WO2023070892A1 - Novel veterinary uterine infusion, preparation method therefor, and use thereof - Google Patents

Abstract

A preparation method for a novel veterinary uterine infusion, belonging to the field of veterinary drug preparation. The preparation method comprises: separately mixing an adsorption carrier with a rifaximin self-microemulsion and a growth repair factor to prepare self-microemulsion drug-loaded particles and growth repair factor drug-loaded particles; mixing a first matrix, a second matrix, and water for infusion to prepare an infusion matrix, mixing the infusion matrix with the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles, then freezing and drying the mixture to acquire a uterine infusion; by using the cell growth promoting effect of the growth repair factor and a cell proliferation microenvironment provided by a gel matrix, accelerating the repair of endometrial epidermal cells, promoting damaged tissue regeneration, and establishing a protective barrier, thereby preventing new infection from occurring in the uterus, and reducing the incidence rate of endometritis.

Description

A novel veterinary uterine injection and its preparation method and application

This application claims the priority of an invention patent application submitted to the China Patent Office on October 29, 2021, with the application number 202111272351.4, and the title of the invention is "a new type of veterinary uterine injection and its preparation method and application". References are incorporated in this application.

technical field

The invention relates to the field of veterinary drug preparations, in particular to a novel uterine injection for veterinary use and its preparation method and application.

Background technique

Dairy cow endometritis is a relatively common disease in the process of raising cattle. It has a high morbidity rate but a low case fatality rate, often in a chronic process. The disease will not only seriously reduce the reproductive ability of the sick cow, but also reduce the milk production to a certain extent, and even lose the ability to lactate. If the symptoms are severe, it will cause infertility, and even can only be eliminated. Cause other diseases, such as metritis and so on. In recent years, with the continuous expansion of dairy cow breeding scale and the widespread application of artificial insemination technology, the incidence of this disease has been on the rise, which seriously damages the economic benefits of dairy cow breeding industry and should be prevented and controlled.

Rifaximin is an artificial semi-synthetic derivative of rifamycin SV. Like other rifamycin antibacterial drugs, it inhibits bacterial RNA synthesis by irreversibly binding to the β-subunit of bacterial DNA-dependent RNA polymerase, and finally inhibits bacterial protein synthesis. Rifaximin has a broad antibacterial spectrum, has high antibacterial activity against most Gram-positive aerobic bacteria, and is also effective against Escherichia coli, Salmonella, Shigella and Gram-positive anaerobic bacteria among Gram-negative bacteria. antibacterial activity. Intrauterine administration of rifaximin has almost no absorption, low level of tissue absorption, no adverse effects on the normal flora of the body, and no obvious side effects. Therefore, intrauterine infusion of rifaximin is very suitable for the treatment of cow metritis.

Uterine injection therapy refers to the perfusion of antibiotics in the uterus of cows to treat and prevent the occurrence of endometritis in cows. However, most of the uterine injections currently on the market are mainly aimed at bactericidal effects, and cannot take into account the repair of the uterine epidermis and tissues. They only focus on "treatment" and ignore "prevention". Injury, abortion, dystocia, retained placenta and irregular artificial insemination will provide opportunities for pathogenic bacteria to invade, and pathogenic bacteria are likely to accumulate in large numbers during this period, causing related diseases. Therefore, the injection takes care of the uterus Repair of epidermis and tissue is necessary.

Contents of the invention

In view of the above problems, the present invention provides a novel veterinary uterine injection and its preparation method and application.

The object of the present invention adopts following technical scheme to realize:

A preparation method of a novel veterinary uterine injection comprises the following steps in sequence:

(1) preparing rifaximin self-microemulsion;

(2) mixing the adsorption carrier with the rifaximin self-microemulsion to obtain self-microemulsion drug-loaded particles; mixing the adsorption carrier with the growth repair factor to obtain the growth repair factor drug-loaded particle;

(3) Mix the first matrix and the second matrix with water for injection to prepare the injection matrix, mix the injection matrix with the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles to prepare the injection matrix uterine injections;

Wherein, the adsorption carrier is one or more of calcium silicate, hydrophilic fumed silica, and microcrystalline cellulose;

The growth repair factor includes epidermal growth factor, and the epidermal growth factor is one or both of oligopeptide-1 and blue copper peptide;

The first matrix is one or more of water-soluble silk fibroin, chitosan, hypromellose, hypromellose, methylcellulose, and polyvinyl alcohol;

The second base is one or more of methyl vinyl ether-maleic anhydride copolymer, polyethylene glycol, sodium carboxymethylcellulose, and glycerol.

Preferably, the rifaximin concentration in the self-microemulsion of rifaximin is not more than 18wt.%, more preferably 1-6wt.%, and most preferably 4wt.%.

Preferably, the mass ratio of the rifaximin self-microemulsion, the adsorption carrier, the epidermal growth factor, the first matrix, and the second matrix is (1-10): (0.3-1.8 )(0.05-0.3):(5-14):(0.45-0.65).

Preferably, the growth repair factor also includes collagen peptide and/or sodium hyaluronate.

Preferably, the concentration of rifaximin in the self-microemulsion of rifaximin is 4wt.%, and the adsorption carrier is a mixture of calcium silicate and hydrophilic fumed silica at a mass ratio of 2:1, so The growth repair factor is a mixture of epidermal growth factor, collagen peptide and sodium hyaluronate in a mass ratio of 0.3:1:3, the first matrix is water-soluble silk fibroin, and the second matrix is methylethylene Ether-maleic anhydride copolymer, the mass ratio of the rifaximin self-microemulsion, the adsorption carrier, the growth repair factor, the first matrix, and the second matrix is 5:1:4.3 :10:0.5.

Preferably, step (4) is also included: freeze-drying the uterine injection prepared in step (3).

Preferably, the preparation method of the rifaximin self-microemulsion is: after mixing the emulsifier and co-emulsifier, adding the oil phase solution, mixing again, adding rifaximin to dissolve, and obtaining the rifaximin Ming self microemulsion.

Preferably, the emulsifier is polyoxyethylene castor oil, castor oil polyoxyethylene ether, polyoxyethylene ether hydrogenated castor oil, propylene glycol monolaurin, caprylic capric macrogol glyceride, Tween 80, One or more of Tween 20;

The co-emulsifier is one or more of glycerol, polyethylene glycol 400, polyethylene glycol 600, diethylene glycol monoethyl ether;

The oil phase solution is one of medium chain triglycerides, isopropyl myristate, ethyl oleate, caprylic capric monoglyceride, caprylic capric triglyceride, caprylic capric triglyceride succinate or several.

Preferably, the mass ratio of the emulsifier, the co-emulsifier and the oil phase solution is 4:1:5.

Another object of the present invention is to provide an application method of the injection prepared by the aforementioned preparation method. Specifically, the injection is added to water for injection, dissolved and shaken well, and the intrauterine injection is carried out when the injection solution is in the state of suspended hydrosol. perfusion.

The beneficial effects of the present invention are:

(1) The present invention utilizes the self-microemulsion system to solubilize the insoluble drug rifaximin, respectively disperse and suspend it in the hydrogel after the rifaximin self-microemulsion and growth repair factor are dispersed and suspended in the hydrogel with an adsorbent, and improve the drug-containing The stability of self-microemulsion and epidermal growth factor, at the same time, the hydrogel can reduce the pain during injection, and can use the cell growth-promoting effect of the growth repair factor and the cell proliferation microenvironment provided by the hydrogel to accelerate the endometrium The repair of epidermal cells can promote the regeneration of damaged tissues and establish a protective barrier. It can not only cure the existing infection of the endometrium, speed up the recovery of the cows' health, but also prevent the occurrence of new infections in the uterus and reduce the incidence of endometritis. Compared with hydrogel, lyophilized powder is easier to store, and the product stability is less affected by storage conditions, and can be reconstituted by adding purified water.

(2) The existing uterine injection mainly injects antibacterial drugs directly to obtain a bactericidal effect, and cannot take into account the repair of the uterine epidermis and tissue. The present invention can promote proliferation, Accelerate the repair to achieve the purpose of prevention and treatment; but the added growth repair factor has poor stability in the aqueous environment of microemulsion and hydrogel, and the present invention adds an adsorbent to suspend the growth repair factor in the hydrogel to improve its stability in aqueous environments.

(3) The rifaximin uterine injection prepared by the present invention is a temperature-sensitive injection, and it is in a fluid state with good fluidity before injection, and the drug-loaded particles that can be easily shaken and suspended have low injection resistance and a particle size of Small size, low viscosity, and easy to use. When the temperature reaches 35°C-40°C, that is, when it is injected into the body, it will become a semi-solid hydrogel state. Compared with direct injection of hydrogel, it can evenly adhere to the inner wall of the uterus and close the pores. , forming an antibacterial layer, the hydrogel formed in the body has good bioadhesion, and the hydrogel is not easy to accumulate at the bottom of the uterus with gravity. The hydrogel system formed in the body of the uterine injection prepared by the invention can be absorbed and utilized by the body, and is non-toxic and environment-friendly.

Description of drawings

The present invention is further described by using the accompanying drawings, but the embodiments in the accompanying drawings do not constitute any limitation to the present invention. For those of ordinary skill in the art, without paying creative work, other embodiments can also be obtained according to the following accompanying drawings Attached picture.

Figure 1 is a pseudo-three-phase diagram of a blank self-microemulsion.

Detailed ways

The present invention is further described in conjunction with the following examples.

Embodiments of the present invention relate to a rifaximin uterine injection, which consists of the following components: rifaximin self-microemulsion, adsorption carrier, growth repair factor, gel matrix, Gantrez AN and water for injection, wherein the The adsorption carrier includes calcium silicate, the growth repair factor includes epidermal growth factor, collagen peptide and sodium hyaluronate, and the epidermal growth factor includes oligopeptide-1 and/or blue copper peptide.

Self-microemulsion system (SMEDDS) is a homogeneous transparent solution composed of oil, surfactant and co-surfactant or a small amount of water, which can be used as a carrier for hydrophobic, poorly absorbed or easily hydrolyzed drugs. By encapsulating the drug in oil droplets, it will spontaneously disperse in the body fluid to form an O/W microemulsion. The system can significantly improve drug bioavailability by improving drug solubility, reducing surface tension, and increasing penetration.

Calcium silicate (model: FLORITE PS-10) is a white fine particle with good fluidity. Calcium silicate can be made into a solid dispersion by coating the amorphous API in the micropores to enhance the poor water solubility. Dissolution of API. At the same time, calcium silicate is also a synthetic calcium silicate with good liquid absorption, which is different from conventional porous materials, with a unique petal-like crystal structure and very obvious pore size and pore volume. These large pores are a key factor in liquid absorption capacity, absorbing 5 times its own weight in liquid and transforming it into a powder. The large pores of calcium silicate expand continuously in the vertical direction, and the opening of the pores is small compared to its volume, making it a good environment to protect the liquid filled in the pores from external oxygen, vapor, or other elements. Calcium silicate can be used not only as a stabilizer for API, but also as an excellent liquid carrier for pharmaceutical preparations.

Epidermal growth factor is an important active protein polypeptide substance in the human body. It can strongly promote the proliferation and growth of human cells, quickly repair damaged mucous membranes, and restore the body's own immunity. It can quickly enter the epidermal tissue of the skin and repair damaged skin. Damage the mucosa, promote its differentiation, proliferation, migration, and finally cover the damaged area, complete the regeneration of the mucosa, enhance immunity, and restore the body's own functions. Due to the characteristics of epidermal growth factor itself, low temperature conditions help to maintain its activity, and the activity will gradually decrease at room temperature and above conditions, so the single component is generally in the form of freeze-dried powder and stored in cold storage. Its stability must be fully considered.

Hydrogel is a material with a network molecular structure formed by the cross-linking of hydrophilic macromolecular chains. Because of its water retention characteristics and mechanical properties similar to human tissues, hydrogels are widely used in various tissues and organs. For repair and reconstruction, injectable hydrogels offer several advantages over other routes of administration and implantation. Hydrogel has a structure similar to that of natural soft tissue. The high water content in the system can simulate the components of the extracellular matrix in terms of structure and function. It can not only effectively anchor and release active substances such as cytokines or drugs, but also protect oxygen, The high permeability of nutrients and other metabolites provides the required places for cell proliferation and differentiation, as well as supporting cell proliferation and migration. The injectable hydrogel based on natural macromolecular silk fibroin has weak antigenicity, good cell adhesion, absorbability and biosafety. The natural macromolecular hydrogel is conducive to cell proliferation and differentiation, and is Processes such as cell ingrowth and collagen deposition provide microenvironmental support.

Gantrez AN is a polymethyl vinyl ether/maleic anhydride copolymer soluble in water and/or ethanol to form a highly polar, non-tacky film with excellent wet bond strength and bioadhesion. Due to its excellent film-forming and adhesive properties, it is suitable for spraying bandages and ostomy adhesives.

Example 1

A new veterinary uterine injection, calculated by 100ml, consists of the following components: Rifaximin self-microemulsion 5g, adsorption carrier 1g, growth repair factor (oligopeptide-1/blue copper peptide: collagen peptide: transparent Sodium hyaluronate = 0.3:1:3) 4.3g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Put calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) in a square cone mixer at a mass ratio of 2:1 and mix them evenly to obtain an adsorption carrier mixture;

(3) Place the adsorption carrier of 90% of the prescription amount in the batching tank, add the rifaximin self-microemulsion of the prescription amount and stir evenly, and prepare the self-microemulsion drug-loaded particles;

(4) Place the adsorption carrier with the remainder (10%) of the prescription amount in a square cone mixer, add the growth repair factor of the recipe amount and stir evenly, and prepare the growth repair factor drug-loaded particles;

(5) Add the water-soluble silk fibroin, Gantrez AN, and water for injection into the vortex mixer in the prescription amount, mix and stir at room temperature until the liquid is in a clear sol state, and then add the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection lyophilized powder; lyophilized powder protected from light Store in cold storage, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well before use, wait for the injection to be in the state of a suspended hydrosol, and infuse it in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Example 2

Same as Example 1, the difference is that it does not contain adsorbents. In the process, rifaximin self-microemulsion and growth repair factor are directly added to the original step (5) to make rifaximin uterine injection. The specific steps are as follows:

A novel veterinary uterine injection, in 100ml, consists of the following components: rifaximin self-microemulsion 5g, growth repair factor (oligopeptide-1/blue copper peptide: collagen peptide: sodium hyaluronate= 0.3:1:3) 4.3g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Add the water-soluble silk fibroin, Gantrez AN, and water for injection into the vortex mixer in the prescription amount, mix and stir at room temperature until the liquid is in a clear sol state, then add the rifaximin Milk and the growth repair factor in the amount of the formula, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection freeze-dried powder; freeze-dried powder avoid Keep in cold storage. When using, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well. After the injection is in the state of suspension hydrosol, infuse in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Example 3

Same as Example 1, the difference is that the adsorption carrier is a hydrophilic fumed silica, and the specific steps are as follows:

A new veterinary uterine injection, calculated by 100ml, consists of the following components: rifaximin self-microemulsion 5g, hydrophilic fumed silica 1g, growth repair factor (oligopeptide-1/blue copper peptide: Collagen peptide: sodium hyaluronate = 0.3:1:3) 4.3g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Place the adsorption carrier of 90% of the prescription amount in the batching tank, add the rifaximin self-microemulsion of the prescription amount and stir evenly, and prepare the self-microemulsion drug-loaded particles;

(3) Place the adsorption carrier with the remainder (10%) of the prescription amount in a square cone mixer, add the growth repair factor of the recipe amount and stir evenly, and prepare the growth repair factor drug-loaded particles;

(4) Add the water-soluble silk fibroin, Gantrez AN, and water for injection into the vortex mixer in the prescription amount, mix and stir at room temperature until the liquid is in a clear sol state, and then add the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection lyophilized powder; lyophilized powder protected from light Store in cold storage, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well before use, wait for the injection to be in the state of a suspended hydrosol, and infuse it in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Example 4

Same as Example 1, the difference is that the adsorption carrier is microcrystalline cellulose, and the specific steps are as follows:

A new veterinary uterine injection, calculated by 100ml, consists of the following components: rifaximin self-microemulsion 5g, microcrystalline cellulose) 1g, growth repair factor (oligopeptide-1/blue copper peptide: collagen Peptide: sodium hyaluronate = 0.3:1:3) 4.3g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Place the adsorption carrier of 90% of the prescription amount in the batching tank, add the rifaximin self-microemulsion of the prescription amount and stir evenly, and prepare the self-microemulsion drug-loaded particles;

(3) Place the adsorption carrier with the remainder (10%) of the prescription amount in a square cone mixer, add the growth repair factor of the recipe amount and stir evenly, and prepare the growth repair factor drug-loaded particles;

(4) Add the water-soluble silk fibroin, Gantrez AN, and water for injection into the vortex mixer in the prescription amount, mix and stir at room temperature until the liquid is in a clear sol state, and then add the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection lyophilized powder; lyophilized powder protected from light Store in cold storage, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well before use, wait for the injection to be in the state of a suspended hydrosol, and infuse it in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Example 5

With embodiment 1, difference is that described first matrix, second matrix are respectively polyvinyl alcohol and glycerol, and concrete steps are as follows:

A new veterinary uterine injection, calculated by 100ml, consists of the following components: Rifaximin self-microemulsion 5g, adsorption carrier 1g, growth repair factor (oligopeptide-1/blue copper peptide: collagen peptide: transparent Sodium hyaluronate=0.3:1:3)4.3g, polyvinyl alcohol 13g, glycerin 0.65g, and the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Put calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) in a square cone mixer at a mass ratio of 2:1 and mix them evenly to obtain an adsorption carrier mixture;

(3) Place the adsorption carrier of 90% of the prescription amount in the batching tank, add the rifaximin self-microemulsion of the prescription amount and stir evenly, and prepare the self-microemulsion drug-loaded particles;

(4) Place the adsorption carrier with the remainder (10%) of the prescription amount in a square cone mixer, add the growth repair factor of the recipe amount and stir evenly, and prepare the growth repair factor drug-loaded particles;

(5) Add the polyvinyl alcohol, glycerol, and water for injection of the prescription amount into the vortex mixer, mix and stir at room temperature until the liquid is in a clear sol state, then add the self-microemulsion drug-loaded particles and The growth repair factor drug-loaded particles were vortex sheared for 10-15 minutes, vacuum freeze-dried, nitrogen-filled and sealed to obtain a content specification of 0.2g: 100ml rifaximin uterine injection lyophilized powder; lyophilized powder refrigerated in the dark For storage, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well before use. After the injection is in the state of suspended hydrosol, infuse in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Comparative example 1 (without the first and second substrates)

A new veterinary uterine injection, calculated by 100ml, consists of the following components: rifaximin self-microemulsion balance, adsorption carrier 0.1g, growth repair factor (oligopeptide-1/blue copper peptide: collagen peptide : sodium hyaluronate = 0.3:1:3) 4.3g;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Put calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) in a square cone mixer at a mass ratio of 2:1 and mix them evenly to obtain an adsorption carrier mixture;

(3) Place the adsorption carrier in a square cone mixer, add the growth repair factor of the formula amount and stir evenly, and prepare the drug-loaded particles of the growth repair factor;

(4) Add the growth repair factor drug-loaded particles into the rifaximin self-microemulsion, and shear with vortex for 10-15 minutes to obtain the rifaximin uterine injection.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Comparative example 2 (without the second matrix)

A new veterinary uterine injection, calculated by 100ml, consists of the following components: Rifaximin self-microemulsion 5g, adsorption carrier 1g, growth repair factor (oligopeptide-1/blue copper peptide: collagen peptide: transparent Sodium hyaluronate=0.3:1:3) 4.3g, chitosan 9g, the balance is water for injection;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Put calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) in a square cone mixer at a mass ratio of 2:1 and mix them evenly to obtain an adsorption carrier mixture;

(3) Place the adsorption carrier of 90% of the prescription amount in the batching tank, add the rifaximin self-microemulsion of the prescription amount and stir evenly, and prepare the self-microemulsion drug-loaded particles;

(4) Place the adsorption carrier with the remainder (10%) of the prescription amount in a square cone mixer, add the growth repair factor of the recipe amount and stir evenly, and prepare the growth repair factor drug-loaded particles;

(5) Add chitosan and water for injection into a vortex mixer, mix and stir at room temperature until the liquid is in a clear sol state, then add the self-microemulsion drug-loaded particles and the growth repair Factor-loaded particles, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection lyophilized powder; Add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well, wait until the injection is in the state of suspended hydrosol, and infuse it in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Comparative example 3 (without growth repair factor)

A new veterinary uterine injection, based on 100ml, consists of the following components: Rifaximin self-microemulsion 5g, adsorption carrier 0.9g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, and the balance is water for injection ;

Its preparation method comprises the following steps:

(1) Weigh 9.6g of polyoxyethylene ether hydrogenated castor oil (Cremophor RH 40) and 48g of diethylene glycol monoethyl ether (Transcutol P) respectively, put them in a vortex mixer and mix them evenly, and then add octanoic acid Capric monoglyceride (Capmul MCM) 38.4g joins in the above-mentioned mixture, vortex mixes, obtains blank self-microemulsion, the rifaximin of 4g is dissolved in the described blank self-microemulsion, makes rifaxi Mingzi microemulsion;

(2) Put calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) in a square cone mixer at a mass ratio of 2:1 and mix them evenly to obtain an adsorption carrier mixture;

(3) The adsorption carrier is placed in the batching tank, the rifaximin self-microemulsion of the prescription amount is added and stirred evenly, and the self-microemulsion drug-loaded particles are obtained;

(4) Add the water-soluble silk fibroin, Gantrez AN, and water for injection into the vortex mixer in the prescription amount, mix and stir at room temperature until the liquid is in a clear sol state, and then add the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles, vortex shearing for 10-15min, vacuum freeze-drying, nitrogen-filled sealing, the prepared content specification is 0.2g: 100ml rifaximin uterine injection lyophilized powder; lyophilized powder protected from light Store in cold storage, add water for injection (100mL/part, calculated as 0.2g rifaximin/part) to dissolve and shake well before use, wait for the injection to be in the state of a suspended hydrosol, and infuse it in the uterus.

The temperature of the preparation environment is controlled at 20°C-25°C, and the humidity is controlled below 60%.

Experimental example

(1) Accelerated stability test

Based on the draft preparation quality standards, according to the "Guiding Principles for Stability Test of Veterinary Drugs" in the appendix of the Chinese Veterinary Pharmacopoeia 2020, accelerated stability tests were carried out for Examples 1 to 5 and Comparative Examples 1 to 3. The properties and content of the specification preparation samples were investigated and determined.

Embodiment 1～Example 5, comparative example 1～comparative example 3 are packed in commercially available packing material (glass bottle), seal, place room temperature under the condition of 25 ℃ and leave sample to investigate for 6 months, the 1st month, 2 Monthly, 3-month, and 6-month sampling inspections.

The accelerated stability test results are shown in the table below:

The results show:

(1) Example 1, Example 5, Comparative Example 2, and Comparative Example 3 have good acceleration stability, and the order of stability is as follows: Example 1, Example 5, Comparative Example 2, Comparative Example 3>Example 3> Example 4>Example 2>Comparative Example 1.

(2) Example 3 (the adsorption carrier is hydrophilic fumed silica) can be seen under the microscope after 6 months of accelerated reconstitution with a small amount of precipitated rifaximin crystals dispersed in the hydrosol, while Example 1, Example 5. The adsorption carriers of Comparative Example 2 and Comparative Example 3 are both mixtures of calcium silicate and hydrophilic fumed silica at a mass ratio of 2:1, indicating that calcium silicate has a larger adsorption capacity and can absorb more self-microbial Milk, so the combination of calcium silicate and hydrophilic fumed silica is the preferred adsorption carrier; from the accelerated stability data of Example 1, Example 5, Comparative Example 2, and Comparative Example 3, it can be found that the adsorption carrier can effectively protect the Faximin self-microemulsion can improve the stability of rifaxime uterine injection freeze-dried powder and its reconstituted direct perfusion uterine injection.

(3) Example 4 (the adsorption carrier is microcrystalline cellulose) started to agglomerate after reconstitution in March, and after reconstitution in June, it can be seen that there are many small agglomerates of different sizes deposited on the bottom of the bottle, which is difficult to form It is in the form of hydrosol, and precipitated rifaximin crystal powder can be seen under the microscope, indicating that compared with hydrophilic fumed silica and calcium silicate, microcrystalline cellulose has a smaller adsorption capacity, and the redispersion after freeze-drying and reconstitution Sex and suspending ability are also poor.

(4) Example 2 (without adsorbent) Because of the lack of protection of adsorbent, rifaximin is directly dispersed in the hydrosol system from the microemulsion, and stratification occurs after reconstitution from the second month of acceleration, and the acceleration time The longer it is, the more obvious the stratification phenomenon is, and the rifaximin content in the uterine injection freeze-dried powder is also significantly reduced, indicating that the adsorbent plays a key role in the stability of the uterine injection freeze-dried powder preparation and its active ingredients.

(5) Comparative example 1 (self-microemulsion drug delivery system) is a rifaximin self-microemulsion preparation in which growth repair factor drug-loaded particles are suspended, and self-microemulsion can improve the solubility of rifaximin and improve bioavailability, but From the properties of the preparation and the degradation of active ingredients, it can be found that the accelerated stability of Comparative Example 1 is relatively poor, and it is estimated that the storage validity period of the rifaximin uterine injection of Comparative Example 1 is the shortest.

(2) Thixotropy - phase transition temperature and phase transition time

The phase transition temperature and phase transition time of the uterine injection agent of the present invention are detected by a test tube inversion method.

1. Phase transition temperature: Take 25ml of liquid uterine injection into a vial, place the vial in a heat-collecting magnetic heating stirrer, and raise the temperature slowly at a rate of 1°C*5min ^-1 , and the temperature rise ranges from 25°C to 50°C. Record the temperature with a mercury thermometer, and measure the temperature T when the liquid in the vial freezes by the vial inversion method.

The experimental results are shown in the table below:

The results show:

(1) The uterine injections of Example 1, Example 3, and Comparative Example 3 are in a suspended hydrosol state at low temperature (25°C-32°C), and become a suspended hydrogel structure at 37°C. It does not flow upside down, and its phase transition temperature is 37°C, which can meet the research and development goal of thixomorphing into a hydrogel when the uterine injection is perfused into the body (about 38°C-39°C).

(2) Compared with Example 1, Comparative Example 2 only made a hydrogel matrix from water-soluble silk fibroin, but the phase transition temperature was similar to that of Example 1 (about 38° C.).

(3) Compared with Example 1, the drug-loaded self-microemulsion and growth repair factor of Example 2 are directly dispersed in the hydrosol system, which causes the phase transition temperature of Example 2 to become 40°C. The liquid uterine injection can still be thixomorphed into a hydrogel when infused into the uterus, but the viscosity of the hydrogel is relatively low.

(4) Compared with Example 1, the adsorption carrier of Example 4 was replaced by microcrystalline cellulose, and its phase transition temperature became 34°C, which may cause the uterine injection agent to be easily affected by air temperature during the perfusion process, and the uterine injection The agent has been partially solidified during the perfusion process with the vas deferens, blocking the vas deferens, and the perfusion operation cannot continue, which seriously affects the operability of the product.

(5) Compared with Example 1, the difference in the hydrogel matrix of Example 5 causes the liquid uterine injection to become a suspended hydrogel structure at 31°C, which is the same as Example 4, which will seriously affect the product the use of enforceability.

(6) The uterine injection of Comparative Example 1 has no thermosensitive thixotropy, which leads to poor adhesion of the preparation in the uterus of cows.

2. Phase change time: put 3 glass tubes containing 25ml of hydrosol uterine injection in a constant temperature water bath at 38.5°C, and observe the changes of the uterine injection. When the uterine injection no longer flows after the glass tube is inverted, the liquid is considered to form a hydrogel, and the minimum time required is the gelation time.

The gel time test results of 3 uterine injections are shown in the table below:

The results show that the liquid uterine injections of Example 1, Example 3, Example 4, Comparative Example 2, and Comparative Example 3 have similar time to hydrogel state at 38.5°C, and the average gelation time of Example 5 is The time is short (about 27s), and these liquid uterine injections can be uniformly dispersed after being perfused into the cow's uterus and form a hydrogel to adhere to the uterine mucosa to exert the drug effect, while the gelation time of Example 2 is longer, which may cause Like the uterine injection of Comparative Example 1, the flowable liquid uterine injection will be deposited at the bottom of the uterus after being injected into the uterus of a cow, and cannot be evenly dispersed on the entire uterine mucosa.

(3) Test of the adhesion of the injection to the wound

The test method for evaluating the adhesion and fit degree of the injection gel to the tissue is to select rats, and after anesthesia by intraperitoneal injection of anesthesia, the hair on the back is shaved, and a circular wound with a diameter of 1 cm is cut with scissors, and the liquid uterine The injection agent is injected into the circular wound, and the degree of fit of the hydrogel to the wound is observed through different deformations.

The results show:

(1) No matter whether the wound is pulled horizontally or vertically with tweezers, or the experimenter grabs the head of the rat with both hind legs and twists the body of the rat to pull the wound, under different deformation effects, the results of Example 1, Example 3, and implementation Example 4, the hydrogel of Comparative Example 3 has good adhesion performance on rat wounds, and no detachment or cracking between the hydrogel and the tissue was observed, which proves that the hydrogel has a good fit and has a good effect on the tissue. Good adhesive properties and role in sealing wounds;

(2) Under different deformation effects, it can be seen that there is a little detachment between the hydrogel of Example 2 and Comparative Example 2 and the tissue on the wound of the rat;

(3) The hydrogel film-forming property of embodiment 5 is the best, and adhesion is the best;

(4) The liquid uterine injection of Comparative Example 1 could not form a hydrogel at the wound.

(4) In vitro degradation performance test

Test method: Take 5 parts of injection gel blocks of the same weight and volume and soak them in PBS containing egg white lysozyme (10mg/mL), keep the temperature at 38.5°C, and observe the state of the hydrogel in PBS until it is completely degraded , to record the time.

The in vitro degradation time results of 5 hydrogel blocks are shown in the table below:

The results show that the hydrogels formed by the liquid uterine injections of Example 1, Example 3, Example 4 and Comparative Example 3 will slowly degrade over time, and can degrade completely in about 18 hours. The water gels of Example 2 and Comparative Example 2 The gel degrades quickly and can be completely degraded in about 16 hours. These formulas can meet the drug withdrawal period requirements of "milk abandonment period 0 days" of rifaximin uterine injection, while the hydrogel block of Example 5 is a full 1 Days (24h) have not been able to degrade completely, and the drug withdrawal period is unqualified, but it can also be degraded completely in about 32h.

(5) Histocompatibility and in vivo degradability tests

Test method: select healthy adult male SD rats, eat and drink freely, maintain a certain ambient temperature and humidity, and make them adapt to the environment. After subcutaneously injecting 0.5 mL of the liquid uterine injection prepared by the present invention on the back of the rat, observe the reaction of the tissues around the injection site at 0h, 3h, 6h, 10h, 14h, 18h, and 22h respectively.

Experimental results: after the subcutaneous injection of the liquid uterine injection on the back of the rat, the routine observation results showed that the biocompatibility of the gel formed in the body by the liquid uterine injection of Examples 1 to 5 and Comparative Examples 1 to 3 Good, no obvious tissue inflammatory reactions such as cysts and capillary congestion at the initial stage of injection, good interaction with subcutaneous tissue, the degradation time of each gel block in subcutaneous tissue is basically consistent with the results of "in vitro degradation performance test", comparative example 1 The uterine injection (self-microemulsion drug delivery system) can be completely absorbed by the subcutaneous tissue in about 6 minutes.

It can be seen that, except that the degradation time of the hydrogel formed in the body of Example 5 is too long, the uterine injections prepared by the other 4 examples all have good histocompatibility and biodegradability, indicating that the hydrogel produced by the present invention The hydrogel of the uterine injection agent in the body can be absorbed and utilized by tissues, and the addition of the second matrix and growth repair factors (comparative example 2 and comparative example 3) will not affect the histocompatibility of the hydrogel block in the body In addition, the self-microemulsion drug delivery system (Comparative Example 1) can be quickly absorbed by tissues and exert its drug effect.

(6) Stimulus evaluation method

The previous 5 experimental results show that embodiment 1 is the best formula for rifaximin uterine injection freeze-dried powder, and the formulas of comparative example 1 and comparative example 2 are all formed by reducing one kind of material in the formula of embodiment 1, Therefore, it can be inferred that the irritation of Comparative Example 1 and Comparative Example 2 is smaller than that of Example 1, so Example 1 and Comparative Example 1 are selected as representative formulations for irritation evaluation.

Twenty-eight adult healthy female New Zealand rabbits were randomly divided into the poisoning group and the control group. They had no symptoms of metritis or estrus.

In the poisoning group, the liquid rifaximin uterine injection was instilled into the vagina with a blunt needle at 1, 3 and 5 times the normal recommended dose, and repeated every 48 hours for 3 consecutive times; The control group was subjected to the same operation with normal saline 0.2ml/kg.

Observe the general condition and local reactions of female rabbits after intravaginal infusion of rifaximin uterine injection: including whether there is pain, restlessness, turbid secretions, local redness and swelling in the genitals, etc.

24 hours after the last administration of the rabbits, the rabbits were killed by air embolism, the vaginal specimens were dissected, cut longitudinally, and the vaginal mucosa was observed with naked eyes for irritations such as hyperemia, redness, increased secretions, and erosion. According to the vaginal mucosa irritation score table and the vaginal mucosa irritation intensity evaluation table, the vaginal mucosa irritation score and stimulation intensity evaluation were performed.

The vaginal mucosa irritation reaction score table is as follows:

shape change	response score
No change or no significant change	0
Mild congestion, a small amount of discharge	1
Moderate congestion, more secretions	2
Severe congestion, edema, a lot of secretions, mucosal degeneration	3

The evaluation table for vaginal mucosa irritation intensity is as follows:

average score	evaluate
0～0.4	non-irritating
0.4～1.5	mild irritation
1.51～2.5	Moderate irritation
>2.5	severe irritant

The evaluation results of the injection to the rabbit vaginal mucosa irritation response intensity are shown in the table below.

The test results show:

(1) During the medication period, the rabbits in the three groups had no abnormalities in their general conditions, and no obvious hyperemia, redness, and abnormal secretions were found at the vaginal opening;

(2) The vaginal tissue taken out was visually observed, no vaginal mucosa hyperemia, edema and bleeding point were found in the control group, only 1 vaginal sample in the poisoned group in Example 1 had mild congestion and a small amount of secretions, and the vaginal mucosa irritation index of the two groups At 0～0.4, it is non-irritating that the liquid uterine injection prepared by Example 1 is non-irritating to the rabbit vaginal mucosa stimulation intensity, while the vaginal mucosa irritation index of Comparative Example 1 is 0.5, illustrating that the liquid uterine injection of Comparative Example 1 is Slight irritation, compared with Example 1, the irritation is greater.

(3) Rifaximin Uterine Injection of Example 1 and Comparative Example 1 with 3 times and 5 times the doses had little irritation to the vaginal mucosa, showing mild irritation.

In summary, Example 1 is similar to the control group in irritation, and less irritating than Comparative Example 1.

(7) Drug efficacy experiment

1. The rifaximin uterine injection of the present invention perfusion detects milk residues in dairy cows

Select 9 dairy cows diagnosed with endometritis in a large dairy farm and have not used any antimicrobial drug treatment, and uterine perfusion of the rifaximin uterine injection described in formula 1 of the present invention. Take a blank milk sample before administration (0h), then use a sterilized uterine washer to inject 100ml of the liquid rifaximin uterine injection of the present invention into the uterine horn, repeat 1 times, a total of two doses. Collect milk samples 1000ml at the 1st, 4th, 8th, 12th, 16th, 20th, 24th, 32nd, 48th, and 60h after the last administration (each milk sample is 250ml in each milk area, and the four milk areas mix homogeneously after sampling), carry out HPLC analysis, detect the rifaximin content in the milk sample, the data result of blood sample concentration and time of milk sample is shown in the following table.

The results show that:

(1) After suffering from the rifaximin uterine injection of embodiment 1, comparative example 1 and comparative example 3 of the dairy cow uterus perfusion of endometritis, the rifaximin dynamic process in the milk of embodiment 1 and comparative example 3 is very Similar, and similar to the first-order absorption one-compartment open model, the concentration of rifaximin in milk is low, and the concentration of rifaximin in milk has dropped to close to the lowest limit of quantification (the limit of quantification of the method is 0.05 μg/ml) at 16 hours after administration. ), rifaximin was not detected in the milk 20h after the administration, which was lower than the maximum residue limit of 0.06 μg/ml in the milk, indicating that Example 1 met the drug withdrawal period requirements, and did not add growth repair factor (comparative example 3 ) did not affect the kinetics of rifaximin in milk.

(2) The data show that the milk sample drug concentration has reached the peak in 1h or 2h of Comparative Example 1 (from the microemulsion drug delivery system), and the rifaximin concentration in the milk after administration for 8h is only measured at 0.06 μg/ml (the highest residual limit), it shows that the self-microemulsion drug delivery system absorbs quickly and degrades quickly, suggesting that the time for the uterine injection of the present invention (embodiment 1) to exert its drug effect is longer than that of the self-microemulsion uterine injection.

In summary, compared with direct administration from microemulsion, the rifaximin uterine injection (Example 1) made by the present invention is more conducive to exerting the drug effect for a long time, but will not increase the amount of drug residue in the milk. risk.

2. Experiment of the therapeutic effect of rifaximin uterine injection of the present invention on cow endometritis

Test drug:

The rifaximin uterine injection described in Example 1 of the present invention has a specification of 100ml;

The rifaximin uterine injection described in Comparative Example 1 of the present invention has a specification of 100ml;

The rifaximin uterine injection described in Comparative Example 3 of the present invention has a specification of 100ml;

Control drug: florfenicol uterine injection, content 10%;

experiment method:

77 dairy cows diagnosed with endometritis were selected from a large dairy farm and randomly divided into 11 groups with 7 cows in each group. See the experimental grouping and treatment table for grouping and treatment.

All medicines are processed by uterine perfusion, and vulva cleaning and disinfection measures are strictly implemented. The plastic sheath of the insemination gun is used as the catheter for drug administration, and it is discarded after use to prevent cross-infection between individual cattle.

The test grouping and treatment table are as follows:

Judgment of treatment effect:

(1) Cure (full recovery): the mucus discharged from the vagina is transparent and has no peculiar smell, other clinical symptoms disappear, the normal estrus cycle is restored, normal mating and pregnancy are confirmed, and the comparison before and after treatment;

(2) Effective (obviously improved): the uterus softened obviously, the contraction was strong, and other symptoms were alleviated, but no pregnancy occurred after mating in estrus. Comparison before and after treatment;

(3) Ineffective (no obvious improvement): compared with before treatment, there is no obvious change, and the treatment is compared before and after treatment;

(4) Interval time (days) from postpartum to first mating day: compared with blank control group;

(5) Recovery conception rate: the cows judged as recovery after treatment were inseminated, and the conception rate during the estrous period, the conception rate of one estrous period and the total conception rate were counted.

The clinical therapeutic effect of described rifaximin uterine injection on cow endometritis is shown in the table below:

The observation period of 7 cows suffering from endometritis in the blank control group was 10 days, and the symptoms did not improve. All cattle were treated with drugs immediately after the observation period to prevent production from being affected.

It can be seen from the clinical treatment effect that the cure rate and effective rate of the high-dose perfusion of the rifaximin uterine injection of embodiment 1 are 85.7%, and the cure rate and effective rate of the middle dose are 71.4% and 85.7% respectively, and the therapeutic effect is obvious. Better than the low-dose group; the therapeutic effect of the contrast drug florfenicol group is the same as the dosage in the rifaximin uterine injection of comparative example 3, and the therapeutic effect is better than the dosage in comparative example 1; the therapeutic effect sorting is: embodiment 1>Control group>Comparative example 3>Comparative example 1>Blank group, but florfenicol perfusion has a certain stimulating effect on dairy cows, showing restlessness.

(8) Other stability experiments

The above experimental results can determine that Example 1 is the optimal combination of the rifaximin uterine injection of the present invention, based on the draft quality standard of the preparation, and according to the "Guiding Principles of Veterinary Drug Stability Test" in the appendix of the Chinese Veterinary Pharmacopoeia 2020 edition. The freeze-dried powder of uterine injection (embodiment 1) has carried out temperature test, light test, high humidity test, long-term stability test, and the proterties of conventional packaging specifications preparation sample, the main index in the inspection and content etc. have been investigated and measured , calculate the validity period according to the inspection results.

(1) Temperature stability test

The preparation of the present invention is packed into a commercially available packaging material (glass bottle), sealed, placed in a refrigerator at -15°C, 4°C and room temperature at 25°C for 30 days, and sampling every 5 days. The results show that the preparation of the present invention has no phenomena such as delamination and discoloration under the above-mentioned conditions, and there is no obvious agglomeration, delamination and precipitation after reconstitution, and it maintains a uniform suspension hydrosol, indicating the temperature stability of the preparation good.

(2) Illumination test

The preparation of the present invention is packed in the commercially available packing material (glass bottle), is sealed, and is placed in the light box that fluorescent lamp is housed or other suitable illumination devices, and illumination is placed 10 days under the condition of 4500 ± 500lx, and respectively Sampling on 5 days and 10 days. The results show that the preparation of the present invention has no phenomena such as delamination and discoloration, and has no obvious agglomeration, delamination and precipitation after reconstitution, and can maintain a uniform hydrosol shape, indicating that the preparation has good light stability.

(3) High humidity test

The preparation of the present invention is packed in the commercially available packing material (glass bottle), seals, places 10 days under the condition of 25 ℃ ± 2 ℃, relative humidity 90% ± 5%, takes samples respectively on the 5th day and the 10th day study. The results show that the hygroscopicity of the preparation of the present invention meets the requirements under the above conditions, no caking, discoloration and other phenomena are found, and there is no obvious agglomeration, delamination, and precipitation after reconstitution, and it remains in a uniform hydrosol shape, indicating that the preparation is stable. Good high humidity stability.

(4) Validity period

The measurement results show that the validity period of this preparation is more than 24 months when stored under the conditions of shading, airtightness, and 2°C-8°C, and the tentative validity period is 24 months.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than limiting the protection scope of the present invention, although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand , the technical solution of the present invention may be modified or equivalently replaced without departing from the spirit and scope of the technical solution of the present invention.

Claims (8)

1. A preparation method of a novel veterinary uterine injection is characterized in that it comprises the following steps in sequence:

   (1) preparing rifaximin self-microemulsion;

   (2) mixing the adsorption carrier with the rifaximin self-microemulsion to obtain self-microemulsion drug-loaded particles; mixing the adsorption carrier with the growth repair factor to obtain the growth repair factor drug-loaded particle;

   (3) Mix the first matrix and the second matrix with water for injection to prepare the injection matrix, mix the injection matrix with the self-microemulsion drug-loaded particles and the growth repair factor drug-loaded particles to prepare the injection matrix uterine injections;

   Wherein, the adsorption carrier is one or more of calcium silicate, hydrophilic fumed silica, and microcrystalline cellulose;

   The growth repair factor includes epidermal growth factor, and the epidermal growth factor is one or both of oligopeptide-1 and blue copper peptide;

   The first matrix is one or more of water-soluble silk fibroin, chitosan, hypromellose, hypromellose, methylcellulose, and polyvinyl alcohol;

   The second base is one or more of methyl vinyl ether-maleic anhydride copolymer, polyethylene glycol, sodium carboxymethylcellulose, and glycerol.
2. The preparation method of a novel veterinary uterine injection according to claim 1, characterized in that the concentration of rifaximin in the self-microemulsion of rifaximin is not more than 18wt.%.
3. The preparation method of a novel veterinary uterine injection according to claim 1, wherein the rifaximin self-microemulsion, the adsorption carrier, the epidermal growth factor, and the first matrix , The mass ratio of the second matrix is (1-10):(0.3-1.8)(0.05-0.3):(5-14):(0.45-0.65).
4. The preparation method of a novel veterinary uterine injection according to claim 1, wherein the growth repair factor also includes collagen peptide and/or sodium hyaluronate.
5. The preparation method of a novel veterinary uterine injection according to claim 1, wherein the concentration of rifaximin in the self-microemulsion of rifaximin is 4wt.%, and the adsorption carrier is mass A mixture of calcium silicate and hydrophilic fumed silica at a ratio of 2:1, and the growth repair factor is a mixture of epidermal growth factor, collagen peptide and sodium hyaluronate at a mass ratio of 0.3:1:3, so The first matrix is water-soluble silk fibroin, the second matrix is methyl vinyl ether-maleic anhydride copolymer, the rifaximin self-microemulsion, the adsorption carrier, the growth repair factor, The mass ratio of the first matrix to the second matrix is 5:1:4.3:10:0.5.
6. The preparation method of a novel veterinary uterine injection according to claim 1, further comprising a step (4): freeze-drying the uterine injection prepared in the step (3).
7. A novel uterine injection for veterinary use, characterized in that it is prepared by the preparation method described in any one of claims 1-6.
8. An application method of the novel veterinary uterine injection according to claim 7, characterized in that the injection is added to water for injection, dissolved and shaken up, and intrauterine perfusion is carried out when the injection solution is in a suspended hydrosol state.

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