Doxycycline hydrochloride soluble powder adapting to different water qualities and preparation method thereof

Abstract

The invention discloses doxycycline hydrochloride soluble powder adapting to different water qualities and a preparation method of the doxycycline hydrochloride soluble powder, and belongs to the technical field of veterinary drug preparations. The doxycycline hydrochloride soluble powder comprises the following components in percentage by mass: 10-50% of doxycycline hydrochloride, 5-20% of an inclusion agent, 20-40% of a buffering agent, 1-5% of a complexing agent and the balance of a filling agent. The invention further provides a preparation method of the doxycycline hydrochloride soluble powder, and the prepared doxycycline hydrochloride soluble powder is good in stability under the conditions of high temperature and high humidity, can adapt to water quality and local water with different hardness and different acidity and alkalinity, can be dissolved in water with the clinical dosage of 300 times for clarification, and is high in stability in an aqueous solution.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drug preparations, and particularly relates to a doxycycline hydrochloride soluble powder suitable for different water qualities and a preparation method thereof. Background Art

[0002] Doxycycline hydrochloride, also known as doxycycline hydrochloride and deoxyoxytetracycline hydrochloride, is a second-generation semi-synthetic tetracycline derivative. It is a light yellow or yellow crystalline powder. It inhibits protein synthesis by binding to the bacterial ribosome, thereby exerting its antibacterial effect. It has a broad antibacterial spectrum and is commonly used in veterinary clinics to treat Escherichia coli disease, salmonellosis, pasteurellosis caused by Gram-positive bacteria and Gram-negative bacteria in pigs and chickens, as well as respiratory diseases caused by mycoplasmas.

[0003] On November 11, 2015, Chinese patent document CN105267977A disclosed a doxycycline soluble powder and a preparation method thereof, using beta-cyclodextrin as an inclusion agent and sodium dodecyl sulfate as a surfactant, ensuring that the doxycycline hydrochloride soluble powder has good stability under room temperature, accelerated (40°C, 70% RH), low temperature (4°C) and frozen (-10°C) conditions, but cannot ensure good stability under high temperature and high humidity conditions; Chinese patent document CN111467311A disclosed on May 2020 that the doxycycline hydrochloride soluble powder has good stability under room temperature, accelerated (40°C, 70% RH), low temperature (4°C) and frozen (-10°C) ... On February 15, a doxycycline hydrochloride soluble powder and a preparation method thereof were disclosed. The solubility of the doxycycline hydrochloride soluble powder was improved by adding anhydrous citric acid and disodium ethylenediaminetetraacetic acid, but the solubility in well water could only reach 6.6 times the clinical dosage; Chinese patent document CN111557916A disclosed a doxycycline hydrochloride soluble powder and a preparation method thereof on July 8, 2020. The stability of the aqueous solution was improved by adding propylene glycol as a dispersant and adopting a granulation process, and the dissolution rate was fast, but the preparation process was complicated.

[0004] At present, there are some shortcomings in the soluble powder of doxycycline hydrochloride. First, the solubility of doxycycline hydrochloride in local water is low; second, the aqueous solution stability of doxycycline hydrochloride is poor, and it is easy to precipitate and block the water line. The industry needs to develop a soluble powder of doxycycline hydrochloride that has good solubility in different water qualities and good aqueous solution stability. Summary of the invention

[0005] The present invention aims to solve the problems in the prior art. Doxycycline hydrochloride is encapsulated by an inclusion agent, and a buffer and a complexing agent are added to increase the solubility and stability of the drug, thereby ensuring that the drug can be dissolved and clarified at a clinical concentration of 300 times in water with different pH values ​​and hardnesses, and the content of the aqueous solution is stable.

[0006] To achieve the above purpose, the specific technical solution of the present invention is as follows:

[0007] In one aspect, the present invention provides a doxycycline hydrochloride soluble powder adaptable to different water qualities, wherein the soluble powder comprises doxycycline hydrochloride, a inclusion agent, a buffer, a complexing agent, and a filler.

[0008] The doxycycline hydrochloride soluble powder comprises, by mass percentage, 10-50% of doxycycline hydrochloride, 5-20% of inclusion agent, 20-40% of buffer, 1-5% of complexing agent, and the remainder is filler.

[0009] Preferably, the doxycycline hydrochloride soluble powder comprises, by mass percentage, 10-50% doxycycline hydrochloride, 5-10% inclusion agent, 20-30% buffer, 2-4% complexing agent, and the remainder is filler.

[0010] The inclusion agent is selected from one or more of beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutyl beta-cyclodextrin.

[0011] Preferably, the inclusion agent is sulfobutyl-beta-cyclodextrin.

[0012] The buffer is selected from two or more of dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, malic acid, tartaric acid, and citric acid.

[0013] Preferably, the buffer is disodium hydrogen phosphate and citric acid, wherein the mass ratio of disodium hydrogen phosphate to citric acid is (0.5-2):(0.5-2).

[0014] Preferably, the weight ratio of disodium hydrogen phosphate to citric acid in the buffer is 1:1.

[0015] The complexing agent is selected from one or more of sodium hexametaphosphate, disodium ethylenediaminetetraacetate, disodium calcium ethylenediaminetetraacetate, and diethylenetriaminepentaacetic acid.

[0016] Preferably, the complexing agent is disodium ethylenediaminetetraacetate.

[0017] The filler is selected from one or more of lactose, anhydrous glucose, sucrose and soluble starch.

[0018] A preferred formulation is: the doxycycline hydrochloride soluble powder comprises, by mass percentage, 10-50% doxycycline hydrochloride, 5-10% sulfobutyl beta-cyclodextrin, 10-15% disodium hydrogen phosphate, 10-15% citric acid, 2-4% disodium edetate, and the balance is anhydrous glucose.

[0019] In another aspect, the present invention also provides a method for preparing a doxycycline hydrochloride soluble powder suitable for different water qualities, comprising the following steps:

[0020] (1) putting the prescribed amount of doxycycline hydrochloride and the inclusion agent into a pulverizer, crushing and screening, and then putting them into a three-dimensional mixer and mixing them evenly to obtain a doxycycline hydrochloride inclusion compound;

[0021] (2) grinding and sieving the prescribed amount of buffer and complexing agent, putting them into a three-dimensional mixer, and mixing them with the doxycycline hydrochloride inclusion complex obtained in step (1) to obtain a mixture;

[0022] (3) The filler is sieved and then put into a three-dimensional mixer to mix with the mixture in step (2). After the mixing is completed, doxycycline hydrochloride soluble powder is obtained.

[0023] The rotation speed of the three-dimensional mixer in step (1), step (2) and step (3) is 20-60 rpm, the mixing time is 5-20 min, and the sieve mesh number is 60-100 mesh.

[0024] Beneficial effects:

[0025] 1. The doxycycline hydrochloride soluble powder prepared by the present invention uses an inclusion agent to include doxycycline hydrochloride, has high stability under room temperature, high temperature and high humidity environment, and ensures the effectiveness of the product during storage and transportation.

[0026] 2. The doxycycline hydrochloride soluble powder prepared by the present invention ensures that doxycycline hydrochloride can adapt to water of different hardness and different pH values ​​by adding an acid-base buffer system and a chelating agent, and also improves the antioxidant property of doxycycline, effectively solving the problem of poor solubility of doxycycline hydrochloride in local water.

[0027] 3. The doxycycline hydrochloride soluble powder prepared by the present invention is soluble in water and clear at a clinical dose of 300 times, and the aqueous solution has high stability.

[0028] 4. The preparation process of the doxycycline hydrochloride soluble powder of the present invention is simple and can be industrialized. DETAILED DESCRIPTION

[0029] The above contents will be further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter being limited to the following embodiments. All technologies realized based on the contents of the present invention are within the scope.

[0030] Example 1

[0031] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0032] Table 1 10% content specification prescription

[0033]

[0034] Example 2

[0035] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0036] Table 2 10% content specification prescription

[0037]

[0038]

[0039] Example 3

[0040] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0041] Table 3 10% content specification prescription

[0042]

[0043] Example 4

[0044] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0045] Table 4 10% content specification prescription

[0046] Element Name of raw materials Addition amount Active ingredients Doxycycline hydrochloride 100g(converted content) Inclusion agent Sulfonyl-Beta-Cyclodextrin 50g Complexing agent Disodium EDTA 20g Fillers Anhydrous glucose Add to 1000g

[0047] Example 5

[0048] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0049] Table 5 20% content specification prescription

[0050]

[0051] Example 6

[0052] A doxycycline hydrochloride soluble powder, the specific composition of which is as follows:

[0053] Table 6 50% content specification prescription

[0054]

[0055] Example 1-6 Preparation process:

[0056] Step 1, putting the prescribed amount of doxycycline hydrochloride and inclusion agent into a grinder, crushing them, passing through an 80-mesh sieve, putting them into a three-dimensional mixer, mixing at 45 rpm for 10 minutes, to obtain a doxycycline hydrochloride inclusion compound;

[0057] Step 2, the prescribed amount of buffer and complexing agent are put into a grinder and crushed, then passed through an 80-mesh sieve, and put into a three-dimensional mixer at 45 rpm for 10 minutes;

[0058] Step 3, pass the prescribed amount of anhydrous glucose through an 80-mesh sieve, put it into a three-dimensional mixer, and continue mixing at 45 rpm for 20 minutes to obtain doxycycline hydrochloride soluble powder suitable for different water qualities.

[0059] Example 7 Solubility Comparative Test

[0060] (1) Preparation of different water qualities

[0061] Soft water (hardness standard 0-150 mg / L): Weigh 0.045 g of anhydrous calcium chloride and 0.020 g of magnesium chloride with crystal water into a 1000 mL volumetric flask, dissolve and dilute to the scale with distilled water to obtain water with a hardness of 50 mg / L.

[0062] Moderately hard water (hardness standard 151 ~ 300 mg / L): weigh 0.152g of anhydrous calcium chloride and 0.070g of magnesium chloride with crystal water into a 1000mL volumetric flask, dissolve and dilute to the scale with distilled water to obtain water with a hardness of 170mg / L.

[0063] Hard water (hardness standard 301 ~ 450 mg / L): weigh 0.304g of anhydrous calcium chloride and 0.139g of magnesium chloride with crystal water into a 1000mL volumetric flask, dissolve and dilute to the scale with distilled water to obtain water with a hardness of 340mg / L.

[0064] Weakly acidic water (pH = 4-6): Take an appropriate amount of purified water and adjust the pH value to 5.0 ± 0.2 with hydrochloric acid solution.

[0065] Weakly alkaline water (pH = 7-9): Take an appropriate amount of purified water and adjust the pH value to 8.0 ± 0.2 with sodium hydroxide solution.

[0066] Local water 1-3: groundwater in a county in Henan, well water in Shandong, and mountain spring water in Guangdong.

[0067] (2) Take an appropriate amount of the doxycycline hydrochloride soluble powder of Examples 1-6 (equivalent to approximately 0.03 g and 3 g of doxycycline), accurately weigh it, add it to 100 mL of water of different hardness and pH and local water 1-3, respectively, stir for 3 minutes to dissolve, and observe the dissolution of 1 times and 300 times the clinical dose.

[0068] (3) Experimental results: The results of the solubility comparison test of 1 times the clinical dose in Table 7 show that the samples prepared by Examples 1, 3, and 4 of the present invention have poor solubility in water of different hardness, water of different pH values, and local water 1-3; the samples of Examples 2, 5, and 6 have good solubility in water of different hardness, water of different pH values, and local water 1-3, and no flocs are precipitated.

[0069] The results of the solubility comparison test at 300 times the clinical dose in Table 8 show that the sample prepared by Example 1 of the present invention has poor solubility in hard water, weak alkaline water, local waters 2 and 3; the samples of Examples 3 and 4 have poor solubility in weak alkaline water, local waters 2 and 3; the samples of Examples 2, 5, and 6 have good solubility in waters of different hardness, waters of different pH values, and local waters 1-3, without precipitation of flocs.

[0070] Table 7 Comparative test results of solubility at 1 times clinical dose

[0071]

[0072] Table 8 Solubility comparison test results of 300 times clinical dose

[0073]

[0074] Example 8 Comparative test of aqueous solution stability

[0075] Take an appropriate amount of the doxycycline hydrochloride soluble powder of Examples 1-6 (approximately equivalent to 0.03 g of doxycycline), accurately weigh it, add it to 100 mL of water of different hardness and pH and local water 1-3 (the water quality is as described in Example 7), stir for 3 minutes to dissolve, and detect the content of doxycycline hydrochloride at 0, 3, 6, 12, and 24 hours after stirring.

[0076] The results in Table 9 show that the labeled contents of the samples prepared in Examples 1, 3 and 4 of the present invention decreased significantly after being dissolved in water of different hardness and pH values ​​and local aqueous solutions, and the stability was poor; the labeled contents of the samples prepared in Examples 2, 5 and 6 did not change significantly in water of different hardness and pH values ​​and local aqueous solutions, and were relatively stable.

[0077] Table 9 Comparative test of aqueous solution stability

[0078]

[0079]

[0080] Example 9 Stability Test

[0081] The samples prepared in Examples 1-6 were packaged in polyethylene terephthalate / aluminum / polyethylene composite packaging bags and then subjected to influencing factor tests, long-term tests and accelerated tests to observe the stability of the soluble powder of the present invention and to confirm whether there were any unstable phenomena such as discoloration, caking, aging, etc.

[0082] (1) Influencing factor test

[0083] The samples prepared in Examples 1-6 were packaged in composite packaging bags and placed in a high temperature (60° C.) and high humidity (25° C., RH 90%±5%) environment. Samples were taken on the 5th and 10th days to observe the properties and detect the concentration of doxycycline hydrochloride.

[0084] The results in Table 10 show that Example 1 slightly agglomerated after 5 days of high temperature and high humidity, and its stability was poor; Examples 2-6 looked the same as before, without discoloration, agglomeration, etc., and the content did not change significantly, indicating that the soluble powder had good stability under high temperature and high humidity conditions.

[0085] Table 10 Test results of influencing factors

[0086]

[0087] (2) Long-term test

[0088] The samples prepared in Examples 1-6 were packaged in composite packaging bags and placed in an environment of 25±2°C and RH60%±10% for 30 months. Samples were taken at 3, 6, 9, 12, 18, and 24 months to observe the properties and detect the concentration of doxycycline hydrochloride. The results showed that Example 1 had slight caking after 24 months, and the content decreased significantly, indicating that the long-term stability was poor; Examples 2-6 had the same appearance after 24 months, without discoloration, caking, etc., and the contents of Examples 2, 5, and 6 did not change significantly, indicating that the stability was good at room temperature.

[0089] Table 11 Long-term test results

[0090]

[0091]

[0092] (3) Accelerated test

[0093] The samples prepared in Examples 1-6 were packaged in composite packaging bags and stored in an accelerated box at 40±2°C and RH75%±5% for 6 months. Samples were taken at 1, 2, 3, and 6 months to observe the properties and detect the concentration of doxycycline hydrochloride. The results showed that Example 1 had slight caking after 6 months of acceleration, and the content decreased significantly, indicating that the thermal storage stability was poor; Examples 2-6 had no discoloration, caking, etc. after 6 months of acceleration, and the contents of Examples 2, 5, and 6 did not change significantly, indicating that the thermal storage stability was good.

[0094] Table 12 Accelerated test results

[0095]

[0096] The present invention has been described in detail above through specific implementation methods and examples, but it should be understood that these descriptions do not constitute any limitation to the scope of the present invention. Without departing from the spirit and protection scope of the present invention, the technical solution and implementation methods of the present invention may be modified, improved and replaced in various ways, all of which fall within the protection scope of the present invention.

Claims

1. A doxycycline hydrochloride soluble powder adapted to different water qualities, characterized in that: The soluble powder contains doxycycline hydrochloride, a inclusion agent, a buffer, a complexing agent and a filler.

2. The soluble powder according to claim 1, characterized in that The soluble powder comprises, by mass percentage, 10-50% of doxycycline hydrochloride, 5-20% of inclusion agent, 20-40% of buffer, 1-5% of complexing agent, and the remainder is filler.

3. The soluble powder according to claim 2, characterized in that The soluble powder comprises, by mass percentage, 10-50% of doxycycline hydrochloride, 5-10% of inclusion agent, 20-30% of buffer, 2-4% of complexing agent, and the remainder is filler.

4. The soluble powder according to any one of claims 1 to 3, characterized in that: The inclusion agent is selected from one or more of beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutyl beta-cyclodextrin.

5. The soluble powder according to any one of claims 1 to 3, characterized in that: The buffer is selected from two or more of dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, malic acid, tartaric acid, and citric acid.

6. The soluble powder according to any one of claims 1 to 3, characterized in that: The buffer is disodium hydrogen phosphate and citric acid; wherein the weight ratio of disodium hydrogen phosphate to citric acid is (0.5-2):(0.5-2).

7. The soluble powder according to any one of claims 1 to 3, characterized in that: The complexing agent is selected from one or more of sodium hexametaphosphate, disodium ethylenediaminetetraacetate, disodium calcium ethylenediaminetetraacetate, and diethylenetriaminepentaacetic acid.

8. The soluble powder according to any one of claims 1 to 3, characterized in that: The filler is selected from one or more of lactose, anhydrous glucose, sucrose, and soluble starch.

9. A method for preparing a doxycycline hydrochloride soluble powder adapted to different water qualities as claimed in any one of claims 1 to 3, comprising the following steps: (1) putting the prescribed amount of doxycycline hydrochloride and the inclusion agent into a grinder, crushing and screening, and then putting them into a three-dimensional mixer and mixing them evenly to obtain a doxycycline hydrochloride inclusion compound; (2) grinding and sieving the prescribed amount of buffer and complexing agent, putting them into a three-dimensional mixer, and mixing them with the doxycycline hydrochloride inclusion complex obtained in step (1) to obtain a mixture; (3) The filler is sieved and then put into a three-dimensional mixer and mixed with the mixture in step (2) to obtain doxycycline hydrochloride soluble powder.

10. The preparation method according to claim 9, characterized in that: The rotation speed of the three-dimensional mixer in step (1), step (2) and step (3) is 20-60 rpm, the mixing time is 5-20 min, and the sieve mesh number is 60-100 mesh.

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