Synergistic doxycycline hydrochloride effervescent tablet as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of veterinary drug preparation, and discloses a synergistic doxycycline hydrochloride effervescent tablet as well as a preparation method and application thereof. The effervescent tablet is prepared from the following raw and auxiliary materials in percentage by weight: 10-15% of doxycycline hydrochloride, 3-5% of composite essential oil microcapsules, 3-7% of bletilla striata polysaccharide, 7-10% of Arabic gum, 1-3% of lauryl sodium sulfate, 38-42% of an effervescing agent, 5-6% of an adhesive, 4-5% of a disintegrating agent, 2-3% of a lubricant and the balance of a filling agent, wherein the weight percentage of the raw and auxiliary materials is 100%. The effervescent tablet prepared by the invention can be completely disintegrated after encountering water, can generate a large number of bubbles and is high in disintegration speed, the contact area between the medicine and an inflammation part is effectively enlarged, the microcapsules can be well adhered to the inner walls of the uterus and the vagina after absorbing water and expanding, the retention time of the medicine is prolonged, and the medicine effect is more lasting. The effervescent tablet is applied to treatment of bovine vaginitis and endometritis, the cure rate can reach 90% or above, and the effervescent tablet is suitable for being applied to intensive large-scale farms.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug preparation technology, and in particular relates to an enhanced doxycycline hydrochloride effervescent tablet, its preparation method and application. Background Technology

[0002] Endometritis and vaginitis are common obstetric diseases in dairy cows. Both can lead to infertility or low conception rates, prolonged calving intervals, and reduced milk production, causing huge economic losses to dairy farmers.

[0003] Bacteria are the main cause of endometritis in dairy cows. Pathogens isolated from the uterus of infected cows include dozens of species such as Staphylococcus, Streptococcus, Brucella, Escherichia coli, Corynebacterium pyogenes, Pseudomonas, Proteus, Necrobacterium necrosis, Pseudomonas aeruginosa, and Genitobacteria. Vaginitis in dairy cows is mainly caused by bacteria, Chlamydia, fungi, viruses, and Trichomonas vaginalis. Therefore, sensitive and broad-spectrum drugs should be selected for treatment of these diseases.

[0004] Doxycycline hydrochloride is a second-generation tetracycline derivative, belonging to the semi-synthetic tetracycline class of antibiotics. Its antibacterial spectrum is similar to that of tetracyclines and oxytetracyclines, including Gram-positive bacteria (Anthrax bacilli, Clostridium tetani, Streptococcus, etc.) and Gram-negative bacilli (Pasteurella multocida, Brucella, Salmonella, etc.). It also has some therapeutic effect against Chlamydia, Mycoplasma, and Rickettsia infections. It has advantages such as a broad antibacterial spectrum, long duration of action, and good antibacterial efficacy. Clinically, it is widely used for infectious diseases of the respiratory and reproductive tracts.

[0005] Currently, the commonly used dosage forms of doxycycline hydrochloride for animals include powder, tablets, and injections. In treating vaginal and uterine diseases in dairy cows, vaginal and uterine irrigation are frequently used. However, these dosage forms have poor solubility, small contact area with the uterine mucosa and vagina, and poor adhesion, resulting in generally unsatisfactory treatment effects. Furthermore, drug-resistant strains of doxycycline hydrochloride have been discovered, so drug resistance issues also need to be considered when using this type of drug.

[0006] For a considerable period to come, antibiotics will remain the primary means of controlling vaginal and uterine diseases in dairy cows. However, simply increasing the dosage is not a simple solution, as this can lead to significant side effects and harm animal health. In the context of the "green trend," plant-based medicines have attracted significant attention due to their low likelihood of developing drug resistance, biodegradability in the environment, minimal long-term residues in livestock products or accumulation through the food chain, and relative safety for humans, animals, and the environment. Therefore, developing highly effective, low-toxicity, and environmentally friendly new veterinary drug formulations has been a hot research topic in veterinary medicine. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides an enhanced doxycycline hydrochloride effervescent tablet and its preparation method. The effervescent tablet uses doxycycline hydrochloride as the active ingredient, and Bletilla striata polysaccharide and compound essential oils as enhancing ingredients. This formulation completely disintegrates upon contact with water, producing a large number of bubbles at a rapid disintegration rate, effectively increasing the contact area between the drug and the inflamed site. The sustained-release microcapsules formed by doxycycline and Bletilla striata polysaccharide, and the microcapsules formed by the compound essential oils, absorb water and swell, adhering well to the uterine and vaginal walls, prolonging the drug's retention time and resulting in a longer-lasting effect.

[0008] This invention provides an enhanced doxycycline hydrochloride effervescent tablet, prepared from the following raw and excipient materials in 100% by weight: Doxycycline hydrochloride 10-15%, Complex essential oil microcapsules 3-5%, Bletilla striata polysaccharide 3-7%, Gum arabic 7-10%, Sodium dodecyl sulfate 1.0%–3.0%, Effervescent tablets 38%–42%, Adhesive 5%–6%, Disintegrant 4%–5%, Lubricant 2%–3%, The remainder is filler; The composite essential oil microcapsules are prepared by a method including the following steps: A. Mix gum arabic and purified water and stir to dissolve at 40-60°C (preferably 50°C); then add hydroxypropyl-β-cyclodextrin and low-viscosity hydroxypropyl methylcellulose E5 and continue stirring to dissolve; then add PEG 4000 and Tween 20 and stir to dissolve; finally add compound essential oil and obtain an emulsion by high-speed shearing and high-pressure homogenization. B. Spray dry the emulsion obtained in step A, controlling the outlet air temperature at 60-70℃ (preferably 65℃) to obtain the composite essential oil microcapsules; The compound essential oil is a mixture of eucalyptus oil, lavender essential oil and thyme essential oil.

[0009] Furthermore, in step A of the preparation of the composite essential oil microcapsules: The mass ratio of gum arabic, hydroxypropyl-β-cyclodextrin, and low-viscosity hydroxypropyl methylcellulose E5 is (1.5–2.5):(0.8–1.2):(0.03–0.08) (preferably 2:1:0.05). The mass ratio of eucalyptus oil, lavender oil and thyme oil in the compound essential oil is (3-5):(1-3):1 (preferably 4:2:1); The ratio of the total mass of the compound essential oil to the total mass of gum arabic and hydroxypropyl-β-cyclodextrin is 1:(6-10) (preferably 1:8). The amount of Tween 20 added is 0.5-2% (preferably 1%) of the total mass of the emulsion. The amount of PEG4000 added is 1-3% (preferably 2%) of the total solids in the emulsion. The total solids content of the emulsion is 12-16% (preferably 14.5%). The high-pressure homogenization is performed under two-stage homogenization conditions, using a homogenizer to homogenize once at 20~30MPa and once at 30~40MPa (preferably once at 25MPa and once at 35MPa).

[0010] Furthermore, the doxycycline hydrochloride exists in the form of microcapsules, namely doxycycline hydrochloride microcapsules, which are prepared by a method comprising the following steps: a. Dissolve doxycycline hydrochloride in water to prepare a 15-20% solution; b. Dissolve Bletilla striata polysaccharide in water to prepare a 15-18% solution; c. Dissolve gum arabic in water to prepare a 10-12% solution; In this application document, all percentages of solution concentration without a unit are mass percentages. d. Mix the solution obtained in step a with the solution obtained in step b, shear at 8000-12000 r / min for 5-8 minutes (preferably shear at 10000 r / min for 5 minutes), and treat with ultrasound at 25-35 kHz for 35-45 minutes (preferably embedding under 25 kHz ultrasound for 35 minutes) to obtain a first embedding solution; e. Mix the primary embedding solution obtained in step d with the solution obtained in step c, shear at 10000-14000 r / min for 8-10 minutes (preferably shear at 12000 r / min for 8 minutes), and treat with ultrasound at 30-45 kHz for 45-55 minutes (preferably embedding at 30 kHz for 45 minutes) to obtain the secondary embedding solution. f. Homogenize the secondary embedding solution obtained in step e at a pressure of 40-50 MPa (preferably 40 MPa) 2-4 times (preferably 2 times). g. Spray dry the homogenized liquid obtained in step f, controlling the inlet air temperature to be 130-140℃ (preferably 135℃), the outlet air temperature to be 55-62℃ (preferably 58℃), and the feed rate to be 3-6 mL / min (preferably 5 mL / min), to obtain the doxycycline hydrochloride microcapsules.

[0011] Furthermore, the effervescent agent includes an acid and an alkali, wherein the acid is citric acid and the alkali is sodium bicarbonate, and the mass ratio of the acid to the alkali is 1.2:1 to 1.3:1 (preferably 1.25:1).

[0012] Furthermore, the filler is selected from lactose, anhydrous glucose, and sucrose; the disintegrant is croscarmellose sodium; the binder is an ethanol solution of povidone K30; and the lubricant is a mixture of magnesium stearate and polyethylene glycol 4000 in a mass ratio of (1.5-2.5):(4.5-5.5) (preferably 2:5).

[0013] Furthermore, based on 100% by weight, the raw materials and auxiliary materials are formulated in any of the following weight percentages: (1) Doxycycline hydrochloride 10%, compound essential oil microcapsules 3%, Bletilla striata polysaccharide 3%, gum arabic 7%, sodium lauryl sulfate 1.0%, effervescent agent 38%, binder 5%, disintegrant 4%, lubricant 2%, and the remainder is filler lactose; (2) Doxycycline hydrochloride 11.5%, compound essential oil microcapsules 4%, Bletilla striata polysaccharide 6%, gum arabic 9%, sodium dodecyl sulfate 1.5%, effervescent agent 40%, binder 5.5%, disintegrant 5%, lubricant 3%, and the remainder is filler anhydrous glucose; (3) 15% doxycycline hydrochloride, 5% compound essential oil microcapsules, 7% Bletilla striata polysaccharide, 10% gum arabic, 2.0% sodium dodecyl sulfate, 42% effervescent agent, 6% binder, 5% disintegrant, 3% lubricant, and the remainder is sucrose filler.

[0014] The present invention also provides a method for producing the aforementioned enhanced doxycycline hydrochloride effervescent tablets, comprising the following steps: S1. Prepare the composite essential oil microcapsules; S2. Prepare the doxycycline hydrochloride microcapsules; S3. Preparation of alkaline granules: Mix the composite essential oil microcapsules obtained in step S1, the alkaline agent in all effervescent agents, 2 / 3 of the sodium dodecyl sulfate, and 1 / 6 of the filler evenly; wet with 1 / 2 of the binder to form a soft material, granulate through a sieve, and dry and granulate the resulting wet granules at 40-50°C (preferably 45°C) for later use. S4. Preparation of acid granules: Mix the doxycycline hydrochloride microcapsules obtained in step S2, the acid in all the effervescent agents, the remaining sodium dodecyl sulfate, and 2 / 3 of the filler evenly; wet with the remaining binder liquid, make a soft material, granulate through a sieve, and dry and granulate the obtained wet granules at 45-55°C (preferably 50°C) for later use. S5. Mixing and tableting: Mix the alkaline particles obtained in step S3 with the acid particles obtained in step S4, add the remaining filler, all disintegrants and all lubricants, mix thoroughly, and then compress into tablets to obtain doxycycline hydrochloride effervescent tablets.

[0015] Furthermore, in steps S3 and S4, both granulation and sizing are performed using a 10-30 mesh sieve (preferably a 20 mesh sieve); in steps S3 and S4, the binder is an anhydrous ethanol solution of povidone K30 with a mass fraction of 4-6% (preferably an anhydrous ethanol solution of povidone K30 with a mass fraction of 5%).

[0016] The present invention also provides the use of the above-mentioned enhanced doxycycline hydrochloride effervescent tablets in the preparation of a medicament for treating bovine endometritis and / or vaginitis.

[0017] This invention incorporates Bletilla striata polysaccharide, which serves as both a synergist and a microcapsule framework material. Bletilla striata polysaccharide (BSP) is a water-soluble, high-molecular-weight viscous polysaccharide, also known as Bletilla striata glucomannan, composed of D-glucose and D-mannose in an approximately 1:4 ratio, polymerized by β-glycosidic bonds to form a spatial helical structure; its average molecular weight is 1.35 × 10⁻⁶. 5 This polysaccharide dissolves in water to form a viscous gel with excellent bioadhesion and is extremely safe for the body. Toxicological safety evaluations show that Bletilla striata polysaccharide is safe, non-irritating, and non-allergenic, thus having a wide range of applications. Modern pharmacological studies have shown that BSP has multiple pharmacological effects, including good antibacterial and anti-inflammatory properties, hemostasis, increasing the expression of immune factors, and promoting wound healing. It also possesses characteristics such as biodegradability, good bioadhesion, and non-antigenicity. The microspheres prepared from it have a good appearance and a three-dimensional network structure, which is beneficial for sustained drug release.

[0018] This invention also includes a compound essential oil composed of eucalyptus oil, lavender oil, and thyme oil. Eucalyptus oil EEO is a colorless to pale yellow liquid with an odor similar to camphor and borneol. Its composition is complex, containing over 70% (v / v) eucalyptol and small amounts of aldehydes and terpenes, with 1,8-cineole as the main chemical component. EEO possesses antibacterial, anti-inflammatory, antiviral, and antioxidant bioactivities, showing particularly significant antibacterial effects against Staphylococcus aureus, Escherichia coli, and Bacillus subtilis. Eucalyptus oil and wild eucalyptus oil are more sensitive to Gram-positive bacteria, and their antibacterial activity increases with increasing oil concentration. The hydrophobicity of EEO can alter the permeability and osmotic pressure of microbial cell membranes, causing leakage of cell contents and ultimately leading to microbial death, making it a promising candidate for development as an antibacterial agent.

[0019] Lavender essential oil is a natural plant essential oil, mainly containing linalool and linalyl acetate, as well as alkenes, esters, and alcohols for flavor. Lavender essential oil has broad-spectrum antibacterial properties, exhibiting strong inhibitory effects against pathogenic bacteria such as Staphylococcus aureus, Listeria monocytogenes, and Salmonella.

[0020] Thyme essential oil is found in the glandular hairs of the cotyledons and flowers of the plant, and mainly contains phenols, monoterpenes, esters, and alcohols. The main component of thyme essential oil is thymol (36%–55%). Thyme essential oil has strong antibacterial and antiseptic properties and is widely used as an adjunct treatment for respiratory inflammatory diseases, urinary tract infections, gastric inflammatory diseases, atrophic arthritis, and oral infections.

[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects: The enhanced doxycycline hydrochloride effervescent tablets of this invention disintegrate rapidly and completely upon contact with water, generating a large number of bubbles. This effectively expands the contact area between the doxycycline hydrochloride microcapsules and the compound essential oil microcapsules and the inflamed area. The microcapsules can absorb water and swell to form a gel, which can quickly adhere to the surface of the uterus or vagina and form a mechanical protective film on the mucosa, thus protecting the mucosa and reducing drug loss.

[0022] Doxycycline hydrochloride microcapsules absorb water and swell to form a gel, which provides a sustained release of doxycycline hydrochloride. The compound essential oil is continuously released in the uterus or vagina of dairy cows under the influence of body temperature, and is more evenly distributed in the uterus or vagina, thus better exerting its antibacterial and anti-inflammatory effects.

[0023] Bletilla striata polysaccharide has multiple pharmacological effects, including good hemostasis, anti-inflammation, increasing the expression of immune factors, promoting wound healing, and antibacterial activity. Therefore, it can stop bleeding, reduce inflammation, and promote repair for mucosal erosion and bleeding caused by endometritis or vaginitis, thus avoiding secondary infection of the wound.

[0024] The amount of compound essential oil added to the formulation is small, and it has no obvious effect when used alone. However, when added to effervescent tablets of doxycycline hydrochloride microcapsules, the cure rate of the formulation for bovine endometritis / vaginitis increased by more than 6.67%.

[0025] The enhanced doxycycline hydrochloride effervescent tablets of the present invention have a good sustained-release effect. Compared with ordinary doxycycline hydrochloride effervescent tablets, it can achieve 1 tablet every 2 days instead of 1 tablet every day, thereby reducing the frequency of medication and improving the convenience of treatment. Attached Figure Description

[0026] Figure 1 The dissolution and release curves are for the effervescent tablets prepared in Examples 1-3 and Comparative Example 1. Detailed Implementation

[0027] The present invention will be further described in detail below through specific implementation examples. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of protection of the present invention. After reading the present invention, any modifications of the present invention in various equivalent forms by those skilled in the art fall within the scope of the appended claims.

[0028] Unless otherwise specified, all raw materials and reagents used in this invention are from the conventional market.

[0029] The composite essential oil microcapsules of the present invention are obtained by the following method: A. Mix gum arabic and purified water, then stir to dissolve at 50°C. Next, add hydroxypropyl β-cyclodextrin and low-viscosity hydroxypropyl methylcellulose E5, and continue stirring for 30 minutes until completely dissolved. Then add PEG4000 and Tween 20, stir to dissolve, and finally add a compound essential oil (eucalyptus oil: lavender oil: thyme oil = 4:2:1, mass ratio). After the addition is complete, disperse and shear at 10000 r / min for 60 s, then homogenize once at 25 MPa and once at 35 MPa using a homogenizer to obtain an emulsion.

[0030] The proportions of each component satisfy the following relationship: The mass ratio of gum arabic: hydroxypropyl-β-cyclodextrin: low-viscosity hydroxypropyl methylcellulose E5 is 2:1:0.05; The mass ratio of the compound essential oil to the total mass of gum arabic and hydroxypropyl-β-cyclodextrin is 1:8; The amount of Tween 20 added is 1% of the total mass of the emulsion; The amount of PEG4000 added is 2% of the total solids in the emulsion; The total solids content in the emulsion is 14.5%.

[0031] The above emulsion was spray-dried, and the spray drying outlet temperature was controlled at 65°C to obtain composite essential oil microcapsules.

[0032] The present invention will be further illustrated below with reference to specific embodiments.

[0033] Example 1: Preparation of enhanced doxycycline hydrochloride effervescent tablets This embodiment provides an enhanced doxycycline hydrochloride effervescent tablet, which is prepared from the following raw and excipient materials by weight percentage (based on the raw and excipient ratio for 1000 enhanced doxycycline hydrochloride effervescent tablets): Doxycycline hydrochloride 10%, compound essential oil microcapsules 3%, Bletilla striata polysaccharide 3%, gum arabic 7%, sodium lauryl sulfate 1%, effervescent agent 38%, binder 5%, disintegrant 4%, lubricant 2%, and the balance is filler lactose.

[0034] The specific dosage of each component is shown in the table below: Preparation method: Preparation of doxycycline hydrochloride microcapsules by spray drying: a. Preparation of Bletilla striata polysaccharide solution: Weigh the prescribed amount of Bletilla striata polysaccharide, add 2752g of distilled water, and heat and stir in a 50℃ water bath to dissolve; b. Preparation of gum arabic solution: Weigh the prescribed amount of gum arabic, add 10267g of distilled water, and heat and stir in a 50℃ water bath to dissolve; c. Preparation of doxycycline hydrochloride solution: Weigh the prescribed amount of doxycycline hydrochloride, add 8000g of distilled water, and stir to dissolve; d. Primary embedding: Doxycycline hydrochloride solution was slowly added to Bletilla striata polysaccharide solution, sheared for 5 min at 10000 r / min using a high-speed disperser, and then embedded for 35 min under 25 kHz ultrasonic conditions to obtain primary embedding solution; e. Secondary embedding: The primary embedding solution is slowly added to the gum arabic solution, sheared at 12000 r / min for 8 min using a high-speed disperser, and then embedded under 30 kHz ultrasonic conditions for 45 min to obtain the secondary embedding solution. f. High-pressure homogenization: The secondary embedding solution was homogenized twice by a high-pressure homogenizer at a pressure of 40 MPa to obtain doxycycline hydrochloride homogenized solution. g. Spray drying: The homogenized solution of doxycycline hydrochloride was spray dried, with the inlet air temperature controlled at 135℃, the outlet air temperature at 58℃, and the feed rate at 5ml / min, to obtain doxycycline hydrochloride microcapsules.

[0035] 2. Preparation of alkaline particles (containing compound essential oil microcapsules) 600g of compound essential oil microcapsules were mixed with 3378g of sodium bicarbonate, 133g of sodium dodecyl sulfate, and 900g of lactose. The mixture was then moistened with 500g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air drying oven at 45°C for 1 hour, and then granulated again through a 20-mesh sieve to obtain alkaline granules for later use. 3. Preparation of acid particles (containing doxycycline hydrochloride microcapsules) The doxycycline hydrochloride microcapsules obtained in step 1 were mixed with 4222g of citric acid, 67g of sodium dodecyl sulfate, and 3600g of lactose. The mixture was then moistened with 500g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air dryer at 50°C for 1 hour, and then granulated again through a 20-mesh sieve to obtain acid granules for later use. 4. Total mixing and tableting Mix the alkaline granules obtained in step 2 with the acid granules obtained in step 3, add the remaining 900g lactose, 800g croscarmellose sodium, 400g magnesium stearate and PEG4000 mixture (mass ratio 2:5), mix thoroughly, and compress into tablets to obtain synergistic doxycycline hydrochloride effervescent tablets.

[0036] Example 2: Preparation of enhanced doxycycline hydrochloride effervescent tablets This embodiment provides an enhanced doxycycline hydrochloride effervescent tablet, which is prepared from the following raw and excipient materials by weight percentage (based on the raw and excipient ratio for 1000 enhanced doxycycline hydrochloride effervescent tablets): Doxycycline hydrochloride 11.5%, compound essential oil microcapsules 4%, Bletilla striata polysaccharide 6%, gum arabic 9%, sodium lauryl sulfate 1.5%, effervescent agent 40%, binder 5.5%, disintegrant 5%, lubricant 3%, and the balance is anhydrous glucose as filler.

[0037] The specific dosage of each component is shown in the table below: Preparation method: 1. Preparation of doxycycline hydrochloride microcapsules by spray drying: a. Preparation of Bletilla striata polysaccharide solution: Weigh the prescribed amount of Bletilla striata polysaccharide, add 6073g of distilled water, and heat and stir in a 50℃ water bath to dissolve; b. Preparation of gum arabic solution: Weigh the prescribed amount of gum arabic, add 14564g of distilled water, and heat and stir in a 50℃ water bath to dissolve; c. Preparation of doxycycline hydrochloride solution: Weigh the prescribed amount of doxycycline hydrochloride, add 11718g of distilled water, and stir to dissolve. d. Primary embedding: Doxycycline hydrochloride solution was slowly added to Bletilla striata polysaccharide solution, sheared at 10000 r / min for 7 min using a high-speed disperser, and then embedded under 30 kHz ultrasonic conditions for 40 min to obtain primary embedding solution; e. Secondary embedding: The primary embedding solution is slowly added to the gum arabic solution, sheared at 12000 r / min for 9 min using a high-speed disperser, and then embedded under 35 kHz ultrasonic conditions for 50 min to obtain the secondary embedding solution. f. High-pressure homogenization: The secondary embedding solution is homogenized twice by a high-pressure homogenizer at a pressure of 45 MPa to obtain doxycycline hydrochloride homogenized solution. g. Spray drying: The homogenized solution of doxycycline hydrochloride was spray dried, with the inlet air temperature controlled at 135℃, the outlet air temperature at 58℃, and the feed rate at 5ml / min, to obtain doxycycline hydrochloride microcapsules.

[0038] 2. Preparation of alkaline particles (containing compound essential oil microcapsules) 800g of compound essential oil microcapsules were mixed with 3556g of sodium bicarbonate, 200g of sodium dodecyl sulfate, and 483g of anhydrous glucose. The mixture was then moistened with 550g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air drying process at 45°C for 1 hour, and then granulated again through a 20-mesh sieve to obtain alkaline granules for later use. 3. Preparation of acid particles (containing doxycycline hydrochloride microcapsules) The doxycycline hydrochloride microcapsules obtained in step 1 were mixed with 4444g citric acid, 100g sodium dodecyl sulfate, and 1933g anhydrous glucose. The mixture was then moistened with 550g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air dryer at 50°C for 1 hour, and then granulated again through a 20-mesh sieve to obtain acid granules for later use. 4. Total mixing and tableting Mix the alkaline granules obtained in step 2 with the acid granules obtained in step 3, and add the remaining 484g of anhydrous glucose, 1000g of croscarmellose sodium, 600g of magnesium stearate and PEG4000 mixture (mass ratio 2:5). After thorough mixing, compress the mixture into tablets to obtain doxycycline hydrochloride effervescent tablets.

[0039] Example 3: Preparation of enhanced doxycycline hydrochloride effervescent tablets This embodiment provides an enhanced doxycycline hydrochloride effervescent tablet, which is prepared from the following raw and excipient materials by weight percentage (based on the raw and excipient ratio for 1000 enhanced doxycycline hydrochloride effervescent tablets): Doxycycline hydrochloride 15%, compound essential oil microcapsules 5%, Bletilla striata polysaccharide 7%, gum arabic 10%, sodium lauryl sulfate 2.0%, effervescent agent 42%, binder 6%, disintegrant 5%, lubricant 3%, and the balance is sucrose filler.

[0040] The specific dosage of each component is shown in the table below: Preparation method: 1. Preparation of doxycycline hydrochloride microcapsules by spray drying: a. Preparation of Bletilla striata polysaccharide solution: Weigh the prescribed amount of Bletilla striata polysaccharide, add 7933g of distilled water, and heat and stir in a 50℃ water bath to dissolve; b. Preparation of gum arabic solution: Weigh the prescribed amount of gum arabic, add 18000g of distilled water, and heat and stir in a 50℃ water bath to dissolve; c. Preparation of doxycycline hydrochloride solution: Weigh the prescribed amount of doxycycline hydrochloride, add 17000g of distilled water, and stir to dissolve; d. Primary embedding: Doxycycline hydrochloride solution was slowly added to Bletilla striata polysaccharide solution, and the mixture was sheared for 8 min at 10000 r / min using a high-speed disperser, and then embedded for 45 min under 35 kHz ultrasonic conditions to obtain the primary embedding solution. e. Secondary embedding: The primary embedding solution is slowly added to the gum arabic solution, sheared for 10 min at 12000 r / min using a high-speed disperser, and then embedded for 55 min under 45 kHz ultrasonic conditions to obtain the secondary embedding solution. f. High-pressure homogenization: The secondary embedding solution is homogenized twice by a high-pressure homogenizer at a pressure of 50 MPa to obtain doxycycline hydrochloride homogenized solution. g. Spray drying: The homogenized solution of doxycycline hydrochloride was spray dried, with the inlet air temperature controlled at 135℃, the outlet air temperature at 58℃, and the feed rate at 5ml / min, to obtain doxycycline hydrochloride microcapsules.

[0041] 2. Preparation of alkaline particles (containing compound essential oil microcapsules) 1000g of compound essential oil microcapsules were mixed with 3733g of sodium bicarbonate, 266g of sodium dodecyl sulfate, and 167g of sucrose. The mixture was then moistened with 600g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air drying process at 45℃ for 1 hour, and then granulated again through a 20-mesh sieve to obtain alkaline granules for later use. 3. Preparation of acid particles (containing doxycycline hydrochloride microcapsules) The doxycycline hydrochloride microcapsules obtained in step 1 were mixed with 4667g citric acid, 134g sodium dodecyl sulfate, and 667g sucrose. The mixture was then moistened with 600g of anhydrous ethanol solution of 5% povidone K30 to form a soft mass, which was then granulated through a 20-mesh sieve. The wet granules were dried in a forced-air dryer at 50°C for 1 hour, and then granulated again through a 20-mesh sieve to obtain acid granules for later use. 4. Total mixing and tableting Mix the alkaline granules obtained in step 2 with the acid granules obtained in step 3, add the remaining 166g sucrose, 1000g croscarmellose sodium, 600g magnesium stearate and PEG4000 mixture (mass ratio 2:5), mix thoroughly, and compress into tablets to obtain doxycycline hydrochloride effervescent tablets.

[0042] Comparative Example 1 (Previous Technology Comparison): Preparation of Ordinary Doxycycline Hydrochloride Effervescent Tablets See Example 2 of patent CN102058559B (A Doxycycline Hydrochloride Effervescent Tablet for Dairy Cows and Its Preparation Method) for the preparation of ordinary doxycycline hydrochloride effervescent tablets (based on the ratio of raw materials and excipients for 1000 ordinary doxycycline hydrochloride effervescent tablets).

[0043] The specific dosage of each component is shown in the table below: (1) Dry doxycycline hydrochloride, tartaric acid, sodium bicarbonate, polyethylene glycol 6000 and anhydrous glucose separately, pass them through an 80-mesh sieve and set aside; (2) Weigh each component in step (1) and mix them in equal increments to obtain a powder mixture; (3) Dissolve polyvinylpyrrolidone in 95% ethanol solution, mix well, and set aside; (4) Spray the ethanol solution of polyvinylpyrrolidone obtained in step (3) evenly into the powder mixture to make a soft material; (5) Add the soft material into the granulator and granulate it with a non-aqueous solvent; (6) Dry the granules obtained in step (5) at 45°C; (7) Granulate through a 20-mesh sieve, add magnesium stearate, and mix well; (8) Place the final mixture into a tablet press and compress it into tablets to obtain ordinary doxycycline hydrochloride effervescent tablets.

[0044] Comparative Example 2 (Control without compound essential oil microcapsules): Preparation of doxycycline hydrochloride effervescent tablets This comparative example is a control effervescent tablet without compound essential oil microcapsules, which was prepared based on Example 2, as follows: Formula adjustment: The compound essential oil microcapsules (800g) in Example 2 were not added; their weight was made up by an equal amount of anhydrous glucose filler. The types and amounts of all other components in the formula are exactly the same as in Example 2.

[0045] Preparation method: The preparation process and all parameters are consistent with the method described in Example 2.

[0046] Preparation of effervescent tablets (Comparative Example 3: Doxycycline hydrochloride-free microcapsule control) This comparative example is a control effervescent tablet without doxycycline hydrochloride microcapsules, which was prepared based on Example 2, as follows: Formula adjustment: "Doxycycline hydrochloride", "Bletilla striata polysaccharide", and "gum arabic" from Example 2 are not added. The weight of the above components is made up by an equal amount of anhydrous glucose as filler. The types and amounts of the remaining components in the formula are exactly the same as in Example 2.

[0047] Preparation method: The preparation process and all parameters are consistent with the method described in Example 2.

[0048] Example 4: Determination of the encapsulation efficiency of compound essential oil microcapsules Method for determining the encapsulation rate of compound essential oil microcapsules: Determination of total oil content in compound essential oil microcapsules: Weigh 0.01g of compound essential oil microcapsules and place them in a round-bottom flask. Add water and boiling stones and shake well to dissolve. Connect a volatile oil measuring device and a reflux condenser to the round-bottom flask. Then place it in an electric heating mantle and heat it to boiling. Maintain a gentle boil for 5 hours and let it stand for 1 hour. Read the amount of volatile oil. The reading is the total oil content of the compound essential oil microcapsules.

[0049] Determination of surface oil in compound essential oil microcapsules: Accurately weigh 0.5g of compound essential oil microcapsules, rinse with anhydrous ethanol, and dry in a vacuum desiccator until constant weight. Finally, weigh the mass of the dried compound essential oil microcapsules. The difference between the two masses is the amount of surface oil in the compound essential oil microcapsules.

[0050] Encapsulation rate: The difference between the total oil content and the surface oil content of the compound essential oil microcapsule is the amount of drug encapsulated in the compound essential oil microcapsule formulation. Then, the encapsulation rate is calculated using formula (1), and the drug loading is calculated using formula (2).

[0051] (4) Test results Three parallel experiments were conducted, and samples 1, 2, and 3 were prepared. The encapsulation efficiency (%) and drug loading (%) were determined, and the results are as follows: The results showed that the average encapsulation rate of the composite essential oil microcapsules prepared under the process conditions was 92.05%, and the average drug loading was 8.73%.

[0052] Example 5: In vitro release test of doxycycline hydrochloride effervescent tablets Effervescent tablets prepared in Examples 1-3 and Comparative Example 1 were used. Dissolution testing was performed according to the method described in the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Dissolution and Release Determination Method III (Small Cup Method). An aqueous solution containing 2% sodium dodecyl sulfate (SDS) was used as the dissolution medium, with a medium volume of 250 ml and a rotation speed of 25 rpm. Samples were taken at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours. The concentration of doxycycline hydrochloride in the dissolution medium was determined using high-performance liquid chromatography (HPLC), and the cumulative release rate was calculated. The results are shown in the table below, and the dissolution-release curve is shown in the figure. Figure 1 .

[0053] Doxycycline hydrochloride release rates (%) in effervescent tablets prepared in Examples 1-3 and Comparative Example 1 The doxycycline hydrochloride effervescent tablets prepared in Examples 1-3 formed numerous gel-like particles in the dissolution vessel after effervescence and disintegration, subsequently dissolving to form a gel-like substance with a certain degree of extensibility, thus exhibiting bioadhesive properties. The release rate reached 80% at 12 hours and over 93% at 24 hours, indicating that the formulation has a sustained-release effect. In contrast, the ordinary doxycycline hydrochloride effervescent tablets prepared in Comparative Example 1 achieved 80% release at 2 hours and were completely released at 6 hours, demonstrating immediate-release properties.

[0054] Example 6 Adhesion test of doxycycline hydrochloride microcapsules Determination of tissue retention: Bovine vaginal mucosa tissue was taken, rinsed clean with phosphate buffer (pH 3.0), fixed on a support, and 20 mg of doxycycline hydrochloride microcapsules or carbomer (control) prepared in Examples 1-3 were evenly sprinkled on the mucosa tissue. The sample was placed in a sealed container with a relative humidity of 92.5% (controlled by saturated sodium chloride solution) for 20 min to allow the sample to fully hydrate. The slide was then tilted at 45° and the flow rate was controlled by an infusion set. The sample was rinsed with 100 ml of phosphate buffer (pH 3.0) at a flow rate of 30 mL / min. The rinse solution was collected in a beaker of known weight, dried at 70°C to constant weight, and weighed.

[0055] Adhesion percentage calculation formula: M is the weight of the drug, g is the weight of the empty beaker, G is the total weight of the beaker and the residue after drying, and m is the weight of solid substances contained in the same volume of rinsing solution.

[0056] Results of in vitro adhesion test (n=4) (X±SD) The tissue retention rates of the three batches of samples were 83.2%, 85.1%, and 87.2%, respectively, with RSD < 5%, indicating that the doxycycline hydrochloride microcapsules had good adhesion.

[0057] Example 7: Clinical efficacy trial for treating bovine vaginitis 1. Clinical diagnostic criteria A dairy cow exhibiting any of the following symptoms is diagnosed with vaginitis: (1) Purulent secretions flow from the vulva from time to time, sticking to the hair around the vulva, tail root and buttocks; (2) Examination of the vagina reveals mild swelling, congestion, or bleeding of the vaginal mucosa; (3) Inflammation in the deep layers of the vaginal mucosa, manifested as continuous discharge of red, foul-smelling purulent secretions from the vulva, accompanied by symptoms such as arched back, tailbone, frequent urination, fever, depression, decreased appetite, and reduced milk production; vaginal examination reveals mucosal swelling, erosion, necrosis, and bleeding, with purulent secretions in the vagina.

[0058] 2. Laboratory animals The experimental dairy cows with vaginitis were selected from five dairy farms in Guangxi Zhuang Autonomous Region. All of them were diagnosed with vaginitis by vaginal dilation.

[0059] 3. Experimental Methods The diagnosed cattle were randomly divided into an experimental group and a control group.

[0060] Experimental group: Divided into 3 groups, with 30 animals in each group, and administered effervescent tablets prepared in Examples 1, 2, and 3, respectively. The administration method was one tablet every 2 days, inserted directly into the vagina.

[0061] Control group: divided into 5 groups, with 30 animals in each group: Comparative Example 1, Comparative Example 2, and Comparative Example 3: The corresponding comparative example tablets were administered once daily, one tablet at a time, directly inserted into the vagina.

[0062] Comparative Example 1-A and Comparative Example 2-A: Comparative Example 1 and Comparative Example 2 tablets were administered, one tablet every two days, directly inserted into the vagina.

[0063] 4. Diagnostic criteria for treatment efficacy (1) Cured: Clinical symptoms completely disappear; (2) Significant effect: Clinical symptoms are relieved, but not completely eliminated; (3) Ineffective: There is no significant change in clinical symptoms, the condition does not improve, or even worsens.

[0064] Explanation of the statistical method for the average number of treatment days: In clinical trials, the treatment period for each affected cow varies depending on individual efficacy. Treatment days refer to the actual number of days elapsed from the first administration date until the cow is deemed "cured." Efficacy assessment is typically conducted before each administration or at fixed observation points. For example, under a "dosing every 2 days" regimen: if a cow is deemed cured at the second observation after the first administration (i.e., the planned second administration day, 3 days after the first administration), its treatment days are recorded as 3 days. Ultimately, the average treatment days for the group = Σ (treatment days per cow) / total number of cows. This method calculates the actual time required from the start of treatment to the production of efficacy, providing a more accurate reflection of the drug's onset speed. The same applies below.

[0065] 5. Treatment Results The experimental results are shown in the table below: 6. Experimental Conclusions The experimental results show that: In Examples 1-3, the medication was administered once every two days, one tablet each time. The cure rate was over 90.00%, the effective rate was 100.00%, and the average treatment duration was 5.62-6.16 days. In Comparative Examples 1-3, the medication was administered once daily. Specifically, Comparative Example 3, containing only compound essential oil microcapsules, had a cure rate of 0% and an effective rate of 13.33%. Comparative Example 1, using ordinary doxycycline hydrochloride effervescent tablets, achieved a cure rate of 90.00% and an effective rate of 100% after an average treatment duration of 8.42 days. Comparative Example 2, using enhanced doxycycline effervescent tablets without essential oil microcapsules, achieved a cure rate of 93.33% and an effective rate of 100% after a treatment duration of 6.54 days. Comparative Examples 1-A and 2-A represent the results of comparative examples 1 and 2 administered the medication once every two days: In comparative example 1-A, the cure rate was 53.33% and the effective rate was 93.33% within an average treatment period of 9.48 days; in comparative example 2-A, the cure rate was 83.33% and the effective rate was 96.67% within an average treatment period of 7.42 days.

[0066] The data above shows that the administration of drugs once every two days in Examples 1-3 was significantly better than that in Comparative Examples 1-2, which was administered once every two days. This is evident in the average number of treatment days, cure rate, and total effective rate. The efficacy of the Example groups was stronger than that of Comparative Example 2-A, indicating that the addition of compound essential oil microcapsules has a synergistic effect. Comparative Example 3 verified that the efficacy of the compound essential oil microcapsules themselves was low, which further illustrates that the synergistic effect is not a simple additive effect. The efficacy of Comparative Example 2-A was stronger than that of Comparative Example 1-A, indicating that the effect of doxycycline hydrochloride microcapsules is stronger than that of ordinary doxycycline hydrochloride: on the one hand, the microcapsules have a sustained-release effect; on the other hand, Bletilla striata polysaccharide has adhesive properties when it comes into contact with water, ensuring that the drug can be fixed in the vagina to exert its efficacy and is not easy to flow out. During the experiment, no mucosal bleeding was found in the Example groups and Comparative Example 2 after treatment, while some other groups had blood streaks in their secretions, indicating that Bletilla striata polysaccharide played a role in hemostasis and mucosal repair. Comparative Example 1, which was administered once a day, had an average treatment duration that was approximately 2 days longer than that of Examples 1-3. Comparative Example 2, which was administered once a day, had an average treatment duration that was between that of Examples 1-3, indicating that the sustained-release, synergistic, and adhesion processes of Examples 1-3 were effective.

[0067] Example 8: Clinical efficacy trial for treating bovine endometritis 1. Clinical diagnostic criteria Endometritis can be diagnosed if any of the following conditions are met: (1) Acute catarrhal or catarrhal purulent endometritis: It often occurs within 10 days after parturition or abortion. Affected cattle sometimes arch their backs and strain, and discharge mucous or mucopurulent secretions from the vulva with a putrid odor. Systemic symptoms are not obvious. (2) Acute fibrinous endometritis: Affected cattle often strain and discharge light red or brownish-yellow secretions from the vulva, containing small pieces of grayish-white mucous tissue. They also have elevated body temperature, depression, reduced or absent appetite, cessation of rumination, and a significant decrease in milk production. (3) Necrotizing endometritis: The affected cattle strain, the vulva turns purple, and a brown or grayish-brown foul-smelling liquid is discharged from the vulva, containing putrefied and decomposed uterine mucosal fragments. The body temperature rises, the spirit is lethargic, the appetite is lost, and lactation stops. (4) Chronic endometritis: The main symptoms are repeated infertility, increased vaginal discharge during estrus, slightly cloudy (occult endometritis) or purulent discharge, and other symptoms are not obvious, so clinical diagnosis is more difficult (especially occult endometritis).

[0068] Clinical diagnosis often relies on the examination of uterine flushing reflux fluid: in cases of occult endometritis, precipitates or flocculent material can be seen in the uterine flushing reflux fluid after standing for a certain period of time; in cases of chronic catarrhal endometritis, the uterine flushing reflux fluid resembles rice water; in cases of chronic catarrhal purulent endometritis, the uterine flushing reflux fluid resembles noodle soup or rice water; and in cases of chronic purulent endometritis, the uterine flushing reflux fluid resembles thin paste or yellow pus.

[0069] 2. Laboratory animals The experimental dairy cows, consisting of 168 cows with postpartum endometritis, were selected from a large dairy farm and were clinically diagnosed with postpartum endometritis.

[0070] 3. Experimental Methods Cows diagnosed with postpartum endometritis were randomly divided into an experimental group and a control group.

[0071] The experimental group consisted of 3 groups, with 28 animals in each group, and each group was given effervescent tablets prepared in Examples 1-3. The control group was divided into 3 groups, with 28 animals in each group, and each group was given the prepared tablets of control ratios 1-3.

[0072] The administration method was uniform for all affected cattle: before treatment, the insemination device was wiped with alcohol and disinfected with ultraviolet light. The cow was restrained and its tail was fixed. After cleaning the cow's anus of dung, the vulva was rinsed with benzalkonium chloride disinfectant and dried. One tablet was then directly inserted deep into the uterus. The experimental group was given the medication once every two days, and the control group was given the medication at the same frequency.

[0073] 4. Diagnostic criteria for treatment efficacy After medication, closely monitor the affected cow's condition, changes in milk production, and uterine discharge, and perform a rectal examination. Incubate the cow at the appropriate time after estrus. Perform pregnancy diagnosis three months after insemination, and assess treatment efficacy according to the following criteria: Clinical cure: The size, shape, and texture of the uterus return to normal, contraction response is basically normal, and the mucus discharged during estrus is clear and transparent. Pregnancy following mating within the first three estrous cycles after the last medication is used as the criterion for clinical cure. Clinical improvement: The size and shape of the uterus have basically returned to normal, but the contraction response is still poor. The mucus discharged during estrus contains a small amount of flocculent material, and mating cannot result in pregnancy. Clinically ineffective: The size and shape of the uterus remain basically unchanged, the contraction response is still weak or absent, and catarrhal or catarrhal purulent mucus is still discharged during estrus.

[0074] 5. Treatment Results The experimental results are shown in the table below: The experimental results show that: In Examples 1-3, the cure rate was 89.29%-92.86%, the effective rate was 92.86%-100.00%, the average treatment duration was 6.92-7.64 days, and the conception rate after 3 months was 92.85%-96.43%. In Comparative Examples 1-3, Comparative Example 3, containing only compound essential oil microcapsules, had a cure rate of 0%, an effective rate of 14.29%, and a conception rate of 0 after 3 months. Comparative Example 1, with an average treatment duration of 9.47 days, had a cure rate of 67.86%, an effective rate of 75%, and a conception rate of 78.57% after 3 months. Comparative Example 2, with a treatment duration of 8.63 days, had a cure rate of 78.57%, an effective rate of 89.29%, and a conception rate of 82.14% after 3 months.

[0075] The data above show that the administration of drugs once every two days in Examples 1-3 was significantly better than that in Comparative Examples 1-3, which were administered once every two days. This is evident in the average treatment duration, cure rate, overall effective rate, and pregnancy rate. The efficacy of Example 2 was stronger than that of Comparative Example 2, indicating that the compound essential oil microcapsules have a synergistic effect. Comparative Example 3 verified that the compound essential oil microcapsules themselves had a low efficacy rate, further demonstrating that the synergistic effect is not a simple additive effect. The efficacy of Comparative Example 2 was stronger than that of Comparative Example 1, consistent with the results of clinical efficacy trials for treating bovine vaginitis, further demonstrating the effectiveness of the sustained-release and adhesion process of the doxycycline hydrochloride microcapsules.

Claims

1. A potentiated doxycycline hydrochloride effervescent tablet, characterized in that, It is prepared from the following raw and auxiliary materials by weight percentage, based on 100% weight: Doxycycline hydrochloride 10-15%, Complex essential oil microcapsules 3-5%, Bletilla striata polysaccharide 3-7%, Gum arabic 7-10%, Sodium dodecyl sulfate 1%–3%, Effervescent tablets 38%–42%, Adhesive 5%–6%, Disintegrant 4%–5%, Lubricant 2%–3%, The remainder is filler; The composite essential oil microcapsules are prepared by a method including the following steps: A. Mix gum arabic and purified water and stir to dissolve at 40-60°C; then add hydroxypropyl-β-cyclodextrin and low-viscosity hydroxypropyl methylcellulose E5 and continue stirring to dissolve; then add PEG 4000 and Tween 20 and stir to dissolve; finally add compound essential oil and obtain an emulsion by high-speed shearing and high-pressure homogenization. B. Spray dry the emulsion obtained in step A, controlling the outlet air temperature at 60-70°C, to obtain the composite essential oil microcapsules; The compound essential oil is a mixture of eucalyptus oil, lavender essential oil and thyme essential oil.

2. The synergistic doxycycline hydrochloride effervescent tablets according to claim 1, characterized in that, In step A of the preparation of the compound essential oil microcapsules: The mass ratio of gum arabic, hydroxypropyl-β-cyclodextrin, and low-viscosity hydroxypropyl methylcellulose E5 is (1.5–2.5):(0.8–1.2):(0.03–0.08). The mass ratio of eucalyptus oil, lavender oil and thyme oil in the compound essential oil is (3-5):(1-3):1; The ratio of the total mass of the compound essential oil to the total mass of gum arabic and hydroxypropyl-β-cyclodextrin is 1:(6-10); The amount of Tween 20 added is 0.5-2% of the total mass of the emulsion; The amount of PEG4000 added is 1-3% of the total solids in the emulsion; The total solids mass fraction of the emulsion is 12-16%; The high-pressure homogenization conditions are two-stage homogenization, using a homogenizer to homogenize once at 20~30MPa and once at 30~40MPa.

3. The synergistic doxycycline hydrochloride effervescent tablets according to claim 1 or 2, characterized in that, The doxycycline hydrochloride exists in the form of microcapsules, namely doxycycline hydrochloride microcapsules, which are prepared by a method comprising the following steps: a. Dissolve doxycycline hydrochloride in water to prepare a 15-20% solution; b. Dissolve Bletilla striata polysaccharide in water to prepare a 15-18% solution; c. Dissolve gum arabic in water to prepare a 10-12% solution; d. Mix the solution obtained in step a with the solution obtained in step b, shear at 8000-12000 r / min for 5-8 minutes, and treat with ultrasound at 25-35 kHz for 35-45 minutes to obtain a primary embedding solution; e. Mix the primary embedding solution obtained in step d with the solution obtained in step c, shear at 10000-14000 r / min for 8-10 minutes, and treat with ultrasound at 30-45 kHz for 45-55 minutes to obtain the secondary embedding solution. f. Homogenize the secondary embedding solution obtained in step e 2 to 4 times under a pressure of 40 to 50 MPa. g. Spray dry the homogenized liquid obtained in step f, controlling the inlet air temperature to 130-140℃, the outlet air temperature to 55-62℃, and the feed rate to 3-6 mL / min, to obtain the doxycycline hydrochloride microcapsules.

4. The synergistic doxycycline hydrochloride effervescent tablets according to any one of claims 1-3, characterized in that, The effervescent agent comprises an acid and an alkali, wherein the acid is citric acid and the alkali is sodium bicarbonate, and the mass ratio of the acid to the alkali is 1.2:1 to 1.3:

1.

5. The synergistic doxycycline hydrochloride effervescent tablets according to any one of claims 1-3, characterized in that, The filler is selected from lactose, anhydrous glucose, and sucrose; the disintegrant is croscarmellose sodium; the binder is an ethanol solution of povidone K30; and the lubricant is a mixture of magnesium stearate and polyethylene glycol 4000 in a mass ratio of (1.5-2.5):(4.5-5.5).

6. The synergistic doxycycline hydrochloride effervescent tablets according to any one of claims 1-3, characterized in that, Based on 100% by weight, the raw materials and auxiliary materials are formulated in any of the following weight percentages: (1) Doxycycline hydrochloride 10%, compound essential oil microcapsules 3%, Bletilla striata polysaccharide 3%, gum arabic 7%, sodium lauryl sulfate 1.0%, effervescent agent 38%, binder 5%, disintegrant 4%, lubricant 2%, and the remainder is filler lactose; (2) Doxycycline hydrochloride 11.5%, compound essential oil microcapsules 4%, Bletilla striata polysaccharide 6%, gum arabic 9%, sodium dodecyl sulfate 1.5%, effervescent agent 40%, binder 5.5%, disintegrant 5%, lubricant 3%, and the remainder is filler anhydrous glucose; (3) 15% doxycycline hydrochloride, 5% compound essential oil microcapsules, 7% Bletilla striata polysaccharide, 10% gum arabic, 2.0% sodium dodecyl sulfate, 42% effervescent agent, 6% binder, 5% disintegrant, 3% lubricant, and the remainder is sucrose filler.

7. A method for preparing synergistic doxycycline hydrochloride effervescent tablets as described in claim 4, characterized in that, Includes the following steps: S1. Prepare the composite essential oil microcapsules as described in claim 1 or 2; S2. Prepare doxycycline hydrochloride microcapsules as described in claim 3; S3. Preparation of alkaline granules: Mix the composite essential oil microcapsules obtained in step S1, the alkaline agent in all effervescent agents, 2 / 3 of the sodium dodecyl sulfate, and 1 / 6 of the filler evenly; wet with 1 / 2 of the binder to form a soft material, granulate through a sieve, and dry and granulate the resulting wet granules at 40-50°C for later use. S4. Preparation of acid granules: Mix the doxycycline hydrochloride microcapsules obtained in step S2, the acid in all the effervescent agents, the remaining sodium dodecyl sulfate, and 2 / 3 of the filler evenly; wet with the remaining binder, make a soft material, granulate through a sieve, and dry and granulate the obtained wet granules at 45-55℃ for later use. S5. Mixing and tableting: Mix the alkaline particles obtained in step S3 with the acid particles obtained in step S4, add the remaining filler, all disintegrants and all lubricants, mix thoroughly, and then compress into tablets to obtain doxycycline hydrochloride effervescent tablets.

8. The method according to claim 7, characterized in that, In steps S3 and S4, both granulation and sizing are performed using a 10-30 mesh sieve; in steps S3 and S4, the binder is an anhydrous ethanol solution of povidone K30 with a mass fraction of 4-6%.

9. Use of an enhanced doxycycline hydrochloride effervescent tablet as described in any one of claims 1-6 or an enhanced doxycycline hydrochloride effervescent tablet prepared by the method described in any one of claims 7-8 in the preparation of a medicament for treating bovine endometritis and / or vaginitis.

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