.5, and the mixture was compressed into 3.2 mm tablets by direct tableting to obtain a progestogen sustained-release preparation.
[0043] Comparative Example 1:
[0044] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0045] (1) Disperse the drug-loaded nanoparticles and 2-(N-morpholino)ethanesulfonic acid buffer solution with a pH of 5.0 at a mass ratio of 1:50, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.075 times the mass of the drug-loaded nanoparticles) and N-hydroxysuccinimide (0.075 times the mass of the drug-loaded nanoparticles), stir at 250 r / min for 2 h at room temperature, add modified chitosan solution (450 times the mass of the drug-loaded nanoparticles), continue stirring for 45 h, separate the precipitate by centrifugation, wash the precipitate with anhydrous ethanol and deionized water for 4 times, respectively, and freeze-dry to obtain hydrophilic drug-loaded nanoparticles;
[0046] (2) Allylprogesterone, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose and lactose were mixed at a mass ratio of 1:7:0.5:1:1.5, and compressed into 3.2 mm tablets by direct tableting to prepare an allylprogesterone sustained-release preparation.
[0047] Comparative Example 2:
[0048] A method for preparing an allergy-progesterone sustained-release preparation comprises the following steps:
[0049] (1) Allylgestaltenes, carboxyl-terminated polylactic-glycolic acid, and dichloromethane were mixed at a mass ratio of 1:0.3:35, stirred at 250 r / min for 2 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonically homogenized at 800 r / min for 15 min, centrifuged to separate the precipitate, washed 4 times with anhydrous ethanol and deionized water, respectively, and freeze-dried to obtain drug-loaded nanoparticles;
[0050] (2) The drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed at a mass ratio of 1:7:0.5:1:1.5, and the mixture was compressed into 3.2 mm tablets by direct tableting to obtain a progestogen sustained-release preparation.
[0051] Test example:
[0052] A total of 90 reserve sows were randomly divided into two groups, one group was the control group, which was directly treated with allylprogesterone; the other group was the experimental group, which was treated with allylprogesterone sustained-release preparation. The two groups of sows used the same feed, feeding environment and feeding methods to reduce the error caused by feeding.
[0053] (1) Dosage method
[0054] The dosing method of the control group: 45 sows were given the oral solution of allylprogesterone according to the instructions, once a day for 14 consecutive days. Each pig was mixed with 20 mg of oral solution of allylprogesterone into the feed every day to ensure that each pig ate all the feed every time. 40 hours after the last administration (14 days), 1000 units of pregnant mare serum gonadotropin were injected intramuscularly into the neck of the sows. After an interval of 80 hours, 100 μg of gonadotropin-releasing hormone was injected intramuscularly into the neck of the sows. After that, artificial insemination was performed once at 24 hours and 40 hours respectively, and pregnancy test was performed 30 days later.
[0055] Dosage method of the test group: 45 sows were orally fed with 4 capsules of the allylprogesterone sustained-release agent prepared in each embodiment and comparative example on the first day, 1000 units of pregnant mare serum gonadotropin were injected intramuscularly into the neck muscle of the sows on day 14, and 100 μg of gonadotropin-releasing hormone was injected intramuscularly into the neck muscle at intervals of 80 h, followed by artificial insemination once at 24 h and 40 h, and a pregnancy test was performed 30 days later.
[0056] (2) Criteria for judging sow pregnancy
[0057] Iodination method: Take about 10 ml of sow urine and put it into a test tube. Use a hydrometer to measure its specific gravity (should be between 1.0 and 1.025). If it is too concentrated, add water to dilute it. Then drop iodine into it and heat it on a gas lamp or alcohol lamp. When the urine reaches the boiling point, the color changes: red from top to bottom indicates pregnancy; light yellow or brown-green indicates non-pregnancy. The results are shown in the table below.
[0058] Table 1
[0059]
[0060] From the comparison of the experimental data of Examples 1 to 3 and Comparative Examples 1 and 2 in Table 1, it can be found that the allylprogesterone sustained-release preparation prepared by the present invention has good sustained-release performance and a high drug release rate.
[0061] By comparison, the number of pregnancies in Examples 1 to 3 is greater than the number of pregnancies in Comparative Example 1, indicating that drug-loaded nanoparticles are prepared by reacting allylprogesterone with carboxyl-terminated polylactic acid-glycolic acid, and the carboxyl-terminated polylactic acid-glycolic acid has good hydrophobicity and can effectively coat the equally hydrophobic allylprogesterone to achieve a good sustained-release effect.
[0062] By comparison, the number of pregnancies in Examples 1 to 3 is greater than the number of pregnancies in Comparative Example 2, indicating that the hydrophilic drug-loaded nanoparticles prepared by reacting the drug-loaded nanoparticles with the modified chitosan solution after being activated by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide can effectively improve the hydrophilicity of the allylprogesterone sustained-release layer, thereby effectively improving its dispersibility in the gastric environment, thereby effectively improving the release rate of the allylprogesterone sustained-release agent.
[0063] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. A method for preparing an allylgestaltenone sustained-release medicament, characterized in that: The method comprises the following preparation steps: (1) Allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane were mixed, stirred at 200-300 r / min for 1.5-2.5 h at room temperature, added dropwise to a 5 mg / ml polyvinyl alcohol aqueous solution, ultrasonicated at 750-850 r / min for 10-20 min using an ultrasonic homogenizer, centrifuged to separate the precipitate, washed with anhydrous ethanol and deionized water for 3-5 times, respectively, and freeze-dried to obtain drug-loaded nanoparticles; (2) Mix chitosan and 1% acetic acid solution at a mass ratio of 1:500, stir at 200-300 r / min at room temperature until chitosan is completely dissolved, adjust the pH to 4-6 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, add 0.13-0.17 times the mass of chitosan 3,4-dihydroxyphenylpropionic acid, increase the speed to 800-1000 r / min, continue stirring for 1-2 h, and The pH value was adjusted to 4-6 with 1 mol / L sodium hydroxide solution and 1 mol / L hydrochloric acid solution, and a carbodiimide solution of 0.2-0.22 times the mass of chitosan was added at 2-3 drops / second. After the addition was completed, the reaction was carried out at 500-600 r / min for 4-5 hours at room temperature, and then the pH value was adjusted to 5.
0. After dialysis with pure water for 2 days, it was dialyzed with phosphate buffer solution for 4-5 hours, and then dialyzed with pure water for 1 day, and then freeze-dried to obtain modified chitosan; (3) The drug-loaded nanoparticles were dispersed in 2-(N-morpholino)ethanesulfonic acid buffer at a pH of 5.0, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride at a mass of 0.05-0.1 times the mass of the drug-loaded nanoparticles and N-hydroxysuccinimide at a mass of 0.05-0.1 times the mass of the drug-loaded nanoparticles were added, and the mixture was stirred at 200-300 r / min for 1.5-2.5 h at room temperature, and a modified chitosan solution at a mass of 400-500 times the mass of the drug-loaded nanoparticles was added, and the stirring was continued for 40-50 h. The precipitate was separated by centrifugation, and the precipitate was washed 3-5 times with anhydrous ethanol and deionized water respectively, and freeze-dried to obtain hydrophilic drug-loaded nanoparticles; (4) The hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose, and lactose were mixed and compressed into 3.2 mm tablets by direct compression to prepare the progestogen sustained-release agent.
2. The method for preparing the sustained-release allylgestaltenone medicament according to claim 1, characterized in that: The mass ratio of allylgestaltenes, carboxyl-terminated polylactic-co-glycolic acid, and dichloromethane in step (1) is 1: (0.2-0.4): (30-40).
3. The method for preparing the sustained-release alkaloid progesterone preparation according to claim 1, characterized in that: The carboxyl-terminated polylactic-co-glycolic acid in step (1) is a carboxyl-terminated polylactic-co-glycolic acid having an average molecular weight of 5000.
4. The method for preparing the allylprogesterone sustained-release medicament according to claim 1, characterized in that: The chitosan described in step (2) is chitosan with a deacetylation degree of 85%.
5. The method for preparing the sustained-release phenotype of claim 1, characterized in that: The preparation method of the carbodiimide solution in step (2) is as follows: carbodiimide and deionized water are mixed in a mass ratio of 1: (25-35).
6. The method for preparing the sustained-release allylprogesterone preparation according to claim 1, characterized in that: The preparation method of the phosphate buffer solution in step (2) is as follows: 8.0 g of sodium chloride, 0.2 g of potassium chloride, 1.44 g of disodium hydrogen phosphate, and 0.24 g of potassium dihydrogen phosphate are dissolved in 800 mL of pure water, the pH of the solution is adjusted to 7.4 with hydrochloric acid, and finally deionized water is added to make the volume to 1 L.
7. The method for preparing the sustained-release allylgestaltenone medicament according to claim 1, characterized in that: The mass ratio of the drug-loaded nanoparticles in step (3) to the 2-(N-morpholino)ethanesulfonic acid buffer solution with a pH of 5.0 is 1:
50.
8. The method for preparing the sustained-release allylprogesterone preparation according to claim 1, characterized in that: In step (4), the mass ratio of the hydrophilic drug-loaded nanoparticles, hydroxypropyl-β-cyclodextrin, magnesium stearate, hydroxypropyl cellulose and lactose is 1:7:0.5:1:1.
5.
9. Use of the medicament obtained by the method for preparing the allylprogesterone sustained-release medicament according to any one of claims 1 to 8 in preparing a sow estrus drug.
Citation Information
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