CN108339002B - Compound medroxyprogesterone acetate composition for pets and application thereof - Google Patents

Compound medroxyprogesterone acetate composition for pets and application thereof Download PDF

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CN108339002B
CN108339002B CN201810207298.1A CN201810207298A CN108339002B CN 108339002 B CN108339002 B CN 108339002B CN 201810207298 A CN201810207298 A CN 201810207298A CN 108339002 B CN108339002 B CN 108339002B
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medroxyprogesterone acetate
compound
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antifertility
pets
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CN108339002A (en
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张凌
韩剑锋
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Sichuan Jixing Animal Pharmaceutical Co.,Ltd.
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Sichuan Jixing Animal Pharmaceutical Co ltd
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Abstract

The invention relates to a compound antifertility composition for pets and application thereof, belonging to the field of veterinary medicines. The effective components of the composition comprise medroxyprogesterone acetate and Chinese herbal medicine extract lithospermum, and also can contain one or more of other Chinese herbal medicine extracts with anti-fertility effect, and the composition comprises 1-150,000 parts of medroxyprogesterone acetate and 1-100,000 parts of lithospermum extract according to the mass parts. The pharmaceutical composition provided by the invention can be suspension, is administered by intramuscular injection, and is convenient and easy to implement. The compound preparation adopts a mode of combining Chinese and western medicines for the first time, reasonably mixes the lithospermum extract and the medroxyprogesterone acetate to form a compound, has synergistic effect, realizes multi-target, multi-link and multi-level antifertility action, can improve the effective contraception rate, reduces the adverse reaction, has obvious effect, exact curative effect, high safety, simple preparation method and convenient operation, is suitable for industrial production, and is suitable for popularization and application in clinical treatment.

Description

Compound medroxyprogesterone acetate composition for pets and application thereof
Technical Field
The invention belongs to the technical field of veterinary medicine and medicine, and particularly relates to a compound medroxyprogesterone acetate composition preparation for combined treatment of traditional Chinese medicine and western medicine and application of the compound medroxyprogesterone acetate composition preparation in anti-fertility treatment of pets.
Background
With the rapid development of the economic society of China, people increasingly choose to raise pets to accompany their lives. The habits of cat and dog breeding have been found in China to ancient times, and the number of the existing pet dogs in China has been up to more than 1.5 hundred million according to official reports, which is equivalent to breeding one pet dog for every 9 Chinese people. There are an average of 10 ten thousand dogs in each city, and the growth is at a rate of ten thousand per year. Nowadays, the problem of excessive reproduction of pet dogs in domestic cities is a social key concern, and according to calculation, a pair of healthy pet cats can mate without any control within 7 years, and the accumulated number of offspring can exceed 30 thousands. The same is true for pet dogs. A large number of wandering animals caused by excessive breeding of pets all cause great burden to society from city construction, city appearance management to animal ethics and other aspects, and if no more attention is paid, serious social problems are caused.
At present, for pet dogs and cats, sterilization surgery is the most commonly used sterilization method, and for female pets, a method of removing a uterus or simultaneously removing the uterus and the ovary is adopted, and the advantages of the female animal sterilization surgery mainly appear as follows: 1) the sterilization problem is solved at one time, and the disease does not relapse; 2) the female animals have no estrus after the operation, thereby bringing convenience for the owner to feed. But the disadvantages are also apparent: 1) the operation is open, and some pets with incomplete heart and lung may have the risks of anesthesia, allergy and death in the operation process; 2) aiming at female animals, the hormone secretion level in the animals is disturbed after ovaries are removed, so that the phenomena of dislike of movement, no generation of qi, eating, reduction of sensitivity to the surrounding environment and the like of the animals after operation are caused, and simultaneously, the metabolism of sterilized pets is slowed down, so that fat accumulation and the phenomenon of fattening occur; 3) pets after sterilization are more likely to suffer from urinary system diseases, possibly increasing the prevalence of prostate cancer, bladder cancer, bone cancer, hemangioma, diabetes and thyroid gland deficiency, while the effects of surgery are irreversible and the animals will not be likely to reproduce after surgery; 4) for some rare species of pets, sterilization surgery is a very serious loss; 5) the level in the industry is uneven, and the difference between the operation level and the charging level is also large; 6) pet owners are usually difficult to accept the pet to perform an operation for insulation. Therefore, medicinal contraception is a safer and more effective contraceptive strategy.
Medroxyprogesterone acetate, a synthetic progestin, increases cervical mucus viscosity; can also inhibit the release of adenohypophysial Luteinizing Hormone (LH) by negative feedback effect on hypothalamus, so that follicle can not mature and ovarian ovulation can be inhibited, thereby having contraceptive effect. When the concentration of the medicine in blood exceeds 0.1g/L, LH and estradiol (E)2) Are inhibited, leading to impaired ovulation and are therefore frequently used as long-acting contraceptives. Medroxyprogesterone acetate is effective in intramuscular injection or oral administration, and the progestogen activity of the medroxyprogesterone acetate is 20-30 times of that of progesterone in subcutaneous injection and 10-15 times of that of ethisterone in oral administration. Because of its higher selectivity and bioavailability than natural progestogen, it is widely used in the medical field and livestock breeding industry. When the medroxyprogesterone acetate contraceptive needle is used as a long-acting injection contraceptive needle, 150mg is injected once, 1 time every 3 months, deep intramuscular injection is performed, and the medroxyprogesterone acetate contraceptive needle is one of the currently effective simple progestational hormone long-acting contraceptive methods with reversible effects, has high contraceptive effective rate and is simple and convenient to use. With the further progress of the researchMedroxyprogesterone acetate is widely used in clinic, but serious adverse reactions such as biliary tract obstruction, thrombophlebitis, galactorrhea, abnormal vaginal bleeding and the like cannot be ignored during application, and other side effects include anaphylaxis, tension, insomnia, somnolence, fatigue, depression, dizziness, headache, urticaria, pruritus, erythra, nausea, swelling and the like.
The clinical application of western contraceptive agents, represented by medroxyprogesterone acetate contraceptive needles, is limited by their serious adverse effects. The adverse observation of the traditional Chinese medicine treatment is based on the syndrome differentiation theory, has little side effect and good clinical effect, and is accepted by the majority of patients. Traditional Chinese herbal medicines or plant extracts are important sources for researching novel contraceptives. Various traditional Chinese medicines have been found to have a certain effect on resisting early pregnancy, such as eupatorium, saffron, musk, murraya jasminorage, raccoon grass, lithospermum, phellodendron amurense, solanum lyratum flower, paris polyphylla, rhododendron, phyllostachys nigra root, pinus massoniana, peach kernel, angelica, fructus cnidii, ligusticum wallichii, lotus stamen, zanthoxylum with seed, semen plantaginis, gypsum, semen ginkgo, black fungus, brassica campestris, radix rehmanniae, radix paeoniae alba, castor bean, rape seed and the like. But also has some limitations, because the efficacy of the Chinese herbal medicine is mild and slow, the effective contraception rate of the pet can not be fully guaranteed, and the Chinese herbal medicine has low bioavailability, long treatment period and the like, the treatment method of the single Chinese herbal medicine can hardly achieve the ideal contraception effect. For example, patent CN 105434501 a discloses the preparation of a Chinese herbal medicine Tianchi extract and its application in contraceptives, which has spermicidal effect with less toxic and side effects, but the contraceptive efficiency needs to be improved after oral administration. If the Chinese herbal medicines or the effective extracts thereof and the medroxyprogesterone acetate can be used together, the comprehensive regulation and control effects of multiple targets, multiple links and multiple levels can be realized by adopting a mode of combining Chinese medicines and western medicines, the contraception efficiency is improved, and the side effect of the contraceptive is reduced.
The lithospermum is a traditional Chinese medicine in China and is rich in resources. Arnebia euchroma is originally recorded in Benjing, which is the root of arnebia euchroma and arnebia euchroma of the perennial herb of the genus alkanna of the family Boraginaceae, and has the functions of cooling blood, activating blood, detoxifying and promoting eruption, with sweet and cold nature, and entering heart and liver meridians. It is traditionally used for measles, scald, and pyocutaneous disease. Modern pharmacological research means reveals that the lithospermum has an inhibiting effect on hypothalamus-pituitary-gonad axis function and has an antifertility medicinal value. The main active ingredients of lithospermum are naphthoquinone pigments (naphthoquinone derivatives), such as: radix Arnebiae (arnebia euchroma (Royle) Johnst) mainly contains radix Arnebiae derivatives such as shikonin, acetylshikonin, and O-isobutyrylshikonin. The radix Arnebiae extract is marketed product with CAS number of 517-89-5, and contains 98% shikonin. Research shows that the gromwell extract can obviously inhibit the weight of the uterus of mice and the expression of estrogen receptors and progestogen receptors, has the antifertility effect on adult animals, and can inhibit the sexual development of adolescent animals.
The inventor finds that the lithospermum extract and the medroxyprogesterone acetate form the pharmaceutical composition, the pharmaceutical composition has a synergistic effect, can improve the effective contraception rate, reduce the toxic and side effects, realize the high-efficiency, safe and economic contraception curative effect on female pets, and enrich the clinical medication for contraception of the female pets.
The invention creatively takes the lithospermum extract and the medroxyprogesterone acetate as a composition preparation as an antifertility treatment medicine for pets. In the compound preparation adopted by the invention, medroxyprogesterone acetate is used as a synthesized luteinizing progestogen, and adenohypophysis Luteinizing Hormone (LH) and estradiol (E) are inhibited by increasing the viscosity of cervical mucus and negative feedback effect on hypothalamus2) The follicle can not grow and mature, and the ovarian ovulation is inhibited, thereby achieving the purpose of contraception. The lithospermum extract is used as a traditional Chinese medicine preparation and plays a role in antifertility by inhibiting the function of hypothalamus-pituitary-gonadal axis. The lithospermum extract and the medroxyprogesterone acetate have synergistic effect as a composition preparation, can realize comprehensive regulation and control effects of multiple targets, multiple nodes and multiple layers, improve the contraception efficiency, reduce the side effect of a contraceptive and enrich the clinical medication of female pet contraception.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a high-efficiency, safe and economic contraceptive composition preparation for female animals, which has stable quality, safety and high efficiency. The lithospermum extract and the medroxyprogesterone acetate are used as a composition preparation, so that the comprehensive contraception effect of multiple target points, multiple links and multiple layers can be synergistically and effectively realized, the contraception efficiency is improved, and the side effect of the contraceptive is reduced.
Based on the situation, the invention aims to provide a compound medroxyprogesterone acetate composition preparation for pets and application thereof.
The invention aims to solve the first technical problem of providing a compound medroxyprogesterone acetate composition for pets.
The invention aims to solve the second technical problem of providing a preparation of a compound medroxyprogesterone acetate composition for pets and a preparation method thereof.
The third technical problem to be solved by the invention is to provide the application of the compound medroxyprogesterone acetate composition for pets in pet birth control and contraception.
In order to solve the first technical problem, the invention provides the technical scheme that.
The compound medroxyprogesterone acetate composition for pets is characterized in that active ingredients of the composition comprise medroxyprogesterone acetate, a lithospermum extract and pharmaceutically acceptable auxiliary materials.
Further, the extract of Lithospermum erythrorhizon can be extracted by conventional extraction methods in the art, for example, CO2The supercritical extraction method comprises extracting total alkannin from radix Arnebiae, extracting with organic solvent solution and alkali solution, direct alkaline hydrolysis, and Cu extraction2+Complexation method and the like. The Lithospermum erythrorhizon extract can be used as a commercially available product, and can be directly purchased from, for example, Shaanxi Rakake biology Co., Ltd., Shaanxi Senfu products Co., Ltd.
Further, the compound medroxyprogesterone acetate composition for pets is characterized by comprising 1-150,000 parts of medroxyprogesterone acetate and 1-100,000 parts of lithospermum extract by mass.
Preferably, the composition comprises 1-1500 parts of medroxyprogesterone acetate and 1-1000 parts of lithospermum extract by weight.
More preferably contains medroxyprogesterone acetate 1-150 parts and radix Arnebiae extract 1-100 parts.
Furthermore, the mass ratio of the active ingredients of the compound medroxyprogesterone acetate composition preparation to the lithospermum extract is preferably 1:20-30: 1.
Furthermore, the pharmaceutical composition also contains other Chinese herbal medicine extracts with antifertility action, which are selected from one or more of eupatorium, saffron, musk, murraya paniculata, raccoon grass, phellodendron, purple eggplant flower, paris polyphylla, rhododendron, black bamboo root, masson pine, peach kernel, angelica, common cnidium fruit, ligusticum wallichii, lotus stamen, pepper with seed, plantain seed, gypsum, ginkgo kernel, black fungus, brassica seed, radix rehmanniae, white peony root, castor bean and rape seed.
Preferably, the pharmaceutical composition also contains other Chinese herbal medicine extracts with antifertility action, including one or more of eupatorium, plantain seed, murraya paniculata, saffron, raccoon grass and solanum torvum flower.
In order to solve the second technical problem, the invention provides the technical scheme that.
The invention discloses an administration form of a compound medroxyprogesterone acetate composition preparation for pets, which can comprise but is not limited to solid preparations such as powder, tablets, granules, pills and capsules, semisolid preparations such as ointments, pastes and gels, and liquid preparations such as one of injections, drops, solutions, emulsions, suspensions and nano preparations.
Preferably, the administration dosage form of the compound medroxyprogesterone acetate composition for pets is preferably suspension.
Further, the compound medroxyprogesterone acetate suspension for pets comprises an active ingredient, a suspending agent, a wetting agent and other medicinal excipients.
Further, the suspending agent comprises one or more of xanthan gum, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, carbomer, poloxamer, tyloxapol, polycarbophil, polyethylene glycol, sodium hyaluronate, sodium alginate, acacia, tragacanth, peach gum and dextran.
Further, the wetting agent comprises one or more mixtures of polysorbates, polyoxyethylene fatty alcohol ethers, polyoxyethylene castor oils, phospholipids, poloxamers, and the like.
Further, the other pharmaceutical excipients may include, but are not limited to, conventional excipients such as flocculants and deflocculants, pH adjusters, dispersants, preservatives, antioxidants, colorants, and the like. The extract is selected from citric acid, citrate, dextran sulfate, tartrate, phosphate, glycinate, sucrose, lactose, mannitol, inulin, sorbitol, xylitol, and maltodextrin.
Furthermore, in the compound medroxyprogesterone acetate suspension, the weight percentage of the medroxyprogesterone acetate is 1 to 70 percent, and the weight percentage of the lithospermum extract is 0.5 to 60 percent.
Preferably, in the compound medroxyprogesterone acetate suspension, the weight percentage of the medroxyprogesterone acetate is 3-30%, and the weight percentage of the lithospermum extract is 2-20%.
An antifertility compound medroxyprogesterone acetate suspension for pets is characterized by comprising the following components in percentage by weight: 3 to 30 percent of medroxyprogesterone acetate, 2 to 20 percent of lithospermum extract, 800.01 to 5 percent of polysorbate, 40000.1 to 5 percent of polyethylene glycol, 0.1 to 5 percent of anhydrous sodium citrate, 0.1 to 10 percent of chlorobutanol and the balance of water for injection.
Further, a preparation method of the compound medroxyprogesterone acetate suspension for pets can include, but is not limited to, a dispersion method, a medium grinding method, a homogenization method, an emulsification method and an agglomeration method.
Preferably, the preparation method thereof is preferably: dissolving suspending agent, stabilizer, antioxidant, etc. in 1000ml of water for injection, dissolving overnight, filtering, sterilizing at 115 deg.C for 30min, and cooling to obtain solvent. The medroxyprogesterone acetate and the lithospermum extract with the prescribed amount are added into a sterile room to prepare suspension, and the suspension is encapsulated in a 1ml ampoule to obtain the compound preparation.
Furthermore, the invention also provides an application of the compound medroxyprogesterone acetate composition in preparing an antifertility drug, wherein the compound medroxyprogesterone acetate composition comprises medroxyprogesterone acetate and a lithospermum erythrorhizon extract.
Furthermore, the invention also provides an application of the compound medroxyprogesterone acetate composition in preparing an antifertility drug, wherein the compound medroxyprogesterone acetate composition comprises 1-70% of medroxyprogesterone acetate and 0.5-60% of lithospermum erythrorhizon extract in percentage by weight. Preferably, the medicine contains 3 to 30 percent of medroxyprogesterone acetate and 2 to 20 percent of lithospermum extract.
In order to solve the third technical problem, the invention performs anti-fertility and toxicity experimental research on the anti-fertility compound medroxyprogesterone acetate suspension for pets.
One is the research of the compound medroxyprogesterone acetate on female mouse contraception experiment. Healthy mature Kunming mice and females are selected for the experiment and randomly divided into seven groups: the first group is a single-component medroxyprogesterone acetate group, the second group is a single-component lithospermum extract group, the third group is a compound medroxyprogesterone acetate low-dose group, the fourth group is a compound medroxyprogesterone acetate middle-dose group, the fifth group is a compound medroxyprogesterone acetate high-dose group, the sixth group is a blank suspension group, the seventh group is a physiological saline group, and 120 suspension preparations in each group are injected into the muscle subcutaneously according to 1ml/5-10 kg of body weight. At 5, 30, 60 and 90d after administration, serum Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) of female mice were measured, and a cage-closing mating experiment was performed simultaneously, and pregnancy of each group of mice was observed to calculate a contraceptive rate. The results show that the low, medium and high groups of the compound medroxyprogesterone acetate can obviously reduce the level of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). The contraception rate of the compound medroxyprogesterone acetate in high group to mice reaches 100 percent, and the antifertility action is obviously better than that of the single-component medroxyprogesterone acetate group or the single-component lithospermum extract group.
And secondly, the toxicity experiment of the compound medroxyprogesterone acetate on the zebra fish is researched. The experiment was set up in eight groups: the first group is a single-component medroxyprogesterone acetate group, the second group is a single-component lithospermum extract group, the third group is a compound medroxyprogesterone acetate low-dose group, the fourth group is a compound medroxyprogesterone acetate middle-dose group, the fifth group is a compound medroxyprogesterone acetate high-dose group, the sixth group is a blank suspension group, the seventh group is a blank control group, and the eighth group is a solvent control group. In the experiment, female zebra fish is selected as a subject to be subjected to an acute toxicity experiment, and normal zebra fish fertilized eggs are selected as the subject to be subjected to a reproductive toxicity experiment. The results show that the use amount of the lithospermum extract is gradually reduced along with the gradual increase of the medroxyprogesterone acetate, and the death rate of the zebra fish also shows a slight increase trend, which indicates that the proportion and the use amount of the lithospermum extract and the medroxyprogesterone acetate can influence the toxicity of the compound preparation. However, it is worth mentioning that the toxicity of the compound preparation is obviously reduced and is very slight compared with the single component of medroxyprogesterone acetate. The lithospermum extract can improve the adverse effect of medroxyprogesterone acetate, and the compound of the lithospermum extract and the medroxyprogesterone acetate has reasonable compatibility and mutually assists.
The invention creatively and reasonably combines the lithospermum extract and the medroxyprogesterone acetate to be used as a composition preparation as an antifertility treatment medicine for pets. In the compound preparation adopted by the invention, medroxyprogesterone acetate is used as a synthesized luteinizing progestogen, and adenohypophysis Luteinizing Hormone (LH) and estradiol (E) are inhibited by increasing the viscosity of cervical mucus and negative feedback effect on hypothalamus2) The follicle can not grow and mature, and the ovarian ovulation is inhibited, thereby achieving the purpose of contraception. The lithospermum extract is used as a traditional Chinese medicine preparation and plays a role in antifertility by inhibiting the function of hypothalamus-pituitary-gonadal axis. The lithospermum extract and the medroxyprogesterone acetate which are used as a composition preparation have a synergistic interaction effect, realize the multi-target, multi-link and multi-level antifertility action, simultaneously achieve the effects of improving the effective contraception rate and reducing the toxic and side effects, realize the high-efficiency, safe and economic contraception curative effect of female pets, and enrich the clinical medication of the contraception of the female pets.
The invention has the advantages.
1. In the field of veterinary medicines, an antifertility compound medroxyprogesterone acetate composition preparation for pets is provided for the first time.
2. In the field of veterinary medicines, an administration preparation of an antifertility compound medroxyprogesterone acetate composition preparation for pets and a preparation method thereof are provided for the first time.
3. In the field of veterinary drugs, the compound preparation adopts a mode of combining Chinese medicines and western medicines for the first time, and the lithospermum extract and the medroxyprogesterone acetate form a compound for synergistic interaction, so that the multi-target, multi-link and multi-level antifertility action is realized, and the aim of improving the effective contraception rate is fulfilled.
4. The invention adopts a mode of combining Chinese and western medicines for the first time, and the lithospermum extract and the medroxyprogesterone acetate are reasonably compatible for the antifertility of pets, so that the adverse reaction of the medicines can be obviously reduced.
5. Compared with a single preparation, the compound preparation formed by the lithospermum extract and the medroxyprogesterone acetate can reduce the probability of pet poisoning, is convenient to use, safe, efficient and environment-friendly. The production process is simple and convenient, the production flow is easy to automate, and the method is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
Examples 1 to 13.
The prescription (suspension, 1000 ml) of the antifertility compound medroxyprogesterone acetate composition for pets is shown in table 1.
TABLE 1 examples 1-13.
Figure 509581DEST_PATH_IMAGE001
The preparation method comprises the following steps: dissolving anhydrous sodium citrate, polyethylene glycol 4000, polysorbate 80, and chlorobutanol in water for injection to 1000ml, filtering, sterilizing at 115 deg.C for 30min, and cooling to obtain solvent. Adding medroxyprogesterone acetate and radix Arnebiae extract in prescription amount into sterile room, adding herba Eupatorii extract, folium Et cacumen Murrayae extract or semen plantaginis extract in examples 11-13 to obtain suspension, and packaging in 1ml ampoule.
Example 14: contraceptive test study in female mice.
1. And (4) experimental design.
1.1. Drugs, experimental animal groups and dosing regimens.
The compound medroxyprogesterone acetate composition preparation is prepared by the implementation steps 2, 5 and 8. Wherein, the medroxyprogesterone acetate is 18mg/ml in the embodiment 2, and the lithospermum extract is 180 mg/ml; example 5 contains medroxyprogesterone acetate 150mg/ml, lithospermum extract 100 mg/ml; example 8 contains medroxyprogesterone acetate 225mg/ml, lithospermum extract 15 mg/ml; a single component gromwell extract (content 200 mg/ml) was prepared using the adjuvant formulation and preparation method of example 2, and a single component medroxyprogesterone acetate (content 300 mg/ml), a blank suspension (adjuvant only) and a saline solution group were prepared using the adjuvant formulation and preparation method of example 8.
Healthy mature Kunming mice with weight of 25-35 g, 840 female mice and 70 male mice are fed with common feed and clean tap water. Female mice were randomly divided into seven groups: the first group is a single-component medroxyprogesterone acetate group, the second group is a single-component lithospermum extract group, the third group is a compound medroxyprogesterone acetate low-dose group prepared in example 2, the fourth group is a compound medroxyprogesterone acetate middle-dose group prepared in example 5, the fifth group is a compound medroxyprogesterone acetate high-dose group prepared in example 8, the sixth group is a blank suspension group, the seventh group is a physiological saline group, and each group is 120 drugs, wherein the suspension preparations in each group are subjected to subcutaneous intramuscular injection according to 1ml/5-10 kg of body weight, and proper amount of water for injection is required to be diluted when in administration.
1.2 measurement of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).
In groups of seven female mice, 10 female mice were randomly selected from each group of seven female mice after administration, and subjected to orbital bleeds, and isotope radioimmunoassays of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) were performed.
1.3 coop mating experiments.
At 5, 30, 60, 90d after administration, seven groups of administered female mice were randomly selected 20 female mice per group and male mice at 2: 1, closing the cages for 1 week at a ratio of 1, checking the vaginas of the female mice every day during the closing period, opening the vulvas by using small tweezers, taking out the successfully mated people with the vaginal embolus, respectively feeding the mice in separate cages, carrying out cervical dislocation 15d after the separate cages to kill the female mice, and observing whether the uterus has fetus or not. The contraception rate (number of non-pregnant animals/number of experimental animals x 100%) was calculated.
2. And (5) experimental results.
2.1 measurement of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).
Follicle Stimulating Hormone (FSH) is a hormone synthesized and secreted by the pituitary gland and belongs to the group of glycosylated protein hormones. Follicle stimulating hormone plays a crucial role in reproductive related physiological processes. Luteinizing Hormone (LH) is produced by the pituitary gland, and female luteinizing hormone is involved in ovulation promotion of follicle stimulating hormone, and formation and secretion of estrogen and progestin. The determination of the Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) content in serum is helpful in determining the hypothalamic-pituitary-gonadal axis functional status. The results of measurement of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) after administration are shown in table 2, and the difference between the levels of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in the blank suspension group and the level of physiological saline group was small at the measurement time used, indicating that the state of the functional state of hypothalamus-pituitary-gonadal axis was not affected by the auxiliary materials in the suspension. The single-component medroxyprogesterone acetate group has the advantages that Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) are remarkably reduced at 5 th, 30 th and 60 th days after administration and are always maintained at reduced levels, and the single-component medroxyprogesterone acetate has an inhibiting effect on the functions of hypothalamus-pituitary-gonadal axis, so that follicles can not mature and ovarian ovulation is inhibited. And the subcutaneous medroxyprogesterone acetate has long-acting effect, and the level of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) is improved at 90 days after administration but is still lower than that of the normal saline group. The single-component lithospermum extract group has larger difference with the normal saline group in 5 th and 30 th days after administration of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which shows that the lithospermum extract also has inhibiting effect on the function of hypothalamus-pituitary-gonadal axis. Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) slowly rise back over the time tested. Example 2 the group of medroxyprogesterone acetate had a significant decrease in Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at 5, 30, 60d after administration, which was lower than the group of medroxyprogesterone acetate alone or the group of comfrey extract alone, indicating that the combined administration of medroxyprogesterone acetate and comfrey extract had a synergistic effect in inhibiting the function of the hypothalamus-pituitary-gonadal axis. Example 8 the 5 th, 30 th, 60 th and 90 th days after administration of the compound medroxyprogesterone acetate high-dose group containing Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) are lower than those of the compound medroxyprogesterone acetate group in example 2 or the compound medroxyprogesterone acetate group in example 5, which shows that the combination of medroxyprogesterone acetate and lithospermum erythrorhizon extract has the inhibition effect on the function of hypothalamus-pituitary-gonadal axis, and the inhibition effect is more obvious when the dosage is larger.
Table 2. results of assays for Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) (mIU/ml, mean ± sd, n = 10).
Figure 653992DEST_PATH_IMAGE002
a P<0.05,b P<0.01, c P<0.005vsAnd (4) a normal saline group.
2.1 antifertility study.
The results of the test of the contraceptive effect of the groups of mice after administration are shown in Table 3.
TABLE 3 comparison of contraceptive rates (%) in groups of female mice.
Figure 467096DEST_PATH_IMAGE002
The experimental mice of each group are dissected, and the pregnant mice of the blank suspension group and the physiological saline group are found to have thick uterus diameter, flesh red and luster, and the embryos of uterine horn are beaded, evenly distributed and well developed. The diameter of the uterus of each compound medroxyprogesterone acetate administration group mouse is obviously smaller than that of a blank suspension group and a normal saline group, and almost no embryo development is seen. The contraceptive rate (%) of the blank suspension group was substantially the same as the level of the saline group over the time of the assay used, indicating that the adjuvant in the suspension did not have an antifertility effect. The contraceptive rates (%) of the monocomponent medroxyprogesterone acetate groups at 5, 30, 60 and 90d after administration were 90%, 94.7%, 81.2% and 77.7%, respectively, indicating that medroxyprogesterone acetate has strong antifertility activity and long-lasting effect, but unfortunately not reaching a contraceptive rate of 100% at each test time point. The contraceptive rate (%) of the mono-component lithospermum extract group at 5 th, 30 th, 60 th and 90 th days after administration was 55.9%, 38.9%, 35% and 15.7% respectively, and the antifertility activity thereof was gradually reduced with the extension of the administration experiment. Example 2 the contraception rates (%) of the compound medroxyprogesterone acetate groups at 5 th, 30 th, 60 th and 90 th days after administration are respectively 100%, 95%, 94.7% and 90%, which are higher than those of the single-component medroxyprogesterone acetate group or the single-component lithospermum erythrorhizon extract group, which shows that the combined administration of medroxyprogesterone acetate and the lithospermum erythrorhizon extract can effectively improve the contraception rate. Example 5 the compound medroxyprogesterone acetate group and example 8 the compound medroxyprogesterone acetate group can achieve 100% contraception rate in 5 th, 30 th, 60 th and 90 th days after administration, which is higher than that in the compound medroxyprogesterone acetate group in example 2, and shows that the antifertility effect of the medroxyprogesterone acetate and lithospermum erythrorhizon extract combination is related to the dosage, and the larger the dosage, the larger the antifertility effect.
3. And (6) concluding.
According to the results of the experiment, through statistical analysis, the compound medroxyprogesterone acetate prepared in the examples 2, 5 and 8 can obviously reduce the levels of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), the contraception rate of the compound medroxyprogesterone acetate prepared in the examples 5 and 8 on mice reaches 100%, and the antifertility action of the compound medroxyprogesterone acetate is obviously superior to that of a single-component medroxyprogesterone acetate group or a single-component lithospermum erythrorhizon extract group. Experiments show that the compound formed by reasonably mixing the lithospermum extract and the medroxyprogesterone acetate in a Chinese and western combination mode has reasonable compatibility and synergistic interaction, realizes multi-target, multi-link and multi-level antifertility action, and ensures effective contraception rate.
Example 15: research on toxicity experiments of compound medroxyprogesterone acetate on zebra fish.
1. And (4) experimental design.
1.1. Drugs, experimental animal groups and dosing regimens.
A compound medroxyprogesterone acetate composition preparation which is prepared by the implementation 3, 6 and 9. Wherein, the embodiment 3 contains 30mg/ml of medroxyprogesterone acetate and 150mg/ml of lithospermum extract; example 6 contains medroxyprogesterone acetate 200mg/ml, alkanna tinctoria extract 40 mg/ml; example 9 contains medroxyprogesterone acetate 250mg/ml, lithospermum extract 12.5 mg/ml; a single component gromwell extract (content 150 mg/ml) was prepared using the adjuvant formulation and preparation method of example 3, a single component medroxyprogesterone acetate (content 250 mg/ml), a blank suspension (adjuvant only) and a saline solution group were prepared using the adjuvant formulation and preparation method of example 9.
Zebra fish is purchased from Shanghai breeding bases, and individuals with healthy bodies and active actions are selected from the experiment to carry out the experiment. The breeding was carried out according to the method described in Zebraphis book, the ratio of light to dark in the fish room was 14 h/10 h, adult zebra fish males and females were separately raised and fed with feed at regular intervals. The night before the experiment 1 d, the male and the female are moved into a spawning tank at the ratio of 1:2, and the male and the female are separated by a partition plate. The next morning, the septate is removed, and the embryo can be collected after the male fish chases the female fish for about 30 min. The embryos are cleaned by fish culture water and transferred into a disposable sterilized plate culture dish. And (3) carrying out light-controlled culture on the embryo in a constant-temperature water bath box at 28.5 ℃, and selecting a proper development time period according to the experimental requirements.
1.2 acute toxicity test.
Female zebra fish healthy and lively in motion are selected as a subject in the experiment, and eight groups are set in the experiment: the first group was a single-component medroxyprogesterone acetate group, the second group was a single-component gromwell extract group, the third group was the compound medroxyprogesterone acetate low-dose group prepared in example 3, the fourth group was the compound medroxyprogesterone acetate medium-dose group prepared in example 6, the fifth group was the compound medroxyprogesterone acetate high-dose group prepared in example 9, the sixth group was a blank suspension group, the seventh group was a blank control group (culture water), and the eighth group was a vehicle control group (1% Dimethylsulfoxide (DMSO)). Mainly because the medroxyprogesterone acetate and the lithospermum extract have low water solubility, dimethyl sulfoxide (DMSO) with the concentration of 1 percent is adopted as a cosolvent for preparation, and each group of suspension is diluted by 1000 times and then infected. And changing 1 time of the medicines with the same volume concentration every 24 hours for 50 each group, wherein the volume of the test solution is 3L, the temperature of the test solution is 26-27 ℃, and the death number of the zebra fish is observed within 72 hours.
1.3 reproductive toxicity test.
The experiment selects normal zebra fish zygote as the subject, and the experiment sets eight groups: the first group was a single-component medroxyprogesterone acetate group, the second group was a single-component gromwell extract group, the third group was the compound medroxyprogesterone acetate low-dose group prepared in example 3, the fourth group was the compound medroxyprogesterone acetate medium-dose group prepared in example 6, the fifth group was the compound medroxyprogesterone acetate high-dose group prepared in example 9, the sixth group was a blank suspension group, the seventh group was a blank control group (culture water), and the eighth group was a vehicle control group (1% Dimethylsulfoxide (DMSO)). Mainly because the medroxyprogesterone acetate and the lithospermum extract have low water solubility, dimethyl sulfoxide (DMSO) with the concentration of 1 percent is adopted as a cosolvent for preparation, and each group of suspension is diluted by 1000 times and then infected. And taking normal zebra fish fertilized eggs from each group, carrying out contamination in a 96-well plate, arranging 64 multiple holes in each group, putting 5 eggs into each hole, carrying out incubation at the temperature of 28 ℃, observing and recording the number of incubated fries, the number of normal-developing fries, the number of dead fries and the number of abnormal fries within 72 hours after contamination.
2. And (5) experimental results.
2.1 determination of acute toxicity.
The result of the determination of the acute toxicity of the zebra fish is shown in table 4, and in the whole experiment process, the number of dead fish tails of the blank suspension group, the blank control group and the solvent control group is 0, which indicates that the solvent used in the experiment does not influence the determination condition of the acute toxicity experiment of the zebra fish, and the auxiliary materials used in the suspension do not influence the determination condition of the suspension preparations of each group on the acute toxicity experiment of the zebra fish. The mortality rate of the single-component medroxyprogesterone acetate group zebra fish reaches 34 percent, which shows that the medroxyprogesterone acetate has large adverse reaction and toxic and side effect. In clinical practice, medroxyprogesterone acetate is frequently reported to cause adverse reactions such as biliary obstruction, thrombophlebitis, galactorrhea, abnormal vaginal bleeding and the like, and other side effects include anaphylactic reaction, tension, insomnia, somnolence, tiredness, depression, dizziness, headache, urticaria, pruritus, erythra, nausea, swelling and the like. The zebra fish of the single-component lithospermum extract group does not die, which shows that the lithospermum extract has mild drug effect and does not cause obvious damage to the zebra fish. Example 9 compared with the single-component medroxyprogesterone acetate group, the compound medroxyprogesterone acetate group has the advantages that the death rate of the zebra fish is remarkably reduced along with the addition of the lithospermum extract, which shows that the medroxyprogesterone acetate and the lithospermum extract are used in combination and are assisted with each other, so that the acute toxicity of the preparation is reduced, and the effect of reducing the toxic and side effects can be achieved. Meanwhile, compared with the three groups of compound medroxyprogesterone acetate groups of examples 3, 6 and 9, the dosage of the lithospermum extract is gradually reduced along with the gradual increase of the dosage of the medroxyprogesterone acetate, and the death rate of the zebra fish also shows a slight increase trend, which shows that the proportion and dosage of the lithospermum extract and the medroxyprogesterone acetate can influence the toxicity of the compound preparation. However, it is worth mentioning that the toxicity of the compound preparation is obviously reduced and is very slight compared with the single component of medroxyprogesterone acetate.
TABLE 4 acute toxicity test results.
Figure 323057DEST_PATH_IMAGE003
2.2 determination of reproductive toxicity.
Both medroxyprogesterone acetate and the lithospermum extract play an antifertility role by inhibiting ovulation of female mammals, the antifertility roles of normal zebra fish fertilized eggs adopted as a subject are not in conflict with each other in reproductive toxicity, and the experimental attempt uses the development condition of embryos to reflect the toxic roles of the medroxyprogesterone acetate and the lithospermum extract.
TABLE 5 reproductive toxicity test results.
Figure 522219DEST_PATH_IMAGE004
The result of the determination of the reproductive toxicity of the zebra fish is shown in table 5, and in the whole experiment process, the blank suspension group, the blank control group and the solvent control group are compared, and the difference has no statistical significance (P is more than 0.05), so that the solvent used in the experiment does not influence the development condition of the zebra fish embryo, and the auxiliary materials used in the suspension also do not influence the investigation of the suspension preparations of each group on the development condition of the zebra fish embryo. The number of malformed fries of the single-component medroxyprogesterone acetate group zebra fish reaches 35.5 percent, and the number of dead fries reaches 39.9 percent, which shows that the medroxyprogesterone acetate causes obvious damage to embryo development and has larger toxic and side effects. Compared with a blank control group or a solvent control group, the difference of the zebra fish of the single-component lithospermum extract group has no statistical significance (P is more than 0.05), and the zebra fish embryo development is hardly influenced by the lithospermum extract. Example 9 compared with the single-component medroxyprogesterone acetate group, the compound medroxyprogesterone acetate group has the advantages that the number of malformed fries and dead fries of the zebra fish is obviously reduced along with the addition of the lithospermum extract, which indicates that the medroxyprogesterone acetate and the lithospermum extract are combined and have the auxiliary effect of reducing the adverse effect of the preparation on the zebra fish embryos. Meanwhile, compared with the three groups of compound medroxyprogesterone acetate groups of examples 3, 6 and 9, the dosage of the lithospermum extract is gradually reduced along with the gradual increase of the dosage of the medroxyprogesterone acetate, and the number of malformed fries and dead fries of the zebra fish also show a slight increase trend, which indicates that the proportion and the dosage of the lithospermum extract and the medroxyprogesterone acetate can influence the toxicity of the compound preparation. However, it is worth mentioning that the toxicity of the compound preparation is obviously reduced and is very slight compared with the single component of medroxyprogesterone acetate.
3. And (6) concluding.
Statistical analysis of the test results shows that the acute toxicity and reproductive toxicity of the compound medroxyprogesterone acetate prepared in example 9 are significantly reduced compared with the single-component medroxyprogesterone acetate group, which indicates that the lithospermum extract can improve the adverse effect of medroxyprogesterone acetate, and the compound of the two is reasonable in compatibility and mutually assisted, so that the adverse reaction and the toxic and side effects of the preparation can be greatly reduced.
The above-mentioned embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Various other modifications and alterations will occur to those skilled in the relevant art based on the foregoing description and examples. This description is not intended to be exhaustive of all embodiments. All obvious modifications and variations of the present invention are intended to fall within the scope of the present invention.

Claims (9)

1. The antifertility compound medroxyprogesterone composition for pets is characterized by comprising the components of medroxyprogesterone acetate, a lithospermum extract and pharmaceutically acceptable auxiliary materials, wherein the antifertility compound medroxyprogesterone composition comprises 1-150 parts of medroxyprogesterone acetate and 1-100 parts of lithospermum extract according to the mass parts, the mass ratio of the medroxyprogesterone acetate to the lithospermum extract is 1:20-30:1, and the CAS number of the lithospermum extract is 517-89-5.
2. The antifertility compound medroxyprogesterone acetate composition for pets according to claim 1, wherein the composition is administered in a form selected from the group consisting of solid formulations selected from the group consisting of powders, tablets, granules, pills and capsules, semi-solid formulations selected from the group consisting of ointments, pastes and gels, and liquid formulations selected from the group consisting of injections, drops, solutions, emulsions, suspensions and nano-formulations.
3. The antifertility compound medroxyprogesterone acetate composition for pets according to claim 2, wherein the pharmaceutical composition is administered in the form of a suspension.
4. The antifertility compound medroxyprogesterone acetate suspension for pets is characterized by comprising the components of medroxyprogesterone acetate, a lithospermum extract and pharmaceutically acceptable auxiliary materials, wherein the suspension comprises 1-150 parts of medroxyprogesterone acetate, 1-100 parts of lithospermum extract according to the mass part, the mass ratio of the medroxyprogesterone acetate to the lithospermum extract is 1:20-30:1, the CAS number of the lithospermum extract is 517-89-5, and the pharmaceutically acceptable auxiliary materials comprise a suspending agent, a wetting agent and other medicinal excipients.
5. The antifertility compound medroxyprogesterone acetate suspension for pets according to claim 4, wherein the suspending agent is selected from one or a combination of more of xanthan gum, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose, carbomer, poloxamer, tyloxapol, polycarbophil, polyethylene glycol, sodium hyaluronate, sodium alginate, acacia, tragacanth, peach gum and dextran, and the wetting agent is selected from one or a mixture of more of polysorbates, polyoxyethylene fatty alcohol ethers, polyoxyethylene castor oils, phospholipids and poloxamers.
6. The antifertility compound medroxyprogesterone acetate suspension for pets according to claim 4, wherein the other pharmaceutical excipients are selected from one or more of flocculating agents, deflocculating agents, pH regulators, dispersing agents, preservatives, antioxidants and coloring agents.
7. The anti-fertility compound medroxyprogesterone acetate suspension for pets according to claim 4, characterized in that the other pharmaceutical excipients are selected from citric acid, citrate, dextran, tartrate, phosphate, glycinate, sucrose, lactose, mannitol, inulin, sorbitol, xylitol, maltodextrin, or a mixture of more thereof.
8. A preparation method of the antifertility compound medroxyprogesterone acetate suspension for pets according to any one of claims 4 to 7, characterized in that the preparation method is selected from a dispersion method, a medium grinding method, a homogenization method, an emulsification method and an agglomeration method.
9. Use of the compound medroxyprogesterone acetate composition of any one of claims 1 to 3 or the compound medroxyprogesterone acetate suspension of any one of claims 4 to 7 in the preparation of a medicament for controlling the fertility of pets.
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