JP7454288B2 - Method for preparing a novel veterinary uterine injection - Google Patents

Description

The present invention relates to the field of veterinary pharmaceutical formulations, and specifically to novel veterinary uterine injections, methods of preparation and uses thereof.

Dairy bovine endometritis is a disease commonly seen when raising cattle, and although the incidence is high, the disease and death rate is low, and in most cases it is chronic. This disease not only severely reduces the reproductive ability of cows, but also reduces milk production to some extent, and in severe cases can cause loss of lactation ability, and if the symptoms are severe, it can also cause infertility, and the cows must be discarded. It can lead to serious complications and is more likely to cause other diseases, such as metritis. In recent years, with the expansion of the scale of dairy cow farming, coupled with the universal application of artificial insemination technology, the occurrence of this disease has been on a continuous increase, seriously harming the economic efficiency of the dairy cow farming industry, and therefore preventing prevention. and treatment is required.

Rifaximin is an artificial semi-synthetic derivative of rifamycin SV. Like other rifamycin antibiotics, it irreversibly binds to the β-subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting bacterial RNA synthesis and ultimately bacterial protein synthesis. Rifaximin has a broad antibacterial spectrum and has high antibacterial activity against most Gram-positive aerobic bacteria, and also has good antibacterial activity against Gram-negative bacteria such as Escherichia coli, Salmonella enterica, Shiga bacteria, and Gram-positive anaerobes. has. Intrauterine perfusion of rifaximin is very useful in the treatment of dairy metritis because rifaximin is poorly absorbed when administered intrauterinely, has a low level of tissue absorption, has no adverse effect on the body's normal bacterial population, and has no obvious toxicity or side effects. suitable for

Uterine injection therapy refers to the treatment and prevention of endometritis in dairy cows by injecting antibiotics into the uterus of dairy cows. However, many of the uterine injections currently on the market have a bactericidal effect as their main purpose, and cannot simultaneously repair the epidermis and tissues of the uterus, emphasizing only ``treatment'' and ignoring ``prevention.'' However, the endometrium may be damaged during calving and midwifery in dairy cows, and miscarriages, difficult births, inability to expel fetal clothes, and lack of standardized artificial insemination procedures all create opportunities for pathogens to invade. At such times, pathogenic bacteria accumulate in large numbers and are likely to cause related diseases, so it is very necessary that the injection agent also acts on the repair of the uterine epidermis and tissue.

To address the above-mentioned problems, the present invention provides a novel veterinary uterine injection, a method for its preparation, and its use.

The object of the present invention is achieved by the following technical solutions.
A method for preparing a novel veterinary uterine injection, the method comprising:
Step (1) of preparing a rifaximin self-microemulsion;
A step (2) of mixing an adsorption carrier and the rifaximin self-microemulsion to prepare self-microemulsion-supporting particles, and mixing an adsorption carrier and a growth repair factor to prepare growth repair factor-supporting particles;
An injection matrix is prepared by mixing a first matrix, a second matrix, and water for injection, and the uterine injection is prepared by mixing the injection matrix, the self-microemulsion-supporting particles, and the growth repair factor-supporting particles. step (3);
The adsorption carrier is one or more of calcium silicate, hydrophilic fumed silica, and microcrystalline cellulose,
The growth repair factor includes epidermal cell growth factor that is one or two of oligopeptide-1 and copper peptide;
The first matrix is one or more of water-soluble silk fibroin, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinyl alcohol,
The second matrix is one or more of methyl vinyl ether-maleic anhydride copolymer, polyethylene glycol, sodium carboxymethyl cellulose, and propylene triol.

Preferably, the concentration of rifoximin in said rifoximin self-microemulsion is 18 wt. % or less, more preferably 1 to 6 wt. %, most preferably 4wt. %.

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

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

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

Preferably, the method further includes a step (4) of lyophilizing the uterine injection prepared in step (3).

Preferably, the method for preparing the rifaximin self-microemulsion includes uniformly mixing an emulsifier and an emulsifier, adding an oil phase solution, and then adding and dissolving rifaximin after further uniform mixing. Preparing the rifaximin self-microemulsion.

Preferably, the emulsifier is polyoxyethylene castor oil, castor oil polyoxyethylene ether, polyoxyethylene hydrogenated castor oil ether, propylene glycol monoglyceryl monolaurate, caprylocaproyl polyoxy-8-glyceride, TWENE 80, TWENE 20 One or more of these.

The emulsification aid is one or more of propylene glycol, polyethylene glycol 400, polyethylene glycol 600, and diethylene glycol monoethyl ether.

The oil phase solution is one or more of medium chain triglycerides, isopropyl myristate, ethyl oleate, caprylic decanoic monoglyceride, caprylic decanoic triglyceride, and caprylic decanoic succinic triglyceride.

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

Another object of the present invention is a method of using the injection prepared by the above-mentioned preparation method, and specifically, the injection is added to water for injection, dissolved, and shaken uniformly, and then the injection The object of the present invention is to provide a method for performing intrauterine perfusion when the drug is in the form of a suspended hydrosol.

The beneficial effects of the present invention are as follows.
(1) In the present invention, rifaximin, a poorly soluble drug, is solubilized using a self-microemulsion system, and the adsorbent is mixed with the rifaximin self-microemulsion and growth repair factors, respectively, and then dispersed and suspended in a hydrogel. In addition to improving the stability of the drug-containing self-microemulsion and epidermal cell growth factor, the hydrogel reduces the pain during injection, and also improves the cell growth promoting effect of the growth repair factor and the cell growth provided by the hydrogel. The microenvironment can be used to speed up the repair of endometrial epidermal cells, promote the regeneration of damaged tissue, and establish a protective barrier, which can cure existing infections in the endometrium and improve the cow's body. It can not only speed up the recovery to health, but also prevent the occurrence of new infections in the uterus and reduce the incidence of endometritis. Compared to hydrogels, freeze-dried powders are easier to store, product stability is less affected by storage conditions, and they can be redissolved by adding purified water.

(2) Conventional uterine injections mainly obtain a bactericidal effect by directly injecting antibacterial drugs, and cannot simultaneously repair the uterine epidermis and tissues. By dispersing them into hydrogels, the added growth-repairing factors can promote proliferation, accelerate repair, and achieve the goals of both prevention and treatment. Due to poor stability, the present invention improves stability in an aqueous environment by adding adsorbents to suspend the growth repair factors in the hydrogel.

(3) The rifaximin uterine injection prepared according to the present invention is a temperature-sensitive injection; it is in a fluid state with good fluidity before injection, and the suspended drug-carrying particles can be easily and uniformly dispersed. It has the characteristics of low injection resistance, small particle size, low viscosity, and ease of use.When the temperature reaches 35℃~40℃, it can be injected in vivo and becomes a semi-solid hydrogel state. Compared to direct injection, the hydrogel can adhere more evenly to the uterine wall, close the pores, and form an antibacterial layer. Due to the action of gravity, it is difficult to deposit at the bottom of the uterus. The hydrogel system formed in vivo by the uterine injection prepared according to the present invention can be absorbed and utilized by living organisms, and is non-toxic and environmentally friendly.

The invention will be further explained with the aid of the drawings, but the examples in the drawings do not constitute a limitation of the invention and a person skilled in the art will be able to derive other drawings based on the following drawings without any creative efforts. You can also get it.

FIG. 3 is a pseudo three-phase diagram of a self-microemulsion.

The invention will be further explained with reference to the following examples.
An embodiment of the present invention relates to a rifaximin uterine injection consisting of a rifaximin self-microemulsion, an adsorption carrier, a growth repair factor, a gel matrix, Gantrez AN, and water for injection, the adsorption carrier comprising calcium silicate, and the growth repair factor , epidermal cell growth factor including oligopeptide-1 and/or copper peptide, collagen peptide and sodium hyaluronate.

Self-microemulsion systems (SMEDDS) are homogeneous, transparent solutions consisting of oil, surfactants and co-surfactants, or small amounts of water, as carriers for drugs that are hydrophobic, poorly absorbed, or easily hydrolyzed. It can function as By encasing the drug in oil droplets, it spontaneously disperses to form an O/W microemulsion when encountering body fluids in vivo. This system can significantly increase drug bioavailability through advantages such as increasing drug solubility, lowering surface tension, and increasing permeability.

Calcium silicate (model number: FLORITE PS-10) is a white fine particle with excellent fluidity. Calcium silicate coats the micropores with amorphous API to prevent the dissolution of API, which has poor water solubility. Promoting solid dispersions can be prepared. On the other hand, calcium silicate is also a synthetic calcium silicate with good liquid absorption properties, and unlike conventional porous materials, it has a unique petal-shaped crystal structure and extremely significant pore diameter and pore volume. These large pores are an important factor in liquid absorption, and can absorb up to five times its own weight in liquid and turn it into a powder. The large pores of calcium silicate continue to expand vertically, and the opening of the pore has a small area compared to its volume, protecting the liquid filled within the pore from external oxygen, vapor, and other elements. to have a good environment. Calcium silicate can be applied in pharmaceutical formulations not only as a stabilizer for APIs but also as an excellent liquid carrier.

Epidermal cell growth factor is an important active protein polypeptide substance in humans, which can strongly promote human cell proliferation, growth, quickly repair damaged mucous membranes, and restore the human body's autoimmunity. , quickly enters the epidermal tissue of the skin, repairs the damaged mucous membrane, promotes its differentiation, proliferation and transfer, and finally covers the damaged area, completes the regeneration of the mucous membrane, strengthens immunity, and supports the body's own restore function. Due to the properties of epidermal cell growth factor itself, cold conditions help maintain its activity, while conditions above room temperature gradually reduce its activity, and for this reason, when it is a single ingredient, it is generally sold as a lyophilized powder. It is kept refrigerated, and its stability must be carefully considered when preparing preparations using epidermal growth factor.

Hydrogel is a material with a network-like molecular structure made up of cross-linked hydrophilic polymer chains, and has water retention properties and mechanical properties similar to those of human tissue, so it is widely applied to repair and reconstruction of various tissues and organs. Injectable hydrogels offer numerous advantages over other routes of administration and implantation. Hydrogels have a structure similar to natural soft tissue, and the high water content property within the system can mimic extracellular matrix components in structure and function, effectively anchoring active substances such as cytokines and drugs. cells that can be absorbed and released, and have high permeability to oxygen, nutrients, and other metabolites, and are necessary to support cell proliferation and differentiation, as well as cell growth and migration. I will provide a. The injectable hydrogel based on natural polymer silk fibroin has weak antigenicity, good cell adhesion, absorption and biosafety, natural polymer hydrogel is favorable for cell growth, differentiation activity, and cell Provides a microenvironment for processes such as growth and collagen deposition.

Gantrez AN is a polymethyl vinyl ether/maleic anhydride copolymer that is soluble in water and/or ethanol and forms a highly polar, non-sticky film with excellent wet adhesive strength and bioadhesion. be able to. Since it has excellent film-forming properties and adhesive properties, it is suitable for spraying on bandages and as an adhesive for stomas.

Example 1
The new veterinary uterine injection contains 5 g of rifaximin self-microemulsion, 1 g of adsorption carrier, and growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1:3) per 100 ml. 4.3 g, water-soluble silk fibroin 10 g, Gantrez AN 0.5 g, and the remainder water for injection.

Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) were placed in a pyramidal mixer at a mass ratio of 2:1 and mixed uniformly to prepare an adsorption carrier mixture.
(3) 90% of the blended amount of adsorption carrier was put into a raw material tank, and the blended amount of rifaximin self-microemulsion was added and uniformly stirred to prepare self-microemulsion-supported particles.
(4) The remainder of the blended amount (10%) of the adsorption carrier was placed in a pyramidal mixer, and the blended amount of growth repair factor was added and uniformly stirred to prepare growth repair factor-supported particles.
(5) Add the blended amounts of water-soluble silk fibroin, Gantrez AN, and water for injection into a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, and then combine the self-microemulsion-supported particles with the growth repair. Add the factor-carrying particles, perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal to prepare a rifaximin uterine injection freeze-dried powder with a content specification of 0.2 g: 100 ml, The freeze-dried powder should be stored in a refrigerator under the protection of light, and when used, water for injection (100 mL/part, equivalent to 0.2 g rifaximin/part) should be added to dissolve it and shaken uniformly, so that the injection agent becomes a suspended hydrosol. Intrauterine perfusion was performed.
The preparation environment temperature was controlled at 20° C. to 25° C., and the humidity was controlled at 60% or less.

Example 2
Same as Example 1, except that it does not contain adsorbent, and in the process, rifaximin self-microemulsion and growth repair factors were directly added to the original step (5) to prepare rifaximin uterine injection, and the specific The steps are as follows.
The new veterinary uterine injection contains 5 g of rifaximin self-microemulsion, 4.3 g of growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1:3), per 100 ml. Consisting of 10 g of water-soluble silk fibroin, 0.5 g of Gantrez AN, and the remainder water for injection.
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Add the formulated amounts of water-soluble silk fibroin, Gantrez AN, and water for injection into a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, and then repair the growth of the rifaximin self-microemulsion and the formulated amount. Add the factor, perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal, prepare rifaximin uterine injection freeze-dried powder with content specification of 0.2 g: 100 ml, and freeze-dry. The powder is stored refrigerated under light protection, and when used, water for injection (100 mL/part, equivalent to 0.2 g rifaximin/part) is added to dissolve it and shaken evenly. When the injectable agent becomes a suspended hydrosol, it can be absorbed into the uterus. Perfusion was performed.
The preparation environment temperature was controlled at 20° C. to 25° C., and the humidity was controlled at 60% or less.

Example 3
The procedure was the same as in Example 1 except that the adsorption carrier was hydrophilic fumed silica, and the specific steps were as follows.
The new veterinary uterine injection contains 5 g of rifaximin self-microemulsion, 1 g of hydrophilic fumed silica, and growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1) per 100 ml. :3) Consisting of 4.3g, water-soluble silk fibroin 10g, Gantrez AN 0.5g, and the balance water for injection,
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) 90% of the blended amount of adsorption carrier was put into a raw material tank, and the blended amount of rifoximin self-microemulsion was added and uniformly stirred to prepare microemulsion-supported particles.
(3) The remainder of the blended amount (10%) of the adsorption carrier was placed in a pyramidal mixer, and the blended amount of growth repair factor was added and uniformly stirred to prepare growth repair factor-supported particles.
(4) Add the blended amounts of water-soluble silk fibroin, Gantrez AN, and water for injection into a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, and then combine the self-microemulsion-supported particles with the growth repair. Add the factor-carrying particles, perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal, prepare lyophilized powder for rifoximin uterine injection with a content standard of 0.2 g: 100 ml, and freeze. The dry powder is stored refrigerated under light protection, and when used, water for injection (100 mL/part, equivalent to 0.2 g/part of rifoximin) is added to dissolve and shaken evenly. When the injection becomes a suspended hydrosol, the uterus Internal perfusion was performed.
The temperature of the preparation environment was controlled at 20°C to 25°C, and the humidity was controlled at 60% or less.

Example 4
The procedure was the same as in Example 1 except that the adsorption carrier was microcrystalline cellulose, and the specific steps were as follows.
The new veterinary uterine injection contains 5 g of rifoximin self-microemulsion, 1 g of microcrystalline cellulose, and growth repair factors (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1:3) per 100 ml. ) 4.3 g, water-soluble silk fibroin 10 g, Gantrez AN 0.5 g, and the remainder injection water,
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and charged into a vortex mixer and vortex mixed, 38.4 g of caprylic acid decanoic acid monoglyceride (Capmul MCM) was added to the above mixture and vortex mixed to obtain a blank self-emulsion, and 4 g of rifoximin was dissolved in the blank self-emulsion to prepare a rifoximin self-emulsion.
(2) 90% of the formulation amount of the adsorption carrier was placed in a raw material tank, and the formulation amount of rifoximin self-supporting microemulsion was added and stirred uniformly to prepare microemulsion-supported particles.
(3) The remaining portion (10%) of the adsorption carrier was placed in a pyramidal mixer, and the growth repair factor was added in the amount formulated and stirred uniformly to prepare growth repair factor-supported particles.
(4) The formulation of water-soluble silk fibroin, Gantrez AN, and water for injection are added to a vortex mixer, and mixed and stirred at room temperature until the liquid becomes a clear sol state, and then the self-supporting microemulsion-supporting particles and the growth repair factor-supporting particles are added, vortex shearing is performed for 10 to 15 minutes, vacuum freeze-drying is performed, and nitrogen gas is filled and sealed to prepare a freeze-dried powder of rifoximin uterine infusion with a content standard of 0.2 g:100 ml. The freeze-dried powder is stored in a refrigerator under a dark place. When using, injection water (100 mL/part, equivalent to 0.2 g/part of rifoximin) is added to dissolve, and the mixture is shaken uniformly. When the infusion becomes a suspended hydrosol state, intrauterine perfusion is performed.
The preparation environment temperature was controlled to 20° C. to 25° C., and the humidity was controlled to 60% or less.

Example 5
The procedure is the same as in Example 1 except that the first matrix and the second matrix were polyvinyl alcohol and propane triol, respectively, and the specific steps are as follows.
The new veterinary uterine injection contains 5 g of rifaximin self-microemulsion, 1 g of adsorption carrier, and growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1:3) per 100 ml. 4.3 g, polyvinyl alcohol 13 g, propanetriol 0.65 g, and the remainder water for injection.
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) were placed in a pyramidal mixer at a mass ratio of 2:1 and mixed uniformly to prepare an adsorption carrier mixture.
(3) 90% of the blended amount of adsorption carrier was put into a raw material tank, and the blended amount of rifaximin self-microemulsion was added and uniformly stirred to prepare self-microemulsion-supported particles.
(4) The remainder of the blended amount (10%) of the adsorption carrier was placed in a pyramidal mixer, and the blended amount of growth repair factor was added and uniformly stirred to prepare growth repair factor-supported particles.
(5) Add mixed amounts of polyvinyl alcohol, propanetriol, and water for injection into a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, and then add the self-microemulsion-supporting particles and the growth repair factor-supporting particles. Add particles, perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal, prepare rifaximin uterine injection freeze-dried powder with content specification of 0.2 g: 100 ml, and freeze-dry. The powder is stored refrigerated under light protection, and when used, water for injection (100 mL/part, equivalent to 0.2 g rifaximin/part) is added to dissolve it and shaken evenly. When the injectable agent becomes a suspended hydrosol, it can be absorbed into the uterus. Perfusion was performed.
The preparation environment temperature was controlled at 20° C. to 25° C., and the humidity was controlled at 60% or less.

Comparative example 1 (first matrix, second matrix not included)
The new veterinary uterine injection contains the remaining rifaximin self-microemulsion, 0.1 g of adsorption carrier, and growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1) in 100 ml. :3) Consisting of 4.3g,
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) were placed in a pyramidal mixer at a mass ratio of 2:1 and mixed uniformly to prepare an adsorption carrier mixture.
(3) The adsorption carrier was placed in a pyramidal mixer, a blended amount of growth repair factor was added, and the mixture was uniformly stirred to prepare growth repair factor-supported particles.
(4) The growth repair factor-carrying particles were added to the rifaximin self-microemulsion, and vortex shearing was performed for 10 to 15 minutes to obtain a rifaximin uterine injection.
The temperature of the preparation environment was controlled at 20°C to 25°C, and the humidity was controlled at 60% or less.

Comparative example 2 (no second matrix)
The new veterinary uterine injection contains 5 g of rifaximin self-microemulsion, 1 g of adsorption carrier, and growth repair factor (oligopeptide-1/copper peptide: collagen peptide: sodium hyaluronate = 0.3:1:3) per 100 ml. 4.3g, chitosan 9g, and the remainder water for injection.
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) were placed in a pyramidal mixer at a mass ratio of 2:1 and mixed uniformly to prepare an adsorption carrier mixture.
(3) 90% of the blended amount of adsorption carrier was put into a raw material tank, and the blended amount of rifaximin self-microemulsion was added and uniformly stirred to prepare self-microemulsion-supported particles.
(4) The remaining amount (10%) of the adsorption carrier was placed in a pyramidal mixer, and the growth repair factor was added and uniformly stirred to prepare growth repair factor-supported particles.
(5) Add the blended amounts of chitosan and injection water to a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, then add the microemulsion-supported particles and the growth repair factor-supported particles, Perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal, prepare rifaximin uterine injection lyophilized powder with a content of 0.2 g: 100 ml, and refrigerate the lyophilized powder under protection from light. When stored and used, injection water (100 mL/part, equivalent to 0.2 g/part of rifoximin) was added to dissolve and shaken uniformly, and when the injectate became a suspended hydrosol, intrauterine perfusion was performed.
The temperature of the preparation environment was controlled at 20°C to 25°C, and the humidity was controlled at 60% or less.

Comparative example 3 (no growth repair factor)
The new veterinary uterine injection preparation consists of 5 g of rifoximin self-microemulsion, 0.9 g of adsorption carrier, 10 g of water-soluble silk fibroin, 0.5 g of Gantrez AN, and the remainder water for injection, in terms of 100 ml.
Its preparation method includes the following steps.

(1) 9.6 g of polyoxyethylene hydrogenated castor oil ether (Cremophor RH 40) and 48 g of diethylene glycol monoethyl ether (Transcutol P) were weighed and put into a vortex mixer, mixed by vortex, and caprylic acid capric acid monoglyceride (Capmul MCM) 38.4 g was added to the above mixture and vortex mixed to obtain a blank self-microemulsion, and 4 g of rifaximin was dissolved in the blank self-microemulsion to prepare a rifaximin self-microemulsion.
(2) Calcium silicate (FLORITE PS-10) and hydrophilic fumed silica (AEROSIL 380) were placed in a pyramidal mixer at a mass ratio of 2:1 and mixed uniformly to prepare an adsorption carrier mixture.
(3) The adsorption carrier was placed in a raw material tank, and a blended amount of rifaximin self-microemulsion was added and stirred uniformly to prepare self-microemulsion-supported particles.
(4) Add the blended amounts of water-soluble silk fibroin, Gantrez AN, and water for injection into a vortex mixer, mix and stir at room temperature until the liquid becomes a clear sol, and then combine the self-microemulsion-supported particles with the growth repair. Add the factor-carrying particles, perform vortex shearing for 10 to 15 minutes, freeze-dry in vacuum, fill with nitrogen gas and seal to prepare a rifaximin uterine injection freeze-dried powder with a content specification of 0.2 g: 100 ml, The freeze-dried powder should be stored in a refrigerator under the protection of light, and when used, water for injection (100 mL/part, equivalent to 0.2 g rifaximin/part) should be added to dissolve it and shaken uniformly, so that the injection agent becomes a suspended hydrosol. Intrauterine perfusion was performed.
The preparation environment temperature was controlled at 20° C. to 25° C., and the humidity was controlled at 60% or less.

Experimental example (1) Accelerated stability experiment Based on the draft quality standards for pharmaceutical preparations and the "Guiding Principles for Veterinary Drug Stability Testing" in the appendix of the 2020 edition of the Chinese Veterinary Pharmacology Dictionary, Examples 1 to 5 and Comparative Examples 1 to An accelerated stability test was conducted on Comparative Example 3, and the properties and content of a preparation sample of normal packaging specifications were discussed and measured.
Examples 1 to 5 and Comparative Examples 1 to 3 were placed in a commercially available packaging material (glass bottle) and sealed, left at room temperature of 25°C, and the samples were left for examination for 6 months. Samples were collected and discussed at 2nd, 3rd, and 6th months.

The results of the acceleration stability experiment are shown in the table below.

The results revealed the following:
(1) Example 1, Example 5, Comparative Example 2, and Comparative Example 3 have excellent acceleration stability, and the stability is as follows: Example 1, Example 5, Comparative Example 2, and Comparative Example 3> Example 3 > Example 4 > Example 2 > Comparative Example 1.
(2) Example 3 (adsorption carrier was hydrophilic fumed silica) was accelerated for 6 months and then redissolved, and it was confirmed under a microscope that a small amount of precipitated rifaximin crystals were dispersed in the hydrosol. On the other hand, in Example 1, Example 5, Comparative Example 2, and Comparative Example 3, the adsorption carrier was a mixture of calcium silicate and hydrophilic fumed silica at a mass ratio of 2:1. It shows that the adsorption capacity of calcium is larger and more self-microemulsion can be adsorbed. Therefore, the adsorption carrier is preferably a combination of calcium silicate and hydrophilic fumed silica. As can be seen from the accelerated stability data of Example 2 and Comparative Example 3, the adsorption carrier can effectively protect the rifaximin self-microemulsion, and the stability of rifaxidin uterine injection lyophilized powder and its redissolved direct perfusion uterine injection. was able to increase.
(3) In Example 4 (the adsorption carrier is microcrystalline cellulose), a cake was observed when it started to re-dissolve after 3 months of acceleration, and when it started to re-dissolve after 6 months of acceleration, lumps of various sizes were deposited on the bottom of the bottle. However, it is difficult to form a hydrosol, and when observed under a microscope, it was observed that rifaximin crystal powder was precipitated.This indicates that the adsorption capacity of microcrystalline cellulose is higher than that of hydrophilic fumed silica or calcium silicate. It was small, and the redispersibility and suspension properties after freeze-drying and re-dissolution were also poor.
(4) In Example 2 (no adsorbent), since there is no protection by an adsorbent, the rifaximin self-microemulsion is directly dispersed in the hydrosol system, and a separation phenomenon appears after redissolution from the second month of acceleration. The longer the time, the more the separation phenomenon becomes more obvious, and the content of rifaximin in the uterine injection lyophilized powder also decreases obviously, which shows that the adsorbent is the uterine injection lyophilized powder formulation and its active ingredients. It was shown that there is an important effect on the stability of
(5) Comparative Example 1 (self-microemulsion administration system) is a rifaximin self-microemulsion preparation in which growth repair factor-carrying particles are suspended, and the self-microemulsion can increase the solubility of rifaximin and increase its bioavailability. However, based on the formulation properties and decomposition of the active ingredient, it was discovered that Comparative Example 1 had poor accelerated stability, and it was predicted that the rifaximin uterine injection of Comparative Example 1 would have the shortest shelf life.

(2) Thixotropy - phase transition temperature and phase transition time The phase transition temperature and phase transition time of the uterine injection preparation of the present invention were detected by an inverted test tube method.
1. Phase transition temperature: Take 25ml of liquid state uterine injection into a vial, put the vial into a regenerative magnetic heating stirrer, and slowly raise the temperature in the range of 25°C to 50°C at a rate of 1°C * 5 min ^-1. The temperature was recorded with a mercury thermometer, and the temperature T at which the liquid in the vial solidified was measured by the vial inversion method.

The experimental results are shown in the table below.

The results revealed the following:
(1) The uterine injections of Example 1, Example 3, and Comparative Example 3 are in a suspended hydrosol state at low temperatures (25°C to 32°C), and change to a suspended hydrogel structure at 37°C. It does not flow when inverted and its phase transition temperature is 37°C, which is suitable for research and development purposes as it becomes a hydrogel due to its thixotropic properties when perfused in vivo (approximately 38°C to 39°C) with a uterine injection.
(2) Compared to Example 1, in Comparative Example 2, a hydrogel matrix was prepared only from water-soluble silk fibroin, but the phase transition temperature was close to that of Example 1 (about 38° C.).
(3) Compared with Example 1, the supported self-microemulsion and growth repair factor of Example 2 are directly dispersed in the hydrosol system, and as a result, the phase transition temperature of Example 2 is 40°C, and the Even when the liquid uterine injection preparation No. 2 was perfused into the uterus, it could form a hydrogel due to its thixotropic properties, but the viscosity of the hydrogel was low.
(4) Compared with Example 1, the adsorption carrier in Example 4 was changed to microcrystalline cellulose, and its phase transition temperature was 34°C, so that the uterine injection was not affected by the temperature during perfusion. The uterine injection agent has already partially coagulated during perfusion through the vas deferens, occluding the vas deferens, making it impossible to continue the perfusion operation, and seriously affecting the feasibility of using the product. .
(5) Compared with Example 1, the hydrogel matrix of Example 5 is different, so the liquid uterine injection becomes a suspended hydrogel structure at 31°C, which, like Example 4, seriously affects the feasibility of using the product. influenced.
(6) The uterine injection preparation of Comparative Example 1 did not have temperature-sensitive thixotropy, and as a result, it had poor adhesion in the uterus of dairy cows.
2. Phase transition time: Three glass tubes containing 25 ml of the uterine injection in a hydrosol state were placed in a constant temperature water bath pot at 38.5°C, and changes in the uterine injection were observed. If the uterine injection agent stopped flowing after inverting the glass tube, the liquid was considered to become a hydrogel, and the minimum required time was the gelation time.

The experimental results of the gelation time of the three uterine injections are shown in the following table.

As a result, the liquid uterine injections of Example 1, Example 3, Example 4, Comparative Example 2, and Comparative Example 3 reached a hydrogel state almost immediately under the condition of 38.5°C, and Example 5 The average gelation time is short (approximately 27 seconds), and after being injected into the uterus of dairy cows, these liquid uterine injections can be dispersed uniformly and become a hydrogel that adheres to the uterine mucosa and exert their medicinal efficacy. On the other hand, in Example 2, the gelation time was long, and like the uterine injection of Comparative Example 1, the liquid uterine injection that could flow after being injected into the uterus of a dairy cow was deposited at the fundus of the uterus and spread throughout the uterine mucosa. Uniform dispersion may not be possible.

(3) Testing the fit of the injectable to the wound The test method for evaluating the adhesion and fit of the injectable gel to the tissue involves selecting a rat, anesthetizing it by intraperitoneally injecting an anesthetic, and then After shaving, a circular wound with a diameter of 1 cm was cut with scissors, and a liquid uterine injection was injected into the circular wound, and the fit of the hydrogel to the wound was observed under different deformations.
As is clear from the results,
(1) Even if you pull the wound horizontally and vertically with tweezers, or even if you grab the rat's head with both hands and twist the legs to pull the wound, under different deformation effects, Example 1, Example 3, The hydrogels of Example 4 and Comparative Example 3 had good adhesion to the wound in rats, and no peeling or cracking was observed between the hydrogel and the tissue, which indicates that the hydrogels fit very well. It has been proven that it has good adhesion properties to tissues and has the effect of closing wounds.
(2) Under different deformation effects, a little peeling was observed between the hydrogels of Example 2 and Comparative Example 2 and the tissue on the wound of the rat.
(3) The hydrogel of Example 5 had the best film formability and the best adhesion.
(4) The liquid uterine injection of Comparative Example 1 could not form a hydrogel at the wound site.

(4) Testing of in vitro decomposition performance Test method: Take 5 parts of the injection gel mass of the same weight and volume and soak each in PBS containing egg white lysozyme (10 mg/mL) for 38.5 minutes until complete decomposition. The state of the hydrogel in PBS was observed at a constant temperature of 0.degree. C., and the time was recorded.

The in vitro degradation time results for the five hydrogel masses are shown in the following table.

As a result, the hydrogels formed by the liquid uterine injections of Examples 1, 3, 4, and Comparative Example 3 slowly decomposed over time and were completely decomposed in about 18 h. The hydrogels of Comparative Example 2 and Comparative Example 2 decomposed quickly, completely decomposing in about 16 h, and all of these formulations met the requirements for the "0 day 0 day of weaning period" drug withdrawal period for rifaximin uterine injections, whereas the hydrogels of Comparative Example 2 The hydrogel mass of No. 5 was not completely decomposed after one full day (24 h) and did not pass the washout period, but it was completely decomposed even after about 32 h.

(5) Test of histocompatibility and in vivo degradability Test method: Healthy adult male SD rats were selected, allowed free access to water and food, maintained constant environmental temperature and humidity, and adapted to the environment. After subcutaneously injecting 0.5 mL of the liquid uterine injection obtained according to the present invention into the back of a rat, the reaction status of the tissue surrounding the injection site was observed at 0 h, 3 h, 6 h, 10 h, 14 h, 18 h, and 22 h, respectively.
Experimental results: From the routine observation results after subcutaneously injecting the liquid uterine injections into the back of rats, it was clear that the liquid uterine injections of Examples 1 to 5 and Comparative Examples 1 to 3 formed in vivo. The gel has good biocompatibility, with no obvious tissue inflammatory reactions such as cysts or capillary hyperemia observed at the initial stage of injection, and good compatibility with the subcutaneous tissue. The decomposition time was almost consistent with the results of the "in vitro decomposition performance test", and the uterine injection of Comparative Example 1 (self-microemulsion administration system) was completely absorbed into the subcutaneous tissue in about 6 minutes.
This indicates that in addition to the too long degradation time of the hydrogel formed in vivo in Example 5, the uterine injections prepared in the other four Examples all had good tissue compatibility and biodegradability. The uterine injection preparation prepared according to the present invention is capable of absorbing and utilizing the in-vivo hydrogel into tissues, and also contains a second matrix and a growth repair factor (Comparative Example 2 and Comparative Example 3). Even without this, the in-vivo tissue compatibility of the hydrogel mass was not affected, and the self-microemulsion administration system (Comparative Example 1) was rapidly absorbed into tissues and was able to exert its medicinal efficacy. .

(6) Irritation evaluation method From the results of the previous five experiments, Example 1 is the optimal formulation for rifaximin uterine injection lyophilized powder, and the formulations of Comparative Examples 1 and 2 are both the same as Example 1. Since one type of material was reduced from the formulation, it can be estimated that the irritation of Comparative Examples 1 and 2 is lower than that of Example 1. We conducted an evaluation.
Twenty-eight healthy normal adult New Zealand rabbits were randomly divided into a virus-infected group and a control group, and these rabbits had no symptoms of metritis and no symptoms of estrus.
For the virus-infected group, liquid rifaximin uterine injection was administered at 1, 3, and 5 times the normal recommended dose, and the drug solution was perfused into the vagina with a blunt needle, repeated once every 48 hours, 3 times in a row. The control group performed the same operation using 0.2 ml/kg of physiological saline.
We observed the general condition and local reactions after rifaximin uterine injection was perfused into the vagina of female rabbits, including pain, anxiety, outflow of cloudy secretions, and redness in the genital area.
24 hours after the last administration of the rabbit, the rabbit was killed using air embolization, dissected, and the vaginal specimen was taken out and longitudinally incised. The presence or absence of stimulus expressions such as Vaginal mucosal irritation response scoring and irritation intensity evaluation were performed based on the vaginal mucosal irritation response score table and the vaginal mucosal mucosal irritation intensity evaluation table.

膣粘膜刺激強度評価表は以下の通りである。

前記注入剤によるカイウサギの膣粘膜刺激反応強度を肉眼観察により評価した結果を次の表に示す。

The evaluation table for vaginal mucosal irritation reaction is as follows.

The vaginal mucosal irritation intensity evaluation table is as follows.

The following table shows the results of evaluating the strength of the stimulation reaction to the vaginal mucous membrane of rabbits caused by the above-mentioned injection agent by visual observation.

The test results revealed the following:
(1) During the administration, no abnormality was observed in the general condition of the rabbits in Group 3, and no obvious congestion, redness, or abnormal discharge was observed at the vaginal opening.
(2) When the removed vaginal tissue was visually observed, the control group found no hyperemia, edema, or bleeding spots on the vaginal mucosa, and one vaginal sample from the virus-infected group in Example 1 showed mild hyperemia and a small amount of vaginal mucosa. There was only secretion, and the vaginal mucosal irritation index of Group 2 was 0 to 0.4. From this, the liquid uterine injection prepared in Example 1 had no effect on the vaginal mucosal irritation intensity of rabbits. On the other hand, the vaginal mucosal irritation index of Comparative Example 1 was 0.5. Therefore, the liquid uterine injection of Comparative Example 1 was mildly irritating, and compared to Example 1. This indicates that it was highly irritating.
(3) The rifaximin uterine injections of Example 1 and Comparative Example 1 at the 3-fold dose and the 5-fold dose were all less irritating to the vaginal mucosa and caused mild irritation.
From the above, Example 1 had similar irritation to the control group, and less irritation than Comparative Example 1.

(7) Experiments on medicinal efficacy 1. Method for detecting milk residue in dairy cows by perfusion of rifaximin uterine injection according to the present invention Nine lactating cows diagnosed with endometritis at a large dairy farm and not treated with any antibacterial drug were selected, and the formulation of the present invention was The rifaximin uterine injection described in 1 was injected into the uterus. A blank milk sample was collected before administration (0 h), and then 100 ml of the liquid rifaximin uterine injection of the present invention was injected into the uterine horns using a sterile uterine irrigator, and 48 h later (same time after 2 days), 1 The administration was repeated twice, totaling two times. 1000 ml of each milk sample was collected at 1, 4, 8, 12, 16, 20, 24, 32, 48, and 60 h after the last dose (250 ml of milk sample was collected in each lactation area each time, Four lactation areas were sampled and mixed uniformly), HPLC analysis was performed to measure the rifaximin content in the milk samples, and the blood concentration and time data results of the milk samples are shown in the table below.

As is clear from the results,
(1) After perfusing the uterus of dairy cows suffering from endometritis with the rifaximin uterine injections of Example 1, Comparative Example 1, and Comparative Example 3, in Example 1 and Comparative Example 3, rifaximin in milk was The kinetic process is very similar, similar to the first-order absorption one-compartment open model, the rifaximin concentration in the milk is low, and after 16 h of administration, the rifaximin concentration in the milk is already at the lowest limit of quantification (the limit of quantification of the method is 0.05 μg/ml), and 20 hours after administration, no rifaximin was measured in the milk, and it was already below the maximum residual limit of 0.06 μg/ml in milk. Example 1 satisfies the requirements for the withdrawal period and also shows that the addition of growth repair factors (Comparative Example 3) does not affect the kinetic process of rifaximin in milk.
(2) From the data, in Comparative Example 1 (self-microemulsion administration system), the drug concentration in the milk sample already reached its peak at 1 h or 2 h, and 8 h after administration, the rifaximin concentration in the milk was 0.06 μg/ml (the highest From this, the self-microemulsion administration system is rapidly absorbed and decomposed, and the time taken for the uterine injection of the present invention (Example 1) to exert its medicinal effect is very low. It was shown that it was longer than the drug.
From the above, the rifaximin uterine injection prepared according to the present invention (Example 1) exhibits long-term medicinal efficacy without increasing the risk of drug remaining in milk, compared to direct administration of autologous microemulsion. can do.

2. Test of the therapeutic effect of the rifaximin uterine injection of the present invention on dairy cow endometritis Investigational drug:
The rifaximin uterine injection of Example 1 of the present invention, standard 100ml;
The rifaximin uterine injection of Comparative Example 1 of the present invention, standard 100ml,
The refaximin uterine injection of Comparative Example 3 of the present invention, standard 100ml,
Control drug: Flufenicol uterine injection, content 10%;
Test method:
Seventy-seven dairy cows diagnosed with endometritis were selected at a large dairy farm and randomly divided into 11 groups, with seven cows in each group, and the grouping and treatments were as shown in the test grouping and treatment table. Ta.
Each drug is processed using the uterine perfusion method, strictly carrying out vulval cleaning and disinfection measures, and all adopting the plastic cannula of the infusion gun as the dosing conduit to prevent cross-infection between individual cows. It was used once and then thrown away.

The test grouping and treatment table is as follows.

Judgment of treatment effect:
(1) Healing (complete recovery): Comparing before and after treatment, the mucus discharged from the vagina is clear and has no strange odor, other clinical symptoms have disappeared, the estrus cycle has returned to normal, mating has been normal, and pregnancy has occurred. did.
(2) Effective (obvious improvement): Comparing before and after treatment, the uterus clearly softened, contractility became stronger, and other symptoms were alleviated, but no pregnancy occurred after estrus and mating.
(3) Ineffective (no obvious improvement): When comparing before and after treatment, there was no obvious change compared to before treatment.
(4) Interval (days) from postpartum to the first day of mating: compared with blank control group.
(5) Overall pregnancy rate: Cows that were determined to be fully recovered after treatment were subjected to sperm infusion, and the intraestrus pregnancy rate, primary estrus pregnancy rate, and total pregnancy rate were calculated.

The clinical therapeutic effects of the rifaximin uterine injection on dairy cow endometritis are shown in the following table.

The observation period for the seven cows suffering from endometritis in the blank control group was 10 days, and the disease state did not improve at all. All cows were treated with medication immediately after the observation period to avoid affecting production.
From the clinical treatment effect, when perfusing with a high dose of the rifoximin uterine injection of Example 1, the cure rate and effective rate were all 85.7%, and the cure rate and effective rate were 71.4%, respectively, at a moderate dose. The therapeutic effect was 85.7%, clearly superior to the low dose group. The therapeutic effect of the control drug fulvenicol group is the same as that of the moderate dose of rifoximin uterine injection in Comparative Example 3, and the therapeutic effect is better than the moderate dose of Comparative Example 1, and the order of the therapeutic effects is Example 1 > Control. Group > Comparative Example 3 > Comparative Example 1 > Blank group, but fluvenicol had a certain stimulating effect on dairy cows after perfusion, and manic anxiety was observed.

(8) Other stability experiments From the above experimental results, it can be confirmed that Example 1 is the optimal combination of the rifoximin uterine injection of the present invention, and based on the draft formulation quality standards, the Chinese Veterinary Pharmacology Dictionary 2020 Based on the "Guiding Principles for Veterinary Drug Stability Testing" in the appendix, the freeze-dried powder for uterine injection of the present invention (Example 1) was subjected to temperature tests, light irradiation tests, high humidity tests, and long-term stability tests. We examined and measured the properties, main indicators and content of standard packaging standard preparation samples, and estimated the shelf life based on the results of the examination.

(1) Temperature stability test The preparation of the present invention was placed in a commercially available packaging material (glass bottle), sealed, and left in a refrigerator at -15°C, 4°C, and room temperature 25°C for 30 days, leaving a sample for analysis. Samples were collected and analyzed every day. The results show that the formulation of the present invention does not exhibit any phenomena such as separation or discoloration under the above conditions, and maintains a uniform suspended hydrosol form without any obvious caking, separation, or precipitation phenomena after redissolution. showed good temperature stability.
(2) Lighting test The preparation of the present invention was placed in a commercially available packaging material (glass bottle), sealed, and placed in a lighting box equipped with a fluorescent lamp or other suitable lighting device for 10 days under the condition of illuminance of 4500 ± 500 lx. The samples were left for 1 day, and samples were taken on the 5th and 10th days. As a result, the preparation of the present invention does not exhibit phenomena such as separation and discoloration, and after redissolution, there is no obvious caking, separation, or precipitation phenomenon, and it maintains a uniform aqueous sol state, and the photostability of this preparation is good. It was shown that
(3) High humidity test The preparation of the present invention was placed in a commercially available packaging material (glass bottle), sealed, and left for 10 days under conditions of 25°C ± 2°C and relative humidity of 90% ± 5%, and on the 5th day of each , samples were taken on the 10th day and discussed. As a result, the formulation of the present invention satisfies the requirements for hygroscopicity under the above conditions, does not exhibit phenomena such as caking or discoloration, and has no obvious caking, separation, or precipitation phenomena after redissolution, and is in the form of a uniform aqueous sol. , indicating that this formulation has good high-humidity stability.
(4) Validity period As a result of measurement, this preparation can be stored for more than 24 months under the conditions of light shielding, airtightness, and 2°C to 8°C, and the provisional shelf life was 24 months.
The above embodiments are only for explaining the technical solution of the present invention, and do not limit the protection scope of the present invention, and the present invention will be explained in detail with reference to preferred embodiments. However, as those skilled in the art can understand, the technical solution of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solution of the present invention.

Claims (2)

Step (1) of preparing a rifaximin self-emulsifying microemulsion ;
An adsorption carrier and the rifaximin self-emulsifying microemulsion are mixed to prepare self-emulsifying microemulsion- supported particles, and an adsorption carrier and a growth repair factor are mixed to prepare growth repair factor-supporting particles. Step (2) and
An injection matrix is prepared by mixing a first matrix, a second matrix, and water for injection, and the injection matrix, the self-emulsifying microemulsion- supporting particles, and the growth repair factor-supporting particles are mixed and injected into the uterus. step (3) of preparing the agent;
The adsorption carrier is one or more of calcium silicate, hydrophilic fumed silica, and microcrystalline cellulose,
The growth repair factor includes epidermal cell growth factor that is one or two of oligopeptide-1 and copper peptide;
The first matrix is one or more of water-soluble silk fibroin, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinyl alcohol,
The second matrix is one or more of methyl vinyl ether-maleic anhydride copolymer, polyethylene glycol, sodium carboxymethyl cellulose, and propylene triol.
The concentration of rifaximin in the rifaximin self-emulsifying microemulsion is 4wt. %, the adsorption carrier is a mixture of calcium silicate and hydrophilic fumed silica in a mass ratio of 2:1, and the growth repair factor is a mixture of epidermal cell growth factor, collagen peptide, and sodium hyaluronate in a mass ratio of 0. .3:1:3, the first matrix is water-soluble silk fibroin, the second matrix is methyl vinyl ether-maleic anhydride copolymer, and the rifaximin self-emulsifying microemulsion , the mass ratio of the adsorption carrier, the growth repair factor, the first matrix, and the second matrix is 5:1:4.3:10:0.5,
A method for preparing a novel veterinary uterine injection, which is characterized by: The novel method for preparing a veterinary uterine injection according to claim 1, further comprising a step (4) of lyophilizing the uterine injection prepared in step (3).

Images