Stable and efficient doxycycline hydrochloride soluble powder and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to stable and efficient doxycycline hydrochloride soluble powder and a preparation method thereof. The efficient and stable doxycycline hydrochloride soluble powder is prepared from composite cyclodextrin, an enteric polymer, beta-carotene and a ginkgo leaf extract. Through beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin composite inclusion and enteric polymer wrapping technologies, the inclusion rate is increased, protection on phenolic hydroxyl groups / enol hydroxyl groups in doxycycline is enhanced, oxidation and hydrolysis are reduced, targeted release of intestinal tracts is realized, and drug failure caused by gastric acid stimulation is avoided.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a stable and highly efficient doxycycline hyclate soluble powder and a preparation method thereof. Background Art

[0002] Doxycycline Hyclate (also known as Doxycycline Hydrochloride) is a broad-spectrum semi-synthetic tetracycline antibiotic, which is used to treat Escherichia coli disease, Salmonella disease, Pasteurella disease caused by Gram-positive and Gram-negative bacteria in pigs and chickens, as well as respiratory diseases caused by mycoplasma. Its antibacterial spectrum is similar to that of tetracycline, and its antibacterial effect is about 10 times stronger than that of tetracycline. The structure is as follows:

[0003]

[0004] The commonly used drug form of doxycycline in clinical practice is its hydrochloride salt, which is in the physical form of crystalline powder, light yellow or yellow in color, odorless and bitter in taste. The phenolic hydroxyl group, enol group, amide group and other groups contained in the structure of doxycycline hyclate are easy to oxidize and hydrolyze; doxycycline hyclate is unstable to light in water and is easy to generate isomers, resulting in the discoloration of its solution system. For animals, especially monogastric animals, doxycycline hyclate will become ineffective due to oxidation or dissociation. Its use effect is reduced, seriously affecting the clinical use of this drug.

[0005] To solve this problem, most of the existing studies focus on making stable doxycycline hyclate preparations by means of adding complexing agents, antioxidants, making non-aqueous solvents and inner and outer packaging. Therefore, it is relatively stable when in the commercially available packaging form or during experimental packaging. Chinese Patent Application CN202111242374.0 prepares a stable doxycycline hyclate soluble powder finished product by adding the complexing agent sodium EDTA2, the antioxidant sodium citrate and citric acid; Patent CN201910482869.7 prepares a stable doxycycline hyclate soluble powder finished product by adding complexing agents such as dimercaprol and antioxidants such as vitamin B. Published Patent CN114028410A and Published Patent CN 114732783A prepare stable solvent preparations by adding complexing agents citric acid and tartaric acid, antioxidants, making non-aqueous solvents, and nitrogen-flushing preparation methods. The above solutions are not very ideal in solving the stability of doxycycline, and will still lead to a reduction in the effective content of doxycycline hyclate and poor treatment effects.

[0006] Since the current clinical use of veterinary drugs mainly adopts the group administration method, including administration by mixing in feed and administration by drinking water. Due to the advantages of simple operation, less labor input, and being applicable to groups, administration by drinking water is gradually widely used in large-scale farms. Especially for doxycycline preparations, they are mainly administered by drinking water. Therefore, finding a method to improve the stability of doxycycline hyclate in water is an urgent problem to be solved in the current field. Summary of the Invention

[0007] The object of the present invention is to overcome the problem of poor stability of doxycycline hydrochloride soluble powder in water and stomach in the prior art, and provides a highly stable doxycycline hydrochloride soluble powder and its preparation method. Through the dual protection of complex inclusion and enteric polymer, the problems of light instability of doxycycline hydrochloride in drinking water and easy oxidation or dissociation and inactivation in the stomach are solved.

[0008] On the one hand, the present invention provides a stable and efficient doxycycline hydrochloride soluble powder, and the doxycycline hydrochloride soluble powder comprises the following raw materials: doxycycline hydrochloride, complex cyclodextrin, enteric polymer, β-carotene, ginkgo biloba extract and filler.

[0009] Preferably, the complex cyclodextrin refers to a composition of β-cyclodextrin and hydroxypropyl-β-cyclodextrin.

[0010] Preferably, the enteric polymer comprises one of L100-55 and L100, preferably L100-55.

[0011] Preferably, the highly stable doxycycline hydrochloride soluble powder comprises the following raw materials in weight percentage: 5-15% of doxycycline hydrochloride, 20-30% of complex cyclodextrin, 10-15% of enteric polymer, 5-10% of β-carotene, 10-15% of ginkgo biloba extract, and the rest is glucose.

[0012] Preferably, the mass percentages of the components in the highly stable doxycycline hydrochloride soluble powder are: 8% of doxycycline hydrochloride, 25% of complex cyclodextrin, 12% of enteric polymer, 7% of β-carotene, 12% of ginkgo biloba extract, and the rest is glucose.

[0013] Preferably, the mass ratio of β-cyclodextrin to hydroxypropyl-β-cyclodextrin in the complex cyclodextrin is 1:2.

[0014] On the other hand, the present invention provides a preparation method of a stable and efficient doxycycline hydrochloride soluble powder, which specifically comprises the following method:

[0015] Step 1: Dissolve complex cyclodextrin, enteric polymer, doxycycline hydrochloride, β-carotene and ginkgo biloba extract in an ethanol-water mixed solvent to form solution A;

[0016] Step 2: Spray-dry the solution A in Step 1 to obtain powder B;

[0017] Step 3: Mix the powder B obtained in Step 2 with glucose evenly, and sieve to obtain the doxycycline hydrochloride soluble powder.

[0018] Preferably, during the spray drying in Step 2, the inlet temperature is set at 180°C and the outlet temperature is set at 60°C.

[0019] Preferably, the sieving in Step 3 refers to sieving through a 60 - 80 mesh sieve.

[0020] In a third aspect, the present invention provides a use of the aforementioned doxycycline hydrochloride soluble powder in the preparation of veterinary antibacterial drugs. The doxycycline hydrochloride soluble powder of the present invention and other pharmaceutically acceptable excipients or drug combinations can be used to prepare veterinary antibacterial drugs.

[0021] Advantages of the present invention:

[0022] 1. The doxycycline hydrochloride soluble powder provided by the present invention improves the inclusion rate through the β - cyclodextrin plus hydroxypropyl - β - cyclodextrin composite inclusion technology, enhances the protection of phenolic hydroxyl / enol hydroxyl groups in doxycycline, and reduces oxidation and hydrolysis;

[0023] 2. Enteric - coated polymer wrapping: The latest enteric - coated polymer is used for wrapping to achieve intestinal - targeted release and avoid the decomposition and invalidation of the drug caused by gastric acid stimulation;

[0024] 3. The β - carotene added in the present invention binds to hydrochloric acid through a covalent bond to enhance light stability; the ginkgo leaf extract scavenges free radicals and inhibits the oxidative decomposition of doxycycline hydrochloride caused by factors such as light. Detailed implementation manners

[0025] The present invention will be further illustrated by the following examples. Unless otherwise specified, the test methods used in the following examples are all conventional methods; the materials, reagents, etc. used, unless otherwise specified, are reagents and materials that can be obtained from commercial channels.

[0026] Preparation method of ginkgo leaf extract:

[0027] The ginkgo leaves are dried to constant weight at 50°C, pulverized and sieved through a 40 - 60 mesh sieve. They are defatted by refluxing with petroleum ether for 2 hours to remove fat - soluble impurities and then dried; at 50°C, they are further extracted with 20 times the mass of 70% ethanol for 4 hours, filtered, and the filtrate is concentrated under reduced pressure and spray - dried to obtain the ginkgo leaf extract, which is sieved through a 40 - mesh sieve and reserved.

[0028] Example 1

[0029] Table 1 Composition prescription of Example 1 (100 g)

[0030]

[0031] The specific preparation process is as follows:

[0032] Step 1: Mix 8.5 g of β - cyclodextrin, 16.5 g of hydroxypropyl - β - cyclodextrin, 12 g of L100 - 55, 10 g of doxycycline hydrochloride, 7 g of β - carotene, and 12 g of ginkgo biloba extract are dissolved in 1200 ml of ethanol - water mixed solvent (V 乙醇 :V 水 = 2:1) to form solution A;

[0033] Step 2: Spray - dry the solution A from Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain powder B;

[0034] Step 3: Mix the powder B obtained in Step 2 evenly with 34 g of glucose, and pass through an 80 - mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0035] Example 2

[0036] Table 2 Composition Prescription of Example 2 (100 g)

[0037]

[0038] The specific preparation process is as follows:

[0039] Step 1: Dissolve 7 g of β - cyclodextrin, 13 g of hydroxypropyl - β - cyclodextrin, 10 g of L100 - 55, 5 g of doxycycline hydrochloride, 5 g of β - carotene, and 10 g of ginkgo biloba extract in 1000 ml of ethanol - water mixed solvent (V 乙醇 :V 水 = 2:1) to form solution A;

[0040] Step 2: Spray - dry the solution A from Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain powder B;

[0041] Step 3: Mix the powder B obtained in Step 2 evenly with 50 g of glucose, and pass through a 60 - mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0042] Example 3

[0043] Table 3 Composition Prescription of Example 3 (100 g)

[0044]

[0045]

[0046] The specific preparation process is as follows:

[0047] Step 1: Dissolve 10 g of β - cyclodextrin, 20 g of hydroxypropyl - β - cyclodextrin, 15 g of L100 - 55, 15 g of doxycycline hydrochloride, 10 g of β - carotene, and 15 g of ginkgo biloba extract are dissolved in 2000 ml of an ethanol - water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0048] Step 2: Spray - dry the Solution A from Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0049] Step 3: Mix the Powder B obtained in Step 2 evenly with 15 g of glucose, and pass through an 80 - mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0050] Example 4

[0051] Table 4 Composition Prescription of Example 4 (100 g)

[0052]

[0053] The specific preparation process is as follows:

[0054] Step 1: Dissolve 5 g of β - cyclodextrin, 10 g of hydroxypropyl - β - cyclodextrin, 8 g of L100 - 55, 3 g of doxycycline hydrochloride, 3 g of β - carotene, and 8 g of ginkgo biloba extract in 800 ml of an ethanol - water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0055] Step 2: Spray - dry the Solution A from Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0056] Step 3: Mix the Powder B obtained in Step 2 evenly with 63 g of glucose, and pass through a 60 - mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0057] Example 5

[0058] Table 5 Composition Prescription of Example 5 (110 g)

[0059]

[0060]

[0061] The specific preparation process is as follows:

[0062] Step 1: Dissolve 12 g of β - cyclodextrin, 24 g of hydroxypropyl - β - cyclodextrin, 18 g of L100 - 55, 18 g of doxycycline hydrochloride, 13 g of β - carotene, and 18 g of ginkgo biloba extract in 3000 ml of an ethanol - water mixed solvent (V乙醇 :V 水 = 2:1) to form Solution A;

[0063] Step 2: Spray-dry the Solution A obtained in Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0064] Step 3: Mix the Powder B obtained in Step 2 evenly with 7 g of glucose, and pass through a 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0065] Comparative Example 1

[0066] Table 6 Composition Prescription of Comparative Example 1 (100 g)

[0067]

[0068] The specific preparation process is as follows:

[0069] Step 1: Dissolve 25 g of β-cyclodextrin, 12 g of L100-55, 10 g of doxycycline hydrochloride, 7 g of β-carotene, and 12 g of ginkgo biloba extract in 1000 ml of ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0070] Step 2: Spray-dry the Solution A obtained in Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0071] Step 3: Mix the Powder B obtained in Step 2 evenly with 34 g of glucose, and pass through a 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0072] Comparative Example 2

[0073] Table 7 Composition Prescription of Comparative Example 2 (100 g)

[0074]

[0075] The specific preparation process is as follows:

[0076] Step 1: Dissolve 25 g of hydroxypropyl-β-cyclodextrin, 12 g of L100-55, 10 g of doxycycline hydrochloride, 7 g of β-carotene, and 12 g of ginkgo biloba extract in 1000 ml of ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0077] Step 2: Spray-dry the Solution A obtained in Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0078] Step 3: Mix the powder B obtained in Step 2 evenly with 34 g of glucose, and sieve through an 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0079] Comparative Example 3

[0080] Table 8 Composition Prescription of Comparative Example 3 (100 g)

[0081]

[0082] The specific preparation process is as follows:

[0083] Step 1: Dissolve 8.5 g of β-cyclodextrin, 16.5 g of hydroxypropyl-β-cyclodextrin, 12 g of L100-55, 10 g of doxycycline hydrochloride, and 12 g of ginkgo leaf extract in 1000 ml of ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0084] Step 2: Spray-dry Solution A obtained in Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain powder B;

[0085] Step 3: Mix the powder B obtained in Step 2 evenly with 41 g of glucose, and sieve through an 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0086] Comparative Example 4

[0087] Table 9 Composition Prescription of Comparative Example 4 (100 g)

[0088] Component Mass (g) Doxycycline Hydrochloride 10 β-Cyclodextrin 8.5 Hydroxypropyl-β-cyclodextrin 16.5 β-Carotene 7 Ginkgo biloba Extract 12 Glucose 46

[0089] The specific preparation process is as follows:

[0090] Step 1: Dissolve 8.5 g of β-cyclodextrin, 16.5 g of hydroxypropyl-β-cyclodextrin, 17 g of L100-55, 10 g of doxycycline hydrochloride, and 12 g of ginkgo leaf extract in 1000 ml of ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0091] Step 2: Spray-dry Solution A obtained in Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain powder B;

[0092] Step 3: Mix the powder B obtained in Step 2 evenly with 34 g of glucose, and sieve through an 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0093] Comparative Example 5

[0094] Table 10 Composition Prescription of Comparative Example 5 (100 g)

[0095]

[0096] The specific preparation process is as follows:

[0097] Step 1: Dissolve 8.5 g of β-cyclodextrin, 16.5 g of hydroxypropyl-β-cyclodextrin, 12 g of L100-55, 10 g of doxycycline hydrochloride, and 7 g of β-carotene in 1000 ml of an ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0098] Step 2: Spray-dry Solution A from Step 1, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0099] Step 3: Mix the Powder B obtained in Step 2 evenly with 46 g of glucose, and pass through an 80-mesh sieve to obtain the doxycycline hydrochloride soluble powder.

[0100] Comparative Example 6

[0101] Table 11 Composition Prescription of Comparative Example 6 (100 g)

[0102]

[0103] The specific preparation process is as follows:

[0104] Step 1: Take the dried Astragalus membranaceus, crush it and pass through a 40-mesh sieve, then extract it with 15 times the mass of 70% ethanol for 4 hours. During the extraction process, the extraction temperature is 68 °C in the first half of the time (i.e., the first 2 h) and 62 °C in the second half of the time (i.e., the last 2 h). Filter, and concentrate the filtrate under reduced pressure, then spray-dry to obtain the Astragalus membranaceus extract, pass through a 40-mesh sieve, and set aside;

[0105] Step 2: Dissolve 8.5 g of β-cyclodextrin, 16.5 g of hydroxypropyl-β-cyclodextrin, 12 g of L100-55, 10 g of doxycycline hydrochloride, 7 g of titanium dioxide, and 12 g of the Astragalus membranaceus extract in 1200 ml of an ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0106] Step 3: Spray-dry Solution A from Step 2, set the inlet temperature at 180 °C and the outlet temperature at 60 °C to obtain Powder B;

[0107] Step 4: Mix the Powder B obtained in Step 3 evenly with 34 g of glucose, and pass through a 60-mesh sieve to obtain the doxycycline hydrochloride soluble powder.

[0108] Comparative Example 7

[0109] Table 12 Prescription of the Composition of Comparative Example 7 (100 g)

[0110] Component Mass (g) Doxycycline Hydrochloride 10 β-Carotene 7 Polyethyl Methacrylate 12 Ginkgo biloba Extract 12 Glucose 59

[0111] The specific preparation process is as follows:

[0112] Step 1: 12 g of polyethyl methacrylate, 10 g of doxycycline hydrochloride, 7 g of β-carotene, and 12 g of ginkgo biloba extract are dissolved in 1200 ml of ethanol-water mixed solvent (V 乙醇 :V 水 = 2:1) to form Solution A;

[0113] Step 2: Spray-dry the Solution A obtained in Step 1, set the inlet temperature at 180°C and the outlet temperature at 60°C to obtain Powder B;

[0114] Step 3: Mix the Powder B obtained in Step 2 evenly with 59 g of glucose, and pass through an 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0115] Comparative Example 8

[0116] Table 13 Prescription of the Composition of Comparative Example 8 (100 g)

[0117] Component Mass (g) Doxycycline Hydrochloride 10 Carboxymethylcellulose 8 Cellulose Acetate Phthalate 20 Tartaric Acid 2 Vitamin E 5 Anhydrous Glucose 55

[0118] The specific preparation process is as follows:

[0119] Step 1: Weigh according to the mass percentages of each component shown in Table 13, and dissolve carboxymethyl cellulose and cellulose acetate phthalate with ethanol to obtain Solution A;

[0120] Step 2: Dissolve the doxycycline hydrochloride with water, and add tartaric acid and vitamin E while stirring and mix evenly to obtain Solution B;

[0121] Step 3: Spray-dry the Solution B, set the inlet temperature at 180°C and the outlet temperature at 60°C to obtain the powder material;

[0122] Step 4: Mix the powder material evenly with the anhydrous glucose, and pass through an 80-mesh sieve to obtain the soluble powder of doxycycline hydrochloride.

[0123] Verification Example:

[0124] 1. Stability Test

[0125] 1.1 Stability of Raw Materials

[0126] The doxycycline hydrochloride in Examples 1-5 and Comparative Examples 1-8 was determined by accelerated stability test. For each example and comparative example, 6 portions of doxycycline hydrochloride soluble powder were taken, each portion being about 5 g. Simulating the market packaging, it was encapsulated with a layer of white plastic bag, externally sealed with a layer of white plastic bag, and then placed in a fiber cardboard box and placed in a constant temperature and humidity chamber at a temperature of 40±2°C; the relative humidity was 75±5%. Samples were taken every 2 months to detect related substances (detection method: using octadecylsilane-bonded silica gel as the filler (the applicable pH range should be greater than 9); using acetate buffer solution [0.25 mol / L ammonium acetate - 0.1 mol / L disodium ethylenediaminetetraacetate - triethylamine (100:10:1), adjusting the pH value to 8.8 with glacial acetic acid or ammonia water] - acetonitrile (85:15) as the mobile phase; column temperature 35°C; detection wavelength 280 nm, flow rate: 1.0 ml / min; injection volume: 20 μl, injection concentration: preparing a solution containing 0.1 mg of doxycycline per 1 ml with 0.01 mol / L hydrochloric acid solution), and the measurement results are shown in Table 14.

[0127] Table 14 Determination of Doxycycline Hydrochloride Content

[0128] Test Drug Initial 2 Months 4 Months 6 Months 8 Months 10 Months 12 Months Example 1 99.95 99.95 99.94 99.92 99.91 99.89 99.88 Example 2 99.91 99.91 99.89 99.86 99.85 99.83 99.81 Example 3 99.89 99.88 99.87 99.85 99.84 99.82 99.80 Example 4 99.88 99.88 99.86 99.85 99.84 99.82 99.81 Example 5 99.92 99.91 99.89 99.87 99.86 99.85 99.83 Comparative Example 1 99.89 99.75 99.67 99.51 99.32 99.10 98.85 Comparative Example 2 99.91 99.77 99.69 99.58 99.41 99.15 98.90 Comparative Example 3 99.90 99.70 99.51 99.32 99.11 89.88 98.42 Comparative Example 4 99.92 98.52 97.21 96.11 94.21 92.01 90.18 Comparative Example 5 99.90 99.66 99.41 99.20 99.01 98.98 98.65 Comparative Example 6 99.89 99.77 99.65 99.55 99.38 99.18 99.05 Comparative Example 7 99.88 98.32 97.01 95.20 91.22 89.63 84.32 Comparative Example 8 99.85 99.04 98.21 97.55 96.66 95.58 93.25

[0129] By comparing the data of Examples 1-5 and Comparative Examples 1-8, it can be found that the stability of the doxycycline hydrochloride soluble powder in Examples 1-5 is much better than that of the soluble powder in Comparative Examples 1-8. Especially through Comparative Example 4 and Comparative Example 7, it is found that without adding the composite inclusion-enteric polymer dual carrier, or only adding a single inclusion compound, the stability of the soluble powder is poor; and through Examples 1-5 and Comparative Examples 3, 5, and 6, it can be found that β-carotene and ginkgo biloba extract can improve the stability of doxycycline hydrochloride, and the effect is better than the combination of titanium dioxide and astragalus extract.

[0130] 1.2 Stability in Centralized Drinking Water

[0131] Taking the doxycycline hydrochloride soluble powder prepared in Examples 1-5 and Comparative Examples 1-8 of the present invention as the source, the stability of the doxycycline hydrochloride soluble powder in centralized drinking water was verified.

[0132] The specific operation of the centralized drinking water stability test is as follows: Add the doxycycline hyclate soluble powder prepared in Examples 1-5 and Comparative Examples 1-8 into water, and prepare solutions with doxycycline hyclate concentrations of 1200 mg / L and 2400 mg / L respectively (in accordance with the doxycycline hyclate drinking water dose of 300 mg / L (calculated as doxycycline) in the 2020 Edition of the Veterinary Pharmacopoeia of China, and converted according to the clinical centralized drinking water for 3 hours and 6 hours, the doxycycline hyclate aqueous solution concentrations are selected as 2400 mg / L and 1200 mg / L for centralized drinking water). Place the solution in an environment with a light intensity of 4500 lux and a temperature of 25°C. According to the detection method of doxycycline hyclate soluble powder in the 2020 Edition of the Chinese Veterinary Pharmacopoeia (the detection method is the same as above), detect the change in the content of doxycycline hyclate in the aqueous solution, detect the content of doxycycline hyclate in the solution at different placement times, and calculate the decomposition rate of doxycycline hyclate. The test results are shown in Tables 15 and 16.

[0133] Table 15 Stability Results of Centralized Drinking Water for 3 Hours (2400 mg / L)

[0134]

[0135]

[0136] Table 16 Stability Results of Centralized Drinking Water for 6 Hours (1200 mg / L)

[0137]

[0138]

[0139] As can be seen from Tables 15 and 16, the doxycycline hyclate soluble powder (Examples 1-5) of the present invention has excellent stability in drinking water and can ensure that its properties remain unchanged under strong light irradiation. Among them, it can be seen from Comparative Example 4, Comparative Example 7 and Comparative Example 8 that the combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin complex inclusion and enteric polymer has an unexpected effect on improving the drug stability; it can be seen from Comparative Example 5, Comparative Example 6 and Comparative Example 8 that β-carotene and ginkgo biloba extract have better effects than flavonoid extract, vitamin E and photosensitive material titanium dioxide in improving the drug stability, and have an unexpected synergistic effect on maintaining the drug stability.

[0140] 2. Dissolution Test

[0141] Gastrointestinal Dissolution Test

[0142] 1. Determination of Swine Gastric Dissolution:

[0143] Preparation of simulated porcine gastric juice: Take 7 mL of dilute hydrochloric acid with a concentration of 1 moL / L and add it to 1000 mL of deionized water. Adjust the pH to 1.5, add 2 g of porcine pepsin, stir and mix evenly, and filter with a 0.2 μm sterile filter head to obtain the simulated porcine gastric juice.

[0144] Experimental method: Weigh 2.0 g of the samples of Examples 1-5 and Comparative Examples 1-8 into dissolution cups respectively, add 250 mL of simulated porcine gastric juice to each, place them in a dissolution tester, set the temperature to 37 °C, and the rotation speed to 75 r / min. After reacting for 1 hour, 2 hours, and 4 hours respectively, take 10 mL of the upper reaction solution, and measure the content of doxycycline hydrochloride by high performance liquid chromatography (the chromatographic conditions are the same as the stability test conditions above). Consider that doxycycline hydrochloride may decompose in gastric juice, so the content determination includes the amount of the decomposed fragments in the doxycycline structure. The results are shown in Table 17.

[0145] Table 17 Content of doxycycline hydrochloride in simulated porcine gastric juice (%)

[0146]

[0147]

[0148] It can be seen from Table 17 that the stability of Examples 1-5 in gastric juice is significantly improved compared with Comparative Examples 1-8. Examples 1-5 are wrapped by the composite inclusion-enteric polymer double carrier technology. After reacting in simulated porcine gastric juice for 4 hours, the released content of doxycycline hydrochloride does not exceed 7%, indicating that the wrapped product is insoluble in strong acid and the outer shell is hardly damaged. While Comparative Example 4 and Comparative Example 7 use ordinary single wrapped products, and the release of doxycycline hydrochloride in gastric juice reaches more than 50%, indicating that the ordinary single-layer β-cyclodextrin has a weak protective effect on doxycycline hydrochloride in gastric juice and the coating layer is easily damaged. Comparative Example 8 only adds ordinary sustained-release agents, complexing agents and antioxidants without adding a wrapping agent, and the release rate of doxycycline hydrochloride in gastric juice reaches 90%, indicating that ordinary sustained-release agents, complexing agents and antioxidants cannot prevent the corrosion of gastric acid, further proving that the composite inclusion-enteric polymer double carrier technology of the present invention can make the drug highly stable in the stomach.

[0149] 2. Determination of porcine intestinal dissolution:

[0150] Preparation of simulated porcine intestinal juice: Take 13.6 g of potassium dihydrogen phosphate in a beaker, add 1000 mL of deionized water, stir to dissolve it completely, and adjust the pH value to 6.8 with 0.1 mol / L NaOH solution. Take 2 g of porcine pancreatic lipase, mix well, and filter with a 0.2 μm sterile filter head to obtain the simulated porcine intestinal juice.

[0151] Experimental method: Weigh 2.0 g of the samples of Examples 1 to 5 and Comparative Example 8 into dissolution cups respectively, add 250 mL of simulated porcine intestinal fluid to each, place them in a dissolution tester, set the temperature to 37 °C, and the rotation speed to 100 r / min. After reacting for 1 hour, 2 hours, and 4 hours respectively, take 10 mL of the upper-layer reaction solution and detect the content of doxycycline hydrochloride. The results are shown in Table 18.

[0152] Table 18 Content of doxycycline hydrochloride in simulated porcine intestinal fluid (%)

[0153]

[0154]

[0155] Through the data analysis of Table 17 and Table 18, it is verified that the doxycycline hydrochloride included by our composite inclusion - dual carrier technology formulation (Examples 1 to 5) remains stable under the acidic conditions of the pig stomach, is destroyed and rapidly released under the neutral conditions of the pig small intestine. After reacting for 4 hours in the simulated porcine intestinal fluid, the release amount of doxycycline hydrochloride is more than 90%, almost completely released, and it is surprisingly found through experiments that the dual protection carrier accelerates the dissolution rate of doxycycline hydrochloride in the intestinal fluid (comparison between Example 1 and Comparative Example 8). It shows that the dual carrier technology can better control the release of doxycycline hydrochloride; the protection in Comparative Example 4 and Comparative Example 7 is ordinary single cyclodextrin and enteric polymer polyethyl methacrylate. Whether under the strong acidic conditions in the stomach or the neutral conditions in the small intestine, doxycycline is easily released, and it cannot be guaranteed to effectively reach the small intestine after passing through the stomach, thus affecting the absorption of doxycycline hydrochloride in the small intestine.

[0156] Therefore, the soluble powder of doxycycline hydrochloride wrapped by the composite inclusion - enteric polymer dual carrier technology prepared by the present invention can ensure that the coating layer will not gradually absorb water and release in the pig stomach, can remain stable under strong acidic conditions, and only gradually releases the drug after reaching the small intestine, thereby exerting its efficacy. Ordinary cyclodextrin, polymer polyethyl methacrylate, and ordinary sustained-release agents, complexing agents, and antioxidants cannot achieve this effect.

[0157] 3. Efficacy test

[0158] Use the following efficacy proof test to respectively test the evaluation indexes of each group in terms of the number of ineffective cases, effective cases, cured cases, cure rate, etc.

[0159] Experimental animals: Select 30-day-old broilers with similar body weights suffering from respiratory tract infection diseases. The whole flock of broilers shows symptoms such as snoring, open-mouthed wheezing, nasal discharge with tears, and reluctance to move. Randomly divide them into 14 groups, with 30 in each group.

[0160] Experimental grouping: The first to fifth groups correspond to the doxycycline hydrochloride soluble powder prepared in Examples 1-5; the sixth to thirteenth groups are the doxycycline hydrochloride soluble powder prepared in Comparative Examples 1-8; the fourteenth group is the blank control group without adding any drugs. The above 14 groups of chicken flocks were fed in the same way. The first to thirteenth groups were treated by drinking water administration, and the fourteenth group of chicken flocks was provided with drinking water without any drugs. They were caged in 14 independent areas.

[0161] Administration method: Calculated by doxycycline hydrochloride, the administration dose of the first to thirteenth groups was 1200 mg / L, and the drug was administered by concentrated drinking water for 6 hours for 5 days. The fourteenth group was provided with drinking water without any drugs, and the others were kept the same as the first to thirteenth groups.

[0162] Pharmacodynamic evaluation: Ineffective means that the symptoms of the disease have no obvious change and remain the same as before treatment; effective means that some or all symptoms have improved and are better than before treatment; cured means that all symptoms have disappeared and the chicken has completely recovered to health, and the data is included in the effective data.

[0163] Test results:

[0164] Table 19 Various pharmacodynamic evaluation indicators

[0165] Group Number of Ineffective Number of Effective Number of Cured Cure Rate First Group 0 30 30 100％ Second Group 1 29 29 96.7％ Third Group 0 30 29 96.7％ Fourth Group 1 29 28 93.3％ Fifth Group 0 30 30 100％ Sixth Group 3 27 24 80％ Seventh Group 2 28 28 93.3％ Eighth Group 1 29 28 93.3％ Ninth Group 7 23 18 60％ Tenth Group 2 28 27 90％ Eleventh Group 1 29 28 93.3％ Twelfth Group 6 24 16 53.3％ Thirteenth Group 4 26 22 73.3％ Fourteenth Group 30 0 0 0

[0166] By analyzing the experimental data obtained in Table 19, it can be found that the cure rate of the doxycycline hydrochloride soluble powder prepared in Examples 1-5 of the present invention for chicken respiratory tract infection diseases can reach more than 90%, which is higher than that of Comparative Examples 1-8. The reason for the low cure rate in the ninth and twelfth groups is that the drug coating is single-layer or uncoated and partially decomposes and loses its efficacy under the action of the external environment or strong acidic gastric juice in the body. However, the soluble powder prepared by the double protection system (the first to fifth groups) of the present invention shows a high cure rate. During the medication period, the diseased chickens did not show any adverse or abnormal behaviors, and their food intake and drinking water were normal, indicating that the doxycycline hydrochloride soluble powder provided by the present invention is stable, efficient, has good palatability, and has a high bioavailability.

[0167] As described above, it is only a part of the embodiments of the present invention, and it is not intended to limit the present invention in other forms. Any person skilled in the art may use the above technical content as a reference for modification or transformation. These equivalent embodiments with equivalent changes. However, any simple modification, equivalent change and transformation made to the above embodiments based on the technical concept of the present invention still fall within the protection scope of the claims of the present invention.

Claims

1. A highly efficient and stable doxycycline hydrochloride soluble powder, characterized in that, The doxycycline hydrochloride soluble powder contains the following components: doxycycline hydrochloride, compound cyclodextrin, enteric polymer, β-carotene, ginkgo biloba extract and filler.

2. The highly efficient and stable doxycycline hydrochloride soluble powder according to claim 1, wherein The doxycycline hydrochloride soluble powder includes the following components in weight percentage: 5-15% of doxycycline hydrochloride, 20-30% of compound cyclodextrin, 10-15% of enteric polymer, 5-10% of β-carotene, 10-15% of ginkgo biloba extract, and the rest is glucose.

3. The highly efficient and stable doxycycline hydrochloride soluble powder according to claim 1, wherein The mass percentages of the components in the doxycycline hydrochloride soluble powder are: 8% of doxycycline hydrochloride, 25% of compound cyclodextrin, 12% of enteric polymer, 7% of β-carotene, 12% of ginkgo biloba extract, and the rest is glucose.

4. The highly efficient and stable doxycycline hydrochloride soluble powder according to claim 1, characterized in that, The compound cyclodextrin refers to a composition of β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of β-cyclodextrin to hydroxypropyl-β-cyclodextrin in the compound cyclodextrin is 1:

2.

5. The highly efficient and stable doxycycline hydrochloride soluble powder according to claim 1, wherein The enteric polymer refers to One of L100-55 and L100.

6. A preparation method of the highly efficient and stable doxycycline hydrochloride soluble powder according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: Step 1: Dissolve the compound cyclodextrin, enteric polymer, doxycycline hydrochloride, β-carotene and ginkgo biloba extract in an ethanol-water mixed solvent to form solution A; Step 2: Spray-dry the solution A obtained in Step 1 to obtain powder B; Step 3: Mix the powder B obtained in Step 2 with glucose evenly, and sieve to obtain the doxycycline hydrochloride soluble powder.

7. The preparation method of the highly efficient and stable doxycycline hydrochloride soluble powder according to claim 6, wherein, When performing the spray-drying in Step 2, set the inlet temperature at 180 °C and the outlet temperature at 60 °C.

8. The preparation method of the highly efficient and stable doxycycline hydrochloride soluble powder according to claim 6, characterized in that, The sieving in Step 3 refers to sieving through a 60-80 mesh sieve.

9. Use of a doxycycline hydrochloride soluble powder as claimed in claim 1 in the preparation of veterinary antibacterial drugs.

10. The use according to claim 9, wherein The doxycycline hydrochloride soluble powder and other pharmaceutically acceptable excipients or drugs are combined to prepare veterinary antibacterial drugs.

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