Vagina sustained-release agent for sheep and preparation method thereof

Abstract

The invention provides a sheep vagina sustained-release preparation and a preparation method thereof, and relates to the technical field of livestock breeding, the sheep vagina sustained-release preparation comprises a skeleton inner core and a silica gel drug-loaded epidermis wrapping the skeleton inner core; the silica gel drug-loaded skin comprises the following components: progesterone, medical silicone rubber, a vulcanizing agent, a pore-foaming agent, an expanding agent and a reinforcing filler. According to the vagina sustained-release agent for sheep provided by the invention, in the use process of the suppository, the medicine is released to a greater extent, the medicine residue is obviously reduced, and the volume of the suppository is expanded to a certain extent after the suppository is in contact with body fluid, so that the phenomenon of suppository falling in the use process can be effectively improved.

Description

Technical Field

[0001] The invention relates to the technical field of animal husbandry, and in particular to a vaginal sustained-release agent for sheep and a preparation method thereof. Background Art

[0002] With the development of animal husbandry, in order to improve breeding efficiency and livestock reproduction rate, traditional animal mating has been replaced by artificial insemination. It is very beneficial to make the herds estrus at the same time to improve the efficiency of artificial insemination, and it is also possible to make those herds that have not yet received artificial insemination enter the estrus period at the same time. At present, the main methods of drug administration for controlling the estrus of ewes at the same time are oral administration, injection and vaginal suppository. The first two methods of administration have certain inconveniences in use, and the drug generally has a short duration of action. If the drug efficacy needs to be maintained for a period of time, it needs to be given multiple times, and the operation is cumbersome. The vaginal suppository method is mainly used for cattle and sheep. It has the advantages of sustained drug release and easy operation, which can overcome the shortcomings of the first two methods of administration.

[0003] In China, the progesterone vaginal suppositories used for synchronous estrus of ewes are mostly sponges as carriers. However, sponges can prevent vaginal secretions from being discharged smoothly, which can easily cause vaginitis. Improper operation can also cause metritis, so they are rarely used. In addition to sponge suppositories, silicone suppositories have also been developed abroad. Silicone vaginal suppositories are molded products with a smooth surface, which can avoid the problem of vaginal secretions not being discharged smoothly. (Specification: progesterone 300mg) is used for estrus synchronization of ewes (sheep and goats) and is widely used in the field of sheep breeding abroad. However, this product has not yet been put on the market in the domestic market, and no domestic company has conducted research and development of related products. It is worth noting that After the product is inserted into the vagina, there is a problem that the drug cannot be completely released during the use cycle. After the plug is removed, there is still 30% to 50% (laboratory tests on Zoetis The results of the test show that the drug remains in the suppository, resulting in a waste of raw materials and the inability to recycle them. In addition, the use cycle of such suppositories is generally 12 to 14 days, and some of the suppositories may fall off during use.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] One of the purposes of the present invention is to provide a vaginal sustained-release agent for sheep, so as to at least solve one of the technical problems existing in the prior art. The vaginal sustained-release agent for sheep provided by the present invention can release the drug to a greater extent during the use of the suppository, significantly reduce the drug residue, and at the same time, the volume will expand to a certain extent after contacting with body fluids, which can effectively improve the phenomenon of the suppository falling off during use.

[0006] The second object of the present invention is to provide a method for preparing a vaginal sustained-release preparation for sheep.

[0007] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0008] In a first aspect, the present invention provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped around the outer surface of the skeleton inner core;

[0009] The silica gel drug-carrying epidermis comprises the following components: progesterone, medical silicone rubber, a vulcanizing agent, a pore-forming agent, an expander and a reinforcing filler.

[0010] Furthermore, the silica gel drug-carrying epidermis comprises the following components by mass percentage:

[0011] 5%-7% progesterone, 0.5%-3.0% vulcanizing agent, 1.0%-6.0% porogen, 5.0%-10% expander, 1.0%-10% reinforcing filler and the balance medical silicone rubber.

[0012] Furthermore, the porogen includes at least one of lactose, PEG3000 and PEG4000.

[0013] Furthermore, the swelling agent includes at least one of glycerol and propylene glycol.

[0014] Furthermore, the vulcanizing agent includes a platinum vulcanizing agent.

[0015] Furthermore, the reinforcing filler includes at least one of light calcium carbonate, silicon dioxide and microcrystalline cellulose.

[0016] In a second aspect, the present invention provides a method for preparing the vaginal sustained-release preparation for sheep, comprising the following steps:

[0017] The formula amount of progesterone, medical silicone rubber, vulcanizer, pore-forming agent, expander and reinforcing filler are mixed to obtain a drug-loaded rubber compound, and then the drug-loaded rubber compound is wrapped on the outside of the skeleton core to form a silica gel drug-loaded epidermis to obtain the vaginal sustained-release agent for sheep.

[0018] Furthermore, the mixing process includes internal mixing and open mixing in sequence;

[0019] Optionally, the mixing process includes: adding progesterone, porogen, expander and reinforcing filler to the medical silicone rubber for internal kneading, and then adding a vulcanizing agent for open kneading to obtain a drug-loaded rubber material;

[0020] Optionally, the mixing process includes: adding a porogen, an expander and a reinforcing filler to the medical silicone rubber for a first internal kneading, then adding progesterone for a second internal kneading, and then adding a vulcanizing agent for an open kneading to obtain a drug-loaded rubber material;

[0021] Optionally, the mixing process includes: adding progesterone to the medical silicone rubber for a first kneading, then adding a porogen, an expander and a reinforcing filler for a second kneading, and then adding a vulcanizer for open kneading to obtain a drug-loaded rubber material.

[0022] Preferably, the total time of the banburying is 40-60 min;

[0023] Preferably, the refining time is 5-15 min.

[0024] Furthermore, the formation process of the silica gel drug-carrying skin includes: wrapping the drug-carrying rubber material on the outside of the skeleton core by injection vulcanization molding;

[0025] Preferably, the vulcanization temperature of the injection vulcanization molding is 90° C.-130° C., and the vulcanization time is 50-200 s.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The sheep vaginal sustained-release agent provided by the present invention uses a skeleton inner core as a skeleton support, and a silica gel drug-loaded epidermis wrapped outside the skeleton inner core is used to exert drug efficacy. The silica gel drug-loaded epidermis component uses progesterone as an active ingredient, and uses a medical silicone rubber elastomer as a drug carrier. The biomacromolecule material has micropores, and the principle of slow drug release can be used to achieve a sustained release effect. At the same time, the material is a non-degradable inert material, does not undergo chemical reactions in the body, is non-toxic and non-irritating, and has good biocompatibility with the body. A porogen is added to the silica gel drug-loaded epidermis component, and a plurality of micropores can be formed in the silica gel drug-loaded epidermis, which is conducive to the release of the drug. An expansion agent is also added to the silica gel drug-loaded epidermis component. The expansion agent absorbs water and expands after contacting a humid environment in the body. On the one hand, it can promote the release of the main component by promoting the dissolution of the porogen, thereby reducing the drug residue in the silica gel. On the other hand, after absorbing moisture and expanding, the product can be prevented from falling off easily. In addition, the vulcanizing agent in the component is used for vulcanization treatment of the silicone rubber to ensure its stability and safety after molding, and the reinforcing filler in the component can improve the mechanical properties of the silicone rubber. The sheep vaginal sustained-release agent provided by the present invention is a sheep vaginal sustained-release suppository. During use, the drug can be released to a greater extent, so that the drug residue is significantly reduced. At the same time, the volume will expand to a certain extent after contacting with body fluids, which can effectively improve the phenomenon of suppository falling off during use. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0029] Figure 1 This is a schematic structural diagram of the vaginal sustained-release preparation for sheep provided by the present invention.

[0030] Icon: 1- skeleton core; 2- silica gel drug-loaded surface. DETAILED DESCRIPTION

[0031] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the case of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms is non-limiting.

[0032] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] The first aspect of the present invention provides a vaginal sustained-release preparation for sheep, such as Figure 1 As shown, it includes a skeleton core 1 and a silicone drug-loaded epidermis 2 wrapped around the skeleton core 1; the silicone drug-loaded epidermis includes the following components: progesterone, medical silicone rubber, vulcanizing agent, pore-forming agent, expander and reinforcing filler.

[0034] The sheep vaginal sustained-release agent provided by the present invention uses a skeleton inner core as a skeleton support, and a silica gel drug-loaded epidermis wrapped outside the skeleton inner core is used to exert drug efficacy. The silica gel drug-loaded epidermis component uses progesterone as an active ingredient, and uses a medical silicone rubber elastomer as a drug carrier. The biomacromolecule material has micropores, and the principle of slow drug release can achieve a sustained release effect. At the same time, the material is a non-degradable inert material, does not chemically react in the body, is non-toxic and non-irritating, and has good biocompatibility with the body. A porogen is added to the silica gel drug-loaded epidermis component, and a plurality of micropores can be formed in the silica gel drug-loaded epidermis, which is conducive to the release of the drug. An expansion agent is also added to the silica gel drug-loaded epidermis component. The expansion agent absorbs water and expands after contacting a humid environment in the body. On the one hand, it can promote the release of the main component by promoting the dissolution of the porogen, thereby reducing the drug residue in the silica gel. On the other hand, after absorbing moisture and expanding, the product can be difficult to fall off. In addition, the vulcanizing agent in the component is used for vulcanization treatment of the silicone rubber to ensure its stability and safety after molding, and the reinforcing filler in the component can improve the mechanical properties of the silicone rubber. The sheep vaginal sustained-release agent provided by the present invention is a sheep progesterone vaginal sustained-release suppository. During use, the drug can be released to a greater extent, so that the drug residue is significantly reduced. At the same time, the volume will expand to a certain extent after contacting with body fluids, which can effectively improve the phenomenon of suppository falling off during use.

[0035] In some preferred embodiments, the silica gel drug-loaded epidermis comprises the following components by mass percentage:

[0036] 6.7% progesterone, 0.5%-3.0% vulcanizing agent, 1.0%-6.0% porogen, 5.0%-10% expander, 1.0%-10% reinforcing filler and the balance medical silicone rubber.

[0037] Taking the mass of the silica gel drug-carrying epidermis as 100%, the added amount of progesterone is 5%-7%, for example, 5%, 6%, 7%, etc., preferably 6.7%;

[0038] Taking the mass of the silica gel drug-carrying epidermis as 100%, the amount of the vulcanizing agent added is 0.5%-3.0%, for example, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, etc.;

[0039] Taking the mass of the silica gel drug-loaded epidermis as 100%, the added amount of the porogen is 1.0%-6.0%, for example, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, etc.;

[0040] Taking the mass of the silica gel drug-carrying epidermis as 100%, the addition amount of the swelling agent is 5.0%-10%, for example, it can be 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10%, etc.;

[0041] Taking the mass of the silica gel drug-loaded epidermis as 100%, the added amount of the reinforcing filler is 1.0%-10%, for example, it can be 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10%, etc.

[0042] Preferably, the silicone drug-loaded epidermis comprises the following components by mass percentage: 6.7% progesterone, 78.1% medical silicone rubber, 1.1% vulcanizing agent, 3% porogen, 7.1% expander and 4% reinforcing filler.

[0043] In some preferred embodiments, the porogen includes at least one of lactose, PEG3000 and PEG4000.

[0044] In the present invention, in order to enable the product to release progesterone evenly within a usage period of 12 to 14 days, an appropriate amount of auxiliary agent, such as lactose or PEG3000 or PEG4000, is added to the prescription. Such pore-forming agents are all water-soluble compounds, which are evenly dispersed in the silica gel. When the progesterone vaginal sustained-release agent is placed in the vagina of an animal, it dissolves after contacting with body fluids, and a plurality of micropores are formed in the silica gel drug-carrying layer, which is conducive to the release of drugs, especially the drugs in the inner layer.

[0045] In some preferred embodiments, the swelling agent includes at least one of glycerol and propylene glycol.

[0046] In the present invention, adding a certain amount of swelling agent, glycerin or propylene glycol can make the preparation absorb water and swell after contacting the humid environment in the body, which can promote the release of the main component on the one hand, and make the product less likely to fall off on the other hand after absorbing moisture and swelling.

[0047] Further explanation, in the present invention, a certain amount of lactose and glycerol are preferably added. Lactose will dissolve after contacting body fluids, significantly increasing the porosity of the silicone rubber surface and even causing the pores to become larger; glycerol will absorb water and swell after contacting a humid environment, further promoting the dissolution of lactose, thereby significantly increasing the amount of raw material released, greatly reducing the drug residue in the silica gel, and thus reducing the amount of raw material used. At the same time, after the drug-containing silica gel layer on the surface of the suppository expands, the phenomenon of the suppository falling off during use can be improved to a certain extent.

[0048] In some preferred embodiments, the vulcanizing agent includes a platinum vulcanizing agent.

[0049] In the present invention, the preparation uses silicone rubber as a carrier material, and the production process involves a vulcanization process, i.e., an injection molding step. This process uses a platinum vulcanizer, which is a high-efficiency halogen-free silicone vulcanizer. It is suitable for vacuum vulcanization and moldless hot air vulcanization of silicone rubber. After molding, it is odorless and non-toxic, and meets FDA testing standards. It is odorless, has no blooming, has good yellowing resistance, has high transparency of the product, and has greatly improved mechanical properties, and is suitable for the production of highly transparent products. Such as: edible products, medical products, etc. The cross-linking temperature is low, and it is energy-saving and efficient.

[0050] In some preferred embodiments, the reinforcing filler includes at least one of light calcium carbonate, silicon dioxide and microcrystalline cellulose.

[0051] In the present invention, a certain amount of reinforcing filler, light calcium carbonate or silicon dioxide (precipitation method) or microcrystalline cellulose is added to improve the mechanical properties of silicone rubber, which can effectively improve the tearing and damage in the demoulding process of injection molding and improve the yield rate.

[0052] The vaginal sustained-release agent for sheep provided by the invention is used for regulating the estrus cycle of young growing ewes and multiparous ewes, is suitable for synchronous estrus and embryo transplantation of cattle, and for treating postpartum anovulation and aestrus.

[0053] Compared with the existing progesterone vaginal sustained-release agents on the market, the vaginal sustained-release agent for sheep provided by the present invention has the following advantages: 1. It has a lower drug loading and a faster drug release rate, which can greatly reduce the use and residue of raw materials; 2. After being implanted in the vagina of an animal and contacting body fluids, its volume will expand to a certain extent, which can effectively reduce the phenomenon of plug drop.

[0054] The second aspect of the present invention provides a method for preparing the vaginal sustained-release preparation for sheep, comprising the following steps:

[0055] The formula amount of progesterone, medical silicone rubber, vulcanizer, pore-forming agent, expander and reinforcing filler are mixed to obtain a drug-loaded rubber compound, and then the drug-loaded rubber compound is wrapped on the outside of the skeleton core to form a silica gel drug-loaded epidermis to obtain the vaginal sustained-release agent for sheep.

[0056] In some preferred embodiments, the mixing process includes internal mixing and open mixing in sequence;

[0057] Optionally, the mixing process includes: adding progesterone, porogen, expander and reinforcing filler to the medical silicone rubber for internal kneading, and then adding a vulcanizing agent for open kneading to obtain a drug-loaded rubber material;

[0058] Optionally, the mixing process includes: adding a porogen, an expander and a reinforcing filler to the medical silicone rubber for a first internal kneading, then adding progesterone for a second internal kneading, and then adding a vulcanizing agent for an open kneading to obtain a drug-loaded rubber material;

[0059] Optionally, the mixing process includes: adding progesterone to the medical silicone rubber for a first kneading, then adding a porogen, an expander and a reinforcing filler for a second kneading, and then adding a vulcanizer for open kneading to obtain a drug-loaded rubber material.

[0060] In the preparation process of the present invention, the silicone rubber and the additives are first mixed evenly in an internal mixer, and the vulcanizer is added in the opening mixing step to prevent the temperature from rising during the internal mixing process, causing the vulcanizer to react prematurely and causing the rubber to be vulcanized prematurely, making it impossible to proceed to the next injection molding process. Among the three mixing processes mentioned above, the last one has a better effect, because the step-by-step addition can reduce dust during the internal mixing process; adding progesterone first can reduce the loss rate of raw material progesterone compared to adding progesterone later.

[0061] Preferably, the total time of the banburying is 40-60 min, for example, it can be 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min, 60 min, etc.;

[0062] Preferably, the refining time is 5-15 min, for example, it can be 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, etc.

[0063] In some preferred embodiments, the formation process of the silica gel drug-loaded skin includes: wrapping the drug-loaded rubber material on the outside of the skeleton core by injection vulcanization molding;

[0064] Preferably, the vulcanization temperature of the injection vulcanization molding is 90°C-130°C, for example, 90°C, 100°C, 110°C, 120°C, 130°C, etc.; the vulcanization time is 50-200s, for example, 50s, 60s, 70s, 80s, 90s, 100s, 110s, 120s, 130s, 140s, 150s, 160s, 170s, 180s, 190s, 200s, etc. The injection pressure is preferably 100 bar.

[0065] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0066] In the following examples and comparative examples, the injection pressure is 100 bar.

[0067] In the following examples and comparative examples:

[0068] The selected progesterone: the particle size is required to be between 10μm and 40μm;

[0069] Selected medical silicone rubber: compound rubber, Shore hardness: 40;

[0070] The selected platinum vulcanizing agent is a two-component platinum vulcanizing agent (including platinum vulcanizing agent A and platinum vulcanizing agent B);

[0071] Selected glycerin: pharmaceutical grade;

[0072] Selected lactose: α-lactose pharmaceutical grade;

[0073] Selected microcrystalline cellulose: PH101 pharmaceutical grade;

[0074] Selected silicon dioxide (precipitation method): SH-CD1 pharmaceutical grade;

[0075] The selected light calcium carbonate: the average particle size is 10-20 microns, model LCC-100;

[0076] The selected PEG3000 has an average particle size of 100 microns.

[0077] Example 1

[0078] The present embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silicone drug-loaded epidermis wrapped around the outer surface of the skeleton inner core, wherein the silicone drug-loaded epidermis comprises the following components by mass percentage: 6.7% progesterone, 1.1% vulcanizing agent, 3.0% porogen, 7.1% expander, 4% reinforcing filler and the balance medical silicone rubber;

[0079] Among them, the vulcanizing agent is platinum vulcanizing agent, the porogen is PEG3000, the swelling agent is glycerol, and the reinforcing filler is light calcium carbonate.

[0080] Example 2

[0081] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped outside the skeleton inner core, and the difference from the embodiment 1 is that the pore-forming agent is lactose;

[0082] The remaining components and contents are consistent with those in Example 1.

[0083] Example 3

[0084] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped outside the skeleton inner core, and the difference from the embodiment 2 is that the reinforcing filler is microcrystalline cellulose;

[0085] The remaining components and contents are consistent with those in Example 2.

[0086] Example 4

[0087] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped outside the skeleton inner core, and the difference from embodiment 2 is that the reinforcing filler is silicon dioxide (precipitation method);

[0088] The remaining components and contents are consistent with those in Example 2.

[0089] Example 5

[0090] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silicone drug-carrying epidermis wrapped around the skeleton inner core, and the difference from Embodiment 4 is that the silicone drug-carrying epidermis comprises the following components by mass percentage: 5% progesterone, 0.5% vulcanizing agent, 6.0% porogen, 5.0% expander, 10% reinforcing filler and the balance medical silicone rubber;

[0091] The remaining agents are consistent with those in Example 4.

[0092] Example 6

[0093] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silicone drug-carrying epidermis wrapped around the skeleton inner core, and the difference from Embodiment 4 is that the silicone drug-carrying epidermis comprises the following components by mass percentage: 7% progesterone, 3.0% vulcanizing agent, 1.0% porogen, 10% expander, 1.0% reinforcing filler and the balance medical silicone rubber;

[0094] The remaining agents are consistent with those in Example 4.

[0095] Example 7

[0096] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-loaded epidermis wrapped around the outside of the skeleton inner core. The difference from Example 4 is that among the components of the silica gel drug-loaded epidermis, the pore-forming agent is 0.5%, the swelling agent is 10.5%, and the remaining components are consistent with Example 4.

[0097] Example 8

[0098] This embodiment provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-loaded epidermis wrapped around the outside of the skeleton inner core. The difference from Example 4 is that among the components of the silica gel drug-loaded epidermis, the pore-forming agent accounts for 6.5%, the swelling agent accounts for 4.5%, and the remaining components are consistent with Example 4.

[0099] Example 9

[0100] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 1. The raw material prescription is shown in Table 1.

[0101] Table 1

[0102]

[0103] The preparation method of the vaginal sustained-release preparation for sheep specifically comprises the following steps:

[0104] (1) Install the nylon skeleton core mold on the injection molding machine, use nylon material as the raw material of the skeleton core, bake the nylon material at 100°C for 4 hours, adjust the parameters of the injection molding machine, set the barrel heating temperature to 280°C ± 10°C, and the pressure to 95 Bar, and prepare the skeleton core by injection molding.

[0105] (2) Weigh 100 parts by weight of silicone rubber and add it to an internal mixer and mix for 10 minutes. Then add 100 parts by weight of progesterone and mix for 20 minutes until the rubber material has a uniform texture and is free of powder.

[0106] (3) Weigh 100 prescription amounts of pore-forming agent PEG3000, expansion agent glycerol, and reinforcing filler light calcium carbonate, mix them appropriately, add them to an internal mixer, and knead for 20 minutes until the rubber material has a uniform texture and is free of powder.

[0107] (4) Transfer the rubber in the internal mixer to the open mixer, adjust the roller spacing appropriately, and start the open mixer. Add 100 prescription amounts of platinum vulcanizer and start the mixer for 10 minutes (the specific process of the open mixer is: first add platinum vulcanizer B and start the mixer for 5 minutes, then add platinum vulcanizer A and start the mixer for 5 minutes). The rubber sheets after the open mixer are separated by food-grade PE film and rolled into a tube to facilitate slicing and weighing later.

[0108] (5) Cut the film into small pieces of about 28g for later use. Put the cut and weighed film into the material cavity according to the operating procedures of the injection molding machine, put the skeleton core into the mold, adjust the parameters of the injection molding machine: vulcanization temperature: 120℃, the upper and lower mold temperatures are the same; vulcanization time 180s, injection molding, and vulcanization molding to form a vaginal sustained-release preparation for sheep with a silicone drug-loaded epidermis wrapped around the outside of the skeleton core.

[0109] Example 10

[0110] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 2. The raw material prescription is shown in Table 2.

[0111] Table 2

[0112]

[0113]

[0114] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 9.

[0115] Embodiment 11

[0116] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 3. The raw material prescription is shown in Table 3.

[0117] Table 3

[0118]

[0119] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 9.

[0120] Example 12

[0121] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 4. The raw material prescription is shown in Table 4.

[0122] Table 4

[0123]

[0124]

[0125] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 9.

[0126] Embodiment 13

[0127] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 5. The raw material prescription is shown in Table 5.

[0128] Table 5

[0129] Element Prescription dosage (1 prescription dosage is 4.5g in total) Progesterone 0.225g Silicone Rubber 3.3075g Platinum vulcanizing agent 0.0225g lactose 0.2700g glycerin 0.2250g Silica (precipitation method) 0.4500g

[0130] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 12.

[0131] Embodiment 14

[0132] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 6. The raw material prescription is shown in Table 6.

[0133] Table 6

[0134]

[0135]

[0136] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 12.

[0137] Embodiment 15

[0138] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 7. The raw material prescription is shown in Table 7.

[0139] Table 7

[0140] Element Prescription dosage (1 prescription dosage is 4.5g in total) Progesterone 0.3015g Silicone Rubber 3.474g Platinum vulcanizing agent 0.0495g lactose 0.0225g glycerin 0.4725g Silica (precipitation method) 0.1800g

[0141] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 12.

[0142] Example 16

[0143] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 8. The raw material prescription is shown in Table 8.

[0144] Table 8

[0145] Element Prescription dosage (1 prescription dosage is 4.5g in total) Progesterone 0.3015g Silicone Rubber 3.4740g Platinum vulcanizing agent 0.0495g lactose 0.2925g glycerin 0.2025g Silica (precipitation method) 0.1800g

[0146] The preparation steps of the vaginal sustained-release preparation for sheep are the same as those in Example 12.

[0147] Embodiment 17

[0148] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 4, and the raw material prescription is consistent with that of Example 12. The preparation steps of the vaginal sustained-release preparation for sheep include:

[0149] Step (1) is consistent with Example 12.

[0150] (2) Weigh 100 parts by weight of silicone rubber and add it to an internal mixer and mix for 10 minutes. Then add 100 parts by weight of progesterone and mix for 20 minutes until the rubber material has a uniform texture and is free of powder.

[0151] (3) Weigh 100 prescription amounts of lactose, glycerol, and silicon dioxide, mix appropriately, add to an internal mixer, and knead for 20 minutes until the rubber material has a uniform texture and is free of powder.

[0152] (4) The rubber compound in the internal mixer is transferred to the open mixer, the roller spacing is adjusted appropriately, and the mixture is open-mixed. 100 grams of platinum vulcanizer is added and the mixture is refining for 5 minutes (the specific refining process is: first add platinum vulcanizer B and refining for 2.5 minutes, then add platinum vulcanizer A and refining for 2.5 minutes). The refining rubber sheets are separated by food-grade PE film and rolled into a tube to facilitate slicing and weighing later.

[0153] (5) Cut the smelted film into small pieces of about 28g for later use. Put the cut and weighed film into the material cavity according to the operating procedures of the injection molding machine, put the skeleton core into the mold, and adjust the parameters of the injection molding machine: vulcanization temperature: 90℃, the upper and lower mold temperatures are the same; vulcanization time: 200s, injection molding.

[0154] Embodiment 18

[0155] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 4, and the raw material prescription is consistent with that of Example 12. The preparation steps of the vaginal sustained-release preparation for sheep include:

[0156] Step (1) is consistent with Example 12.

[0157] (2) Weigh 100 parts by weight of silicone rubber and add it to an internal mixer and mix for 16 minutes. Then add 100 parts by weight of progesterone and mix for 17 minutes until the rubber material has a uniform texture and is free of powder.

[0158] (3) Weigh 100 prescription amounts of lactose, glycerol, and silicon dioxide, mix appropriately, add to an internal mixer, and knead for 17 minutes until the rubber material has a uniform texture and is free of powder.

[0159] (4) Transfer the rubber in the internal mixer to the open mixer, adjust the roller spacing appropriately, and perform open mixing. Add 100 prescription amounts of platinum vulcanizer and perform open mixing for 15 minutes (the specific open mixing process is: first add platinum vulcanizer B and perform open mixing for 7 minutes, then add platinum vulcanizer A and perform open mixing for 8 minutes). The opened mixed rubber sheets are separated by food-grade PE film and rolled into a tube to facilitate slicing and weighing later.

[0160] (5) Cut the smelted film into small pieces of about 28g for later use. Put the cut and weighed film into the material cavity according to the operating procedures of the injection molding machine, put the skeleton core into the mold, and adjust the parameters of the injection molding machine: vulcanization temperature: 130℃, the upper and lower mold temperatures are the same; vulcanization time 50s, injection molding (injection pressure: 100ar) vulcanization molding.

[0161] Embodiment 19

[0162] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 4, and the raw material prescription is consistent with that of Example 12. The preparation steps of the vaginal sustained-release preparation for sheep include:

[0163] Step (1) is consistent with Example 12.

[0164] (2) Weigh 100 parts of silicone rubber and add it to an internal mixer and mix for 5 minutes. Then add 100 parts of progesterone, lactose, glycerin, and silicon dioxide and mix until the rubber has a uniform color and a smooth surface without any granularity. The process takes about 40 minutes.

[0165] (3) Transfer the rubber in the internal mixer to the open mixer, adjust the roller spacing appropriately, and start the open mixer. Add 100 prescription amounts of platinum vulcanizer and start the mixer for 10 minutes (the specific process of the open mixer is: first add platinum vulcanizer B and start the mixer for 5 minutes, then add platinum vulcanizer A and start the mixer for 5 minutes). The rubber sheets after the open mixer are separated by food-grade PE film and rolled into a tube to facilitate slicing and weighing later.

[0166] (4) Cut the smelted film into small pieces of about 28g for later use. Put the cut and weighed film into the material cavity according to the operating procedures of the injection molding machine, put the skeleton core into the mold, and adjust the parameters of the injection molding machine: vulcanization temperature: 120℃, the upper and lower mold temperatures are the same; vulcanization time 180s, injection molding.

[0167] Embodiment 20

[0168] This embodiment provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Example 4, and the raw material prescription is consistent with that of Example 12. The preparation steps of the vaginal sustained-release preparation for sheep include:

[0169] Step (1) is consistent with Example 12.

[0170] (2) Weigh 100 parts of silicone rubber and add them to an internal mixer and mix them for 10 minutes. Then weigh 100 parts of lactose, glycerol and light calcium carbonate and mix them appropriately. Then add them to the internal mixer and mix them for 20 minutes until the rubber material has a uniform texture and is free of powder.

[0171] (3) Weigh 100 grams of the prescription amount of progesterone and add it to an internal mixer and mix for 20 minutes until the rubber compound has a uniform texture and is free of powder.

[0172] (4) Transfer the rubber in the internal mixer to the open mixer, adjust the roller spacing appropriately, and start the open mixer. Add 100 prescription amounts of platinum vulcanizer and start the mixer for 10 minutes (the specific process of the open mixer is: first add platinum vulcanizer B and start the mixer for 5 minutes, then add platinum vulcanizer A and start the mixer for 5 minutes). The rubber sheets after the open mixer are separated by food-grade PE film and rolled into a tube to facilitate slicing and weighing later.

[0173] (5) Cut the smelted film into small pieces of about 28g for later use. Put the cut and weighed film into the material cavity according to the operating procedures of the injection molding machine, put the skeleton core into the mold, and adjust the parameters of the injection molding machine: vulcanization temperature: 120℃, the upper and lower mold temperatures are the same; vulcanization time: 180s, injection molding.

[0174] Comparative Example 1

[0175] This comparative example provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped around the skeleton inner core. The difference from Example 4 is that it does not contain a porogen, and the other components are consistent with Example 4.

[0176] Comparative Example 2

[0177] This comparative example provides a vaginal sustained-release preparation for sheep, comprising a skeleton inner core and a silica gel drug-carrying epidermis wrapped around the skeleton inner core. The difference from Example 4 is that it does not contain a swelling agent, and the other components are consistent with Example 4.

[0178] Comparative Example 3

[0179] This example provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Comparative Example 1, and the raw material prescription is shown in Table 9. The preparation method is consistent with that of Example 12.

[0180] Table 9

[0181] Element Prescription dosage (1 prescription dosage is 4.5g in total) Progesterone 0.3015g Silicone Rubber 3.6495g Platinum vulcanizing agent 0.0495g glycerin 0.3195g Silica (precipitation method) 0.1800g

[0182] Comparative Example 4

[0183] This example provides a method for preparing a vaginal sustained-release preparation for sheep, which is prepared using the raw materials of Comparative Example 2, and the raw material prescription is shown in Table 10. The preparation method is consistent with that of Example 12.

[0184] Table 10

[0185] Element Prescription dosage (1 prescription dosage is 4.5g in total) Progesterone 0.3015g Silicone Rubber 3.8340g Platinum vulcanizing agent 0.0495g lactose 0.1350g Silica (precipitation method) 0.1800g

[0186] Test Case

[0187] Test samples: The vaginal sustained-release preparations for sheep prepared in Examples 9-20 and Comparative Examples 3-4 were used as samples for testing.

[0188] Test method:

[0189] According to the laboratory investigation and research, the embodiment is evaluated in three aspects: production process feasibility, in vitro cumulative dissolution volume, clinical thrombus drop rate and main component residual rate. On the premise that the production process is feasible, the in vitro cumulative dissolution volume and clinical thrombus drop and residual tests are continued.

[0190] (1) The production process is feasible:

[0191] The evaluation was mainly carried out from two aspects: adhesiveness to roller, integrity of rubber coating and flexibility. The evaluation results of each sample are shown in Table 11.

[0192] Table 11

[0193]

[0194] According to Table 11, Examples 9, 10, 15, 19, 20 and Comparative Example 4 are not feasible in terms of technology, so they are not examined in the following two tests.

[0195] (2) Cumulative dissolution in vitro

[0196] The detection method is as follows:

[0197] Cumulative dissolution: Preparation of standard curve

[0198] Take an appropriate amount of progesterone reference substance, weigh it accurately, dissolve it in ethanol and quantitatively dilute it to make a solution containing about 1 mg per 1 ml, shake it well, accurately measure 0.2 ml, 0.5 ml, 1.0 ml, 1.2 ml and 1.5 ml respectively, put them into a 50 ml volumetric flask, and dilute it to the scale with ethanol. Determine it according to the UV-visible spectrophotometry method (Appendix 0401), measure the absorbance at a wavelength of 239 nm, and draw a standard curve (A=kC+b) with concentration C (μg / ml) as the horizontal axis and absorbance A as the vertical axis.

[0199] Determination method: Take 6 samples of this product and follow the dissolution and release determination method (Appendix 0931 Method 2), using 1100ml of ethanol-water (625:375) as the dissolution medium, the water bath temperature is 37±0.5℃, the speed is 100 rpm, operate according to the method, fix the sample on the paddle, take about 10ml of solution after 1 hour, 4 hours, 9 hours, 15 hours and 24 hours, accurately transfer 4ml of the above 1 hour solution to a 10ml volumetric flask, 2ml of the 4 hour solution to a 10ml volumetric flask, and 2ml of the solution at other time points to a 20ml volumetric flask, dilute to the scale with ethanol, shake well, and measure the absorbance. Calculate the cumulative dissolution amount of each sample at each time point according to the following formula.

[0200] Sample concentration after sampling at each time point (before dilution)

[0201] Cumulative dissolution amount at each time point (%) = {C n ×[V 2 -(n-1)V 1 ]+(C n-1 +……+C 2 +C 1)×V 1}÷W 标 ;

[0202] Where: W 标 The amount of raw material progesterone in the prescription;

[0203] A is the absorbance of the sample; b is the intercept of the standard curve; k is the slope of the standard curve; D is the dilution factor, 2.5 or 5 or 10; V1 is the fixed sampling volume at each time point; V2 is the volume of the dissolution solvent, 1100 ml.

[0204] The results of the cumulative dissolution amount at each time point in each embodiment within 14 days are shown in Table 12.

[0205] Table 12

[0206]

[0207]

[0208] From the data in Table 12, it can be seen that Example 12 has the best performance in terms of cumulative dissolution amount in that the main component can be completely dissolved in 10 days, and the overall release is basically uniform. The following is an analysis of each embodiment and comparative example:

[0209] Example 11: The release is slightly slower than that of Example 12, and the main component needs 14 days to be completely dissolved; Example 12: The release is fast and stable, and the overall performance is the best; Example 13: The dissolution amount is close to that of Example 11, and the main component also needs 14 days to be completely dissolved; Example 14: The release is slow, and the main component cannot be completely dissolved within 14 days, and there may be a problem of oversulfurization. Example 16: The dissolution amount is close to that of Example 14, and the main component cannot be completely dissolved within 14 days; Example 17: Similar to Example 12, but with slight differences; Example 18: Similar to Example 12, but with slight differences;

[0210] Comparative Example 3: The main component could not be completely dissolved within 14 days, and the overall dissolution was slow.

[0211] Since the in vitro and in vivo correlation of this product cannot be evaluated, especially when using an ethanol-water system as the dissolution medium; clinical trials were conducted on the preferred embodiments in Table 12 at the same time, the thrombus removal phenomenon was observed within a 14-day medication cycle, and the residual progesterone in the product after thrombus removal was detected.

[0212] (3) Statistics of thrombus drop rate and detection of residual progesterone in the main component (sample size: 20 heads per sample)

[0213] Progesterone content detection method:

[0214] Chromatographic conditions and system suitability test: Octylsilane bonded silica gel was used as filler (Welch UltimatePlus C8 4.6*250mm, 5μm or chromatographic column with equivalent performance); methanol: acetonitrile: water (25:35:40) was used as mobile phase, flow rate was 1.0ml / min, column temperature was 30℃, detection wavelength was 241nm, 25mg of progesterone was taken, placed in a 25ml volumetric flask, 10ml of 0.1mol / L sodium hydroxide methanol solution was added to dissolve, placed in a 60℃ water bath for 4 hours, cooled, adjusted to neutral with 1mol / L hydrochloric acid solution, diluted to the scale with methanol, shaken well, and used as system suitability solution. Accurately measure 10μl of system suitability solution, inject into liquid chromatograph, and record the chromatogram to twice the retention time of the main component peak. The separation degree between progesterone and the degradation product with a relative retention time of about 1.1 should be greater than 4.0.

[0215] Determination method: Take one outer covering (drug-containing matrix) under the weight difference item, accurately weigh it, cut it into pieces, put it in a Soxhlet extractor, add 300ml of ethanol, extract for 16 hours or extract for 2 days, 8 hours a day. Pour the extraction solution into a 500ml volumetric flask, rinse the extractor with 15-20ml of ethanol 3 times, add this solution to the volumetric flask, dilute it to the scale with ethanol, shake it well, filter it, and get the test solution. Take an appropriate amount of progesterone reference substance, accurately weigh it, dissolve it with ethanol and quantitatively dilute it to make a solution containing about 0.6mg per 1ml as the reference substance solution. Accurately measure 5μl of the reference substance solution and the test solution, respectively inject them into the liquid chromatograph, and record the chromatogram. Calculate the peak area according to the external standard method, and then multiply it by 1.06 to get it.

[0216] Note: 1.06 is the verified extraction recovery rate.

[0217]

[0218] C pair: concentration of reference solution;

[0219] A pair: progesterone peak area in the reference substance;

[0220] A supply: progesterone peak area in the test sample;

[0221] D supply: dilution volume of test solution;

[0222] W 平均 : Average weight of 10 samples (excluding nylon thorns), mg;

[0223] W 供 : Sample (excluding nylon thorn) weight, mg;

[0224] Labelled amount: 300 mg;

[0225] The results of the thrombus drop rate and the main component residual progesterone test are shown in Table 13.

[0226] Table 13

[0227]

[0228]

[0229] As shown in Table 13, Example 12 is the best performing product, with the lowest progesterone residue after thrombus removal, the main component is basically released, and there is no thrombus drop. The main component residues of Examples 11, 13, 14, 16, 17, and 18 are 5% to 10%, which may be related to the slight difference in the prescription process. The content of the swelling agent in the product of Example 16 is relatively low, not within the preferred range of the present invention, and the expansion volume cannot reach the expected level, so there is a thrombus drop; Comparative Example 3 performs poorly, and about 20% of the main component cannot be released. During clinical use, the volume of the thrombus cannot expand after absorbing water, and there are problems such as thrombus drop, which is not suitable as a reference.

[0230] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A vaginal sustained-release preparation for sheep, characterized in that: It comprises a skeleton inner core and a silica gel drug-carrying epidermis wrapped outside the skeleton inner core; The silica gel drug-carrying epidermis comprises the following components: progesterone, medical silicone rubber, a vulcanizing agent, a pore-forming agent, an expander and a reinforcing filler.

2. The vaginal sustained-release preparation for sheep according to claim 1, characterized in that: The silica gel drug-carrying epidermis comprises the following components by mass percentage: 5%-7% progesterone, 0.5%-3.0% vulcanizing agent, 1.0%-6.0% porogen, 5.0%-10% expander, 1.0%-10% reinforcing filler and the balance medical silicone rubber.

3. The vaginal sustained-release preparation for sheep according to claim 1, characterized in that: The porogen includes at least one of lactose, PEG3000 and PEG4000.

4. The vaginal sustained-release preparation for sheep according to claim 1, characterized in that: The swelling agent includes at least one of glycerol and propylene glycol.

5. The vaginal sustained-release preparation for sheep according to claim 1, characterized in that: The vulcanizing agent includes a platinum vulcanizing agent.

6. The vaginal sustained-release preparation for sheep according to claim 1, characterized in that: The reinforcing filler includes at least one of light calcium carbonate, silicon dioxide and microcrystalline cellulose.

7. The method for preparing the vaginal sustained-release preparation for sheep according to any one of claims 1 to 6, characterized in that: The following steps are involved: The formula amount of progesterone, medical silicone rubber, vulcanizer, pore-forming agent, expander and reinforcing filler are mixed to obtain a drug-loaded rubber compound, and then the drug-loaded rubber compound is wrapped on the outside of the skeleton core to form a silica gel drug-loaded epidermis to obtain the vaginal sustained-release agent for sheep.

8. The method for preparing the vaginal sustained-release preparation for sheep according to claim 7, characterized in that: The mixing process includes internal mixing and open mixing in sequence; Optionally, the mixing process includes: adding progesterone, porogen, expander and reinforcing filler to the medical silicone rubber for internal kneading, and then adding a vulcanizing agent for open kneading to obtain a drug-loaded rubber material; Optionally, the mixing process includes: adding a porogen, an expander and a reinforcing filler to the medical silicone rubber for a first internal kneading, then adding progesterone for a second internal kneading, and then adding a vulcanizing agent for an open kneading to obtain a drug-loaded rubber material; Optionally, the mixing process includes: adding progesterone to the medical silicone rubber for a first kneading, then adding a porogen, an expander and a reinforcing filler for a second kneading, and then adding a vulcanizer for open kneading to obtain a drug-loaded rubber material.

9. The method for preparing the vaginal sustained-release preparation for sheep according to claim 8, characterized in that: The total time of the banburying is 40-60min; Preferably, the refining time is 5-15 min.

10. The method for preparing the vaginal sustained-release preparation for sheep according to claim 7, characterized in that: The formation process of the silica gel drug-loaded skin includes: wrapping the drug-loaded rubber material on the outside of the skeleton core by injection vulcanization molding; Preferably, the vulcanization temperature of the injection vulcanization molding is 90° C.-130° C., and the vulcanization time is 50-200 s.

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