CN116803375A - Oral solution of allyl progestogen and preparation method thereof - Google Patents

Oral solution of allyl progestogen and preparation method thereof Download PDF

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CN116803375A
CN116803375A CN202310681361.6A CN202310681361A CN116803375A CN 116803375 A CN116803375 A CN 116803375A CN 202310681361 A CN202310681361 A CN 202310681361A CN 116803375 A CN116803375 A CN 116803375A
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allyl
oral solution
progestogen
cyclodextrin
homogenizing
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梁劲康
雍燕
张桂君
温永茹
程含波
方炳虎
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Guangdong Wens Dahuanong Biotechnology Co ltd
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Guangdong Wens Dahuanong Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention belongs to the field of novel veterinary preparations, and in particular relates to an oral solution of allyl progestogen and a preparation method thereof. The oral solution of the allyl progestogen provided by the invention comprises, by weight, 0.1-1.0 part of the allyl progestogen, 0.1-5.0 parts of a inclusion agent, 0.2-2.0 parts of an antioxidant, 0.1-2.0 parts of a preservative and the balance of a solvent. The oral solution of the allyl progestogen provided by the invention has high water solubility and low temperature tolerance, can be completely dissolved in culture drinking water, is administered by a drinking water way, saves time and labor, and also avoids the problems of uneven administration and the like; meanwhile, the use of an oil solvent is avoided under the condition of not influencing the use, solidification is not easy to occur under the low-temperature condition, and the stable performance is good.

Description

Oral solution of allyl progestogen and preparation method thereof
Technical Field
The invention belongs to the field of novel veterinary preparations, and in particular relates to an oral solution of allyl progestogen and a preparation method thereof.
Background
In recent years, more and more large-scale farms are moving towards a production batch management mode: the whole batch of sows or the reserve sows are synchronously oestrus, so that the sows or the reserve sows can finish breeding and delivery in the same time, thereby reducing the workload and being more beneficial to swinery management. And the batch production management enables the swinery to flow directionally, realizes a strict full-in and full-out management mode, and has unique advantages for preventing and controlling major animal epidemic situations such as African swine fever and the like. One of the core contents of batch production management is that hormone medicines are adopted to enable sows to heat synchronously, namely, after proper treatment, the sows heat in the same time, so that intensive production and management are convenient to organize.
Allyl progestogen is an artificially synthesized steroid progestogen, and can inhibit pituitary gland from secreting gonadotrophin during administration, prevent follicular development and oestrus, and recover from secreting gonadotrophin after administration, thereby promoting follicular development and oestrus. Therefore, the allyl progestogen is widely applied to the synchronous estrus management of sows in a high-efficiency farm. The allyl progestogen is taken to the sow in 15-20 mg/day dose in 14-18 days continuously, which can successfully lead the sow to synchronously estrus and can obviously improve the reproductive performance of the sow.
Currently, the agricultural rural department of China has approved allylic pregnene and its oral solution for use in livestock breeding. Because the solubility of the allyl progestogen in water is poor, when the allyl progestogen is developed into an oral solution preparation by domestic and overseas animal insurance enterprises, the allyl progestogen is mostly dissolved in an oil solvent to prepare corresponding products. The oral solutions of allyl pregna such as French Shiwa, french Vickers, intel and GmbH are all products prepared by dissolving allyl pregna in soybean oil. Similarly, the patent of CN108042485B and CN109260208B both use vegetable oil such as soybean oil, peanut oil or palm oil to dissolve allyl progestogen to prepare oral solution. The oily allyl progestogen oral solution cannot be administered by a drinking water way, and is mostly administered by direct drenching or mixed feeding by spraying on feed. However, the above administration method is time-consuming and laborious, and there are many clinical limitations: if the feed is directly administered by drenching, a feeder is commonly shared by a plurality of sows, so that animal epidemic diseases are easily spread, and the biological safety management is not facilitated. On the other hand, when the medicine is administrated by drenching, the feeder catheter is required to be inserted into the esophagus of a sow, the compliance is poor, and the medicine is easy to cause stress reactions such as nausea and vomiting, so that the medicine is spitted by the sow, the dosage is insufficient, and further adverse reactions such as follicular cyst of the sow are caused, and the health of the sow is also not facilitated. In the process of spraying the oral solution of the allyl progestogen on the feed, the allyl progestogen is easy to adhere to the wall of the trough, so that the dosage is inaccurate, and a series of subsequent adverse reactions are caused. In addition, since the oil can be coagulated in a low-temperature environment, the oral solution of the allyl progestin prepared by the oil solvent can be thickened or coagulated in cold winter, and is difficult to be administrated by filling through a feeder, and proper heating treatment is needed before use. The heating temperature of the oral solution of the allyl progestogen needs to be strictly controlled, and the excessive temperature easily causes the degradation of the medicine to influence the medicine effect and brings inconvenience to the breeding user.
Therefore, aiming at the technical problems of the oil-type allylic oral solution in the prior art, the development of a novel allylic oral solution is urgently needed to solve the problems of the drug administration biosafety, inaccurate drug administration dosage, drug effect affected by temperature and the like caused by the limitation of the solubility performance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an allyl progestogen oral solution and a preparation method thereof. The oral solution of the allyl pregna is composed of the allyl pregna, the auxiliary materials with high water solubility and the solvent, can be completely dissolved in water, has good water solubility and is colorless clear oily liquid; the preparation method avoids the heating process, has lower content of related substances, higher content of medicines, is resistant to low-temperature environment, has good stability, and is a novel preparation of the oral solution of the allyl progestin which is difficult to solidify in low-temperature environment and can be administrated by a drinking water way.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first object of the present invention is to provide an oral solution of allyl progestogen, comprising, by weight, 0.1 to 1.0 parts of allyl progestogen, 0.1 to 5.0 parts of a inclusion agent, 0.2 to 2.0 parts of an antioxidant, 0.1 to 2.0 parts of a preservative and the balance of a solvent.
Preferably, the inclusion agent is cyclodextrin and derivatives thereof.
Preferably, the cyclodextrin and its derivative are one or more than two of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.
Preferably, the inclusion agent is one or two of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.
Preferably, the antioxidant is one or more of thioglycerol, hydroxy ethanol, propyl gallate and butyl gallate.
Preferably, the antioxidant is one or two of thioglycerol and hydroxy ethanol.
Preferably, the preservative is one or more of phenethyl alcohol, ethyl hydroxybenzoate, butyl hydroxybenzoate, propyl hydroxybenzoate, methyl hydroxybenzoate, benzoic acid, sorbic acid, benzalkonium bromide, benzalkonium chloride and thimerosal.
Preferably, the preservative is phenethyl alcohol.
The invention adopts phenethyl alcohol as preservative, and has good compatibility with solvents (propylene glycol, polyethylene glycol and glycerol methylal) adopted by the invention.
Preferably, the solvent is one or more of propylene glycol, polyethylene glycol and glycerol methylal.
Preferably, the polyethylene glycol is polyethylene glycol 200, polyethylene glycol 300 or polyethylene glycol 400.
Preferably, the solvent is one or two of propylene glycol and polyethylene glycol 200.
Another object of the present invention is to provide a method for preparing an oral solution of allyl progestogen as described above, characterized by comprising the steps of:
(1) Preparation: the raw materials including the allyl progestogen, the solvent, the inclusion agent, the antioxidant and the preservative are respectively weighed according to the process formula proportion for standby;
(2) Mixing and homogenizing: sequentially adding the raw materials and the auxiliary materials weighed in the step (1) into a stirring tank, stirring and uniformly mixing the raw materials and the auxiliary materials at a certain stirring temperature, and homogenizing after the raw materials and the auxiliary materials are completely dissolved to obtain a liquid medicine;
(3) Filtering and sub-packaging: filtering the liquid medicine obtained in the step (2) by a filter rod, sub-packaging, filling nitrogen, and sealing and preserving.
Preferably, in the step (2), the stirring temperature is 18-35 ℃; in the homogenizing treatment, the homogenizing power is 20-100 HZ, and the homogenizing time is 15-40 min.
Preferably, the stirring temperature in the step (2) is 20-30 ℃.
Preferably, the filtering of the liquid medicine in the step (3) through a filter rod comprises two-stage filtering of the liquid medicine; the pore diameters of the two-stage filter rods are 45.0-55.0 mu m and 25.0-35.0 mu m respectively.
It is another object of the present invention to provide the use of an oral solution of allylic progestogen prepared according to the above method for the preparation of a product for inhibiting the release of gonadotropins.
The coating agent comprises the following components: the cyclodextrin and the derivative thereof with a cavity structure are adopted as the inclusion agent, and can well form an inclusion compound with the allyl progestogen. According to the invention, the inclusion agent is added into the formula of the oral solution of the allyl progestogen, so that an inclusion compound can be formed with the main medicine, the solubility of the allyl progestogen in water can be improved, and the stability of the allyl progestogen can be improved. The dosage of the inclusion agent needs to be adjusted according to the content of the allyl progestogen, and the dosage of the inclusion agent is too low to completely form the allyl progestogen into an inclusion compound, so that the solubilization and stabilization effects can not be achieved; if the dosage is too high, the production cost is increased.
Antioxidant: the invention adopts one or more than two of thioglycerol, hydroxy ethanol, propyl gallate and butyl gallate as oxidant, and has good compatibility with the dissolvent (propylene glycol, polyethylene glycol and glycerol methylal) adopted by the invention. The reason for this is mainly because allyl progestogen is relatively sensitive to oxygen and is very susceptible to oxidative degradation. The invention can avoid the oxidation inactivation of the allylic drug by adding a proper amount of antioxidant into the formula, wherein the dosage of the antioxidant needs to be adjusted according to the content and the category of the allylic drug.
Preservative: according to the invention, the preservative is added into the formula of the oral solution of the allyl progestin, so that the problem that the product quality is affected due to bacteria breeding in the storage process of the oral solution of the allyl progestin is avoided.
A solvent: according to the invention, the propylene glycol, the polyethylene glycol, the glycerol methylal and other organic solvents are used as solvents, so that the allyl progestogen can be well dissolved, and the propylene glycol and the polyethylene glycol can isolate the contact of the allyl progestogen and oxygen to a certain extent, so that the allyl progestogen is prevented from being oxidized and degraded. The invention adopts the organic solvents such as propylene glycol, polyethylene glycol, glycerol methylal and the like as solvents to play a role of latent solvent, can improve the solubility of the allyl progestogen in water in cooperation with the inclusion agent, and avoids the quality problems such as drug precipitation after the sample is diluted with water.
Compared with the prior art, the invention has the following beneficial effects:
the oral solution of the allyl progestogen provided by the invention has high water solubility, can be completely dissolved in the drinking water for cultivation, can be administered by a drinking water way, saves time and labor, also avoids the problems of uneven administration and the like, realizes accurate administration and ensures the drug effect.
The novel allyl progestogen oral solution provided by the invention can keep good fluidity under the low-temperature condition, has good low-temperature tolerance, avoids using an oil solvent under the condition of not influencing use, is not easy to solidify under the low-temperature condition, and has good stability.
The preparation method of the oral solution of the allyl progestogen provided by the invention has the advantages that the raw materials and the auxiliary materials used are simple and easy to obtain, the preparation process is simple, and the preparation method is more suitable for industrial mass production.
Detailed Description
The above-described aspects of the present invention will be described in further detail with reference to the following embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples.
EXAMPLE 1 preparation of 0.2% oral solution of Albumin (10L) according to the invention
The preparation of the oral solution of the allyl progestogen provided by the invention comprises the following steps:
(1) Preparation: according to the technological formula, respectively weighing 20g of allyl progestogen, 20g of beta-cyclodextrin, 30g of thioglycerol and 100g of phenethyl alcohol as raw materials for standby;
(2) Mixing and homogenizing: sequentially adding the raw materials and the auxiliary materials weighed in the step (1) into a stirring tank, adding polyethylene glycol 200 to make the solution system 10L, stirring the raw materials and the auxiliary materials for 10min at the temperature of 25 ℃ and the speed of 100rpm, uniformly mixing, homogenizing after the raw materials and the auxiliary materials are completely dissolved, starting a homogenizer, setting the power at 30Hz, and homogenizing and shearing for 20min to obtain a liquid medicine;
(3) Filtering and sub-packaging: filtering the liquid medicine obtained in the step (2) by a filter membrane of 50.0 mu m and a filter membrane of 30.0 mu m respectively for two times, then sub-packaging the liquid medicine into aluminum bottles, filling nitrogen and sealing.
EXAMPLE 2 preparation of 0.4% oral solution of Albumin (10L) according to the invention
The preparation of the oral solution of the allyl progestogen provided by the invention comprises the following steps:
(1) Preparation: 40g of allylpregna, 60g of beta-cyclodextrin, 50g of thioglycerol and 100g of phenethyl alcohol are respectively weighed according to the technological formula proportion for standby;
(2) Mixing and homogenizing: sequentially adding the raw materials and the auxiliary materials weighed in the step (1) into a stirring tank, adding propylene glycol to make the solution system 10L, stirring the raw materials and the auxiliary materials for 15min at the temperature of 25 ℃ and the speed of 200rpm, uniformly mixing, homogenizing after the raw materials and the auxiliary materials are completely dissolved, starting a homogenizer, setting the power at 50Hz, and homogenizing and shearing for 20min to obtain a liquid medicine;
(3) Filtering and sub-packaging: filtering the liquid medicine obtained in the step (2) by a filter membrane of 50.0 mu m and a filter membrane of 30.0 mu m respectively for two times, then sub-packaging the liquid medicine into aluminum bottles, filling nitrogen and sealing.
EXAMPLE 3 preparation of 0.8% oral solution of Albumin (10L) according to the invention
The preparation of the oral solution of the allyl progestogen provided by the invention comprises the following steps:
(1) Preparation: according to the technological formula, 80g of allyl progestogen, 100g of hydroxypropyl-beta-cyclodextrin, 60g of hydroxy ethanol and 150g of phenethyl alcohol are respectively weighed for standby application;
(2) Mixing and homogenizing: sequentially adding the raw materials and the auxiliary materials weighed in the step (1) into a stirring tank, adding propylene glycol to make the solution system 10L, stirring the raw materials and the auxiliary materials for 30min at the temperature of 25 ℃ and the speed of 200rpm, uniformly mixing, homogenizing after the raw materials and the auxiliary materials are completely dissolved, starting a homogenizer, setting the power at 60Hz, and homogenizing and shearing for 30min to obtain a liquid medicine;
(3) Filtering and sub-packaging: filtering the liquid medicine obtained in the step (2) by a filter membrane of 50.0 mu m and a filter membrane of 30.0 mu m respectively for two times, then sub-packaging the liquid medicine into aluminum bottles, filling nitrogen and sealing.
Comparative example 1 preparation of oily 0.4% oral solution (10L) of Albumin
Referring to the formula process of the allyl progestogen oral solution marketed by a certain animal insurance enterprise, the grease allyl progestogen oral solution is prepared, comprising the following steps:
(1) Preparation: 40g of allylpregna, 0.7g of tert-butyl-4-hydroxy anisole (BHA), 0.7g of 2, 6-di-tert-butyl-p-cresol (BHT) and 9.13kg of soybean oil are respectively weighed according to the process formula proportion for standby;
(2) Heating and dissolving: 5kg of soybean oil was taken and heated to 60℃and then the prescribed amounts of BHA and BHT were added and stirred well. Cooling the oil solution to 40 ℃, adding the prescription amount of allyl progestogen raw material medicine, and continuously stirring. After the medicine is completely dissolved, adding the rest soybean oil, stirring uniformly, and filtering to obtain the oil-type allylprogestogen solution with the content of 0.4%.
Comparative example 2
The amount of the inclusion agent β -cyclodextrin used in this comparative example was 210g as compared with example 2, and the same as in example 2 was repeated.
Comparative example 3
The amount of the inclusion agent β -cyclodextrin used in this comparative example was 2g as compared with example 2, and the same as in example 2 was followed.
Comparative example 4
The amount of thioglycerol used as an antioxidant in this comparative example was 90g compared to example 2, and the same as in example 2.
Comparative example 5
The amount of thioglycerol used as an antioxidant in this comparative example was 5g as compared with example 2, except that example 2 was used.
Comparative example 6
In this comparative example, the inclusion agent β -cyclodextrin was replaced with polyvinyl alcohol as compared with example 2, except that example 2 was used.
Experiment-evaluation of physicochemical Properties of oral solution of Algestrel of the present invention
(1) Sample Property
The oral solutions of the allylpregnane of examples 1 to 3 and comparative examples 1 to 6 were taken, and the properties were visually observed and compared. Since the comparative example 1 uses soybean oil or the like as a solvent system, the finished product is a yellow clear oily liquid. The oral solution of the allyl progestogen provided by the invention adopts propylene glycol or PEG 200 and the like as solvent systems, so that the samples of the examples 1-3 and the samples of the comparative examples 2-6 are colorless clear oily liquids.
TABLE 1 evaluation results of Properties of examples and comparative examples of oral solutions of allyl pregna of the present invention
Sample of Sample Property
Example 1 Colorless clear oily liquid
Example 2 Colorless clear oily liquid
Example 3 Colorless clear oily liquid
Comparative example 1 Yellow clear oily liquid
Comparative example 2 Colorless clear oily liquid
Comparative example 3 Colorless clear oily liquid
Comparative example 4 Colorless clear oily liquid
Comparative example 5 Colorless clear oily liquid
Comparative example 6 Colorless clear oily liquid
(2) Related substances and drug content detection
The samples of examples 1 to 3 and comparative examples 1 to 6 of the present invention were examined for the content of the relevant substances and drugs with reference to the method for the detection in the quality standard of the oral solution of allylic pregna in annex of the national institute of agriculture and rural area bulletin No. 415 of the people's republic of China. The results show that the contents of the related substances and medicines in the samples of examples 1-3 and comparative examples 1-6 according to the invention are all in accordance with the regulations. The content of the relevant substances in the sample of example 2 of the present invention was lower than that of comparative example 1, which simulates a commercially available oil-and-fat type sample, at the same drug content specification, probably because the degradation of the allylic drug was avoided without heat treatment during the preparation of example 2.
TABLE 2 results of detection of the content of substances and drugs in oral solutions of allyl pregna of the present invention and related products on the market
Note that: ND in the table indicates that the detection limit is lower and not detected.
(3) Evaluation of solubility in Water test results
The samples of the invention examples 1-3 and comparative examples 1-6 are respectively added into purified water and standard hard water according to the proportion of 1:10, 1:50 and 1:100, and after being uniformly stirred, the dissolution conditions of different allyl progestogen oral solutions in the purified water and the standard hard water are observed and inspected.
The experimental results are shown in the following table 3, and it is clear from the results that the samples of examples 1 to 3 of the present invention can be completely dissolved in purified water and standard hard water in the proportions of 1:10, 1:50 and 1:100, and are colorless clear solutions, and no drug precipitation is observed after the samples are left stand for 8 hours. The samples of comparative examples 2 to 5 were also soluble in purified water and standard hard water at a ratio of 1:10, 1:50 and 1:100, and were colorless clear solutions, and no drug precipitation was observed after 8h of standing. Comparative example 6 samples were also soluble in purified water and standard hard water at ratios of 1:10, 1:50 and 1:100 as colorless clear solutions, but a small amount of white floats appeared in the solution after 8h of standing. The comparative example 1 sample was not dissolved in water due to the use of soybean oil as a solvent system, and oil drops were formed to float on the water surface, indicating that the comparative example 1 oil-type oral solution sample of allylpregna was not administered by the drinking water route.
Therefore, the oral solution of the allyl progestogen provided by the invention has high water solubility, can be completely dissolved in the drinking water for cultivation, is used for administration by a drinking water way, saves time and labor, and also avoids the problems of uneven administration and the like.
TABLE 3 dissolution of samples of oral solutions of allyl pregna of the present invention in purified water and standard hard water
(4) Evaluation test results of Low temperature resistance
The samples of examples 1 to 3 and comparative examples 1 to 6 of the present invention were placed under low temperature conditions of 4℃and-20℃respectively, and the tolerance of the different oral solutions of allylpregna to low temperature environments was examined with the presence or absence of precipitate or solidification state of the samples as an index.
The experimental results are shown in Table 4 below, and the samples of examples 1 to 3 were oil-like liquids which were able to withstand the influence of low temperature environments by using an organic solvent such as propylene glycol or polyethylene glycol 200 as a solvent and were still good in fluidity after being left to stand at 4℃and-20℃for 24 hours. Since the freezing point of soybean oil is about 0 ℃ to-5 ℃, soybean oil and the like are used as solvents for the sample of the comparative example 1 of the oily allylpregna oral solution, and the sample is placed at 4 ℃ for 24 hours, the sample does not observe the solidification phenomenon, but the fluidity of the sample solution is poorer than that of the sample solution at normal temperature; and after the sample of the comparative example 1 is placed at the temperature of minus 20 ℃ for 2 hours, the sample can observe the solidification phenomenon, and the use is affected. Since the formulation composition of the oral solutions of the allylpregna of comparative example 3, comparative example 4 and comparative example 5 is similar to that of the samples of examples 1 to 3, the oral solutions of the allylpregna have better tolerance to low temperature environments. The samples of comparative example 2 and comparative example 6 were left at 4℃for 24 hours without any abnormality and were colorless clear solutions, but after the above samples were left at-20℃for 24 hours, a small amount of white precipitate was observed in each of the samples, indicating that the samples of comparative example 2 and comparative example 6 were poor in resistance to low temperature environments.
Therefore, the oral solution of the allyl progestogen provided by the invention avoids using an oil agent as a solvent, is not easy to solidify under the low-temperature condition, is resistant to low temperature, and greatly reduces the influence of temperature change on the use of the oral solution of the allyl progestogen.
TABLE 4 results of investigation of the tolerance of samples of oral solutions of allyl pregna of the present invention to low temperature environments
Note that: in the table x, the sample is still in liquid state, and no sample precipitation or solidification phenomenon is found; and v represents that the sample has precipitates or is coagulated, etc.
Experiment II stability investigation test of oral solution of allyl progestogen of the present invention
As the allyl progestogen belongs to a high-temperature sensitive medicine, and referring to the stability test guiding principle in Chinese animal pharmacopoeia (2020 edition), the conditions of investigation of a high-temperature influence factor test and an acceleration test of an allyl progestogen oral solution are selected, wherein the conditions are 40+/-2 ℃ and 30+/-2 ℃ and the relative humidity is 65+/-5%.
Samples of examples 1 to 3 and comparative examples 1 to 6 of the present invention were placed in a stability test box at 40.+ -. 2 ℃ and were sampled and tested on days 0, 5 and 10, respectively, to examine the stability of the oral solutions of allyl progestogen under high temperature influence factors.
Samples of examples 1 to 3 and comparative examples 1 to 6 of the present invention were placed in stability test chambers at 30.+ -. 2 ℃ and 65%.+ -. 5% relative humidity, and were sampled and tested at months 0, 1, 3 and 6, respectively, to examine the stability of the oral solutions of allyl progestogen under accelerated test conditions.
The experimental results are shown in the following table 5, and it is clear from the results in table 5 that after the samples of examples 1 to 3 of the present invention are placed for 10 days under the condition of high temperature influence factor of 40 ℃, the properties of the samples are not changed significantly, the drug content is reduced but still can meet the regulations, which indicates that the samples have better stability under the condition of high temperature influence factor test, and the drug content stability is basically consistent with the currently commercially available lipid-type allylpregna solution (comparative example 1). However, when the inclusion agent is too low (comparative example 3), the antioxidant is too low (comparative example 5) and other inclusion agents (comparative example 6) are selected, the formulated samples of the oral solution of the allylic progestin are degraded under high temperature conditions, resulting in a significant decrease in the drug content.
As can be seen from the results in Table 6, the samples of examples 1 to 3 of the present invention were not significantly changed in properties after being left under the accelerated test conditions for 6 months, and the drug content was reduced but still satisfied the regulations, indicating that the samples were stable under the accelerated test conditions and the stability was substantially consistent with the currently commercially available lipid-type allylpregna solution (comparative example 1). However, when the inclusion agent is too low (comparative example 3), the antioxidant is too low (comparative example 5) and other inclusion agents (comparative example 6) are selected, the prepared oral solution sample of the allyl progestin is changed from colorless to pale yellow after being placed for 6 months under the condition of accelerated test, and the medicine is degraded to obviously reduce the content.
TABLE 5 results of stability investigation of oral solutions of allyl pregna of the present invention under high temperature influencing factors
TABLE 6 stability investigation results of the oral solution of allyl pregna of the present invention under accelerated test conditions
Experiment III evaluation of the contemporaneous estrus of sow induced by the oral solution of allyl progestogen of the invention
The effect of the inventive example 2 oral solution sample of allylpregna and comparative example 1 oily oral solution sample of simulated commercial homologous products on inducing synchronous estrus in sows was evaluated using a backup sow as a test animal.
Test animals and test sites: the healthy backup sow of 60 and 220 days old is selected from a certain pig farm in the new county of the YunFu city of Guangdong province. All test animals are fed with standard mixed feed according to the requirement of the growing period, the test period is carried out with feeding management according to the conventional method, and strict epidemic prevention and disinfection measures are implemented.
The test method comprises the following steps: the 60 sows were randomly divided into 3 groups of 20 in each of the test, control and blank groups. Wherein animals of the test group and the control group were fed with the samples of the oral solutions of the allyl pregna of example 2 and comparative example 1 at a dose of 20mg, respectively, for 18 days. While the blank group is not processed at all. And detecting oestrus of the sow by a boar oestrus method, recording oestrus conditions, breeding oestrus sows, and identifying gestation conditions by B ultrasonic at 23 days and 28 days after breeding.
Test results: the experimental results are shown in the following tables 7 and 8, and the results in table 7 and table 8 are combined to show that the oral solution of the allyl progestin of the embodiment 2 of the present invention has obvious effect of adjusting the synchronous estrus of the sow, and has no obvious difference with the effect of the comparative example 1 simulating the similar products on the market. The oral solution of the allyl progestogen in the embodiment 2 is used in a dosage of 20mg, which can control the oestrus of the sow within 2-3 days, can realize the effect of synchronous oestrus and synchronous gestation of the sow and achieves the aim of high-efficiency cultivation in batch production.
TABLE 7 effect of different oral solutions of allyl pregnenes on oestrus in replacement gilts after feeding
TABLE 8 sow oestrus and mating statistics at different times after stop feeding of different oral solutions of allyl pregnancies
In summary, compared with the commercial allyl progestogen oral solution, the allyl progestogen oral solution provided by the invention is a novel preparation of the allyl progestogen oral solution which is not easy to solidify in a low-temperature environment and can be administrated by a drinking way, and the application prospect of the allyl progestogen oral solution is further expanded.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims (10)

1. The oral solution of the allyl progestogen is characterized by comprising, by weight, 0.1-1.0 part of the allyl progestogen, 0.1-5.0 parts of a coating agent, 0.2-2.0 parts of an antioxidant, 0.1-2.0 parts of a preservative and the balance of a solvent.
2. The oral solution of allyl progestin according to claim 1, wherein the inclusion agent is cyclodextrin and derivatives thereof.
3. The oral solution of allylic pregna according to claim 2, wherein the cyclodextrin and its derivative is one or more of α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, methyl- β -cyclodextrin and hydroxypropyl- β -cyclodextrin.
4. The oral solution of allyl progestin according to claim 1, wherein the antioxidant is one or more of thioglycerol, hydroxyethanol, propyl gallate and butyl gallate.
5. The oral solution of allyl pregna of claim 1, wherein the preservative is one or more of phenethyl alcohol, ethyl hydroxy benzoate, butyl hydroxy benzoate, propyl hydroxy benzoate, methyl hydroxy benzoate, benzoic acid, sorbic acid, benzalkonium bromide, benzalkonium chloride, and thimerosal.
6. The oral solution of allyl progestin according to claim 1, wherein the solvent is one or more of propylene glycol, polyethylene glycol and glycerol formal.
7. A method for preparing the oral solution of allyl progestin as claimed in claim 1, comprising the steps of:
(1) Preparation: the raw materials including the allyl progestogen, the solvent, the inclusion agent, the antioxidant and the preservative are respectively weighed according to the process formula proportion for standby;
(2) Mixing and homogenizing: sequentially adding the raw materials and the auxiliary materials weighed in the step (1) into a stirring tank, stirring and uniformly mixing the raw materials and the auxiliary materials at a certain stirring temperature, and homogenizing after the raw materials and the auxiliary materials are completely dissolved to obtain a liquid medicine;
(3) Filtering and sub-packaging: filtering the liquid medicine obtained in the step (2) by a filter rod, sub-packaging, filling nitrogen, and sealing and preserving.
8. The method for preparing an oral solution of allyl pregna according to claim 1, wherein the stirring temperature in step (2) is 18 to 35 ℃; in the homogenizing treatment, the homogenizing power is 20-100 HZ, and the homogenizing time is 15-40 min.
9. The method of preparing an oral solution of allyl progestin according to claim 1, wherein the filtering of the medical fluid through a filter rod in step (3) comprises performing a secondary filtration of the medical fluid; the pore diameters of the two-stage filter rods are 45.0-55.0 mu m and 25.0-35.0 mu m respectively.
10. Use of an oral solution of allylic progestogen prepared according to the method of claim 7 for the preparation of a product for inhibiting gonadotrophin release.
CN202310681361.6A 2023-06-09 2023-06-09 Oral solution of allyl progestogen and preparation method thereof Pending CN116803375A (en)

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