Doxycycline hydrochloride oral paste and preparation method thereof

Abstract

The invention provides a doxycycline hydrochloride oral paste and a preparation method thereof. The doxycycline hydrochloride oral administration paste is prepared from the following components: doxycycline hydrochloride, a complexing agent, a capsule wall material, medicinal auxiliary materials and purified water. The doxycycline hydrochloride oral paste is stable in property, small in irritation, remarkable in drug effect, high in bioavailability, easy to take and simple in preparation method, and meets the requirement of large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of veterinary drug preparations, and in particular to a doxycycline hydrochloride oral paste and a preparation method thereof. Background Art

[0002] Doxycycline hydrochloride is a tetracycline antibiotic widely used in veterinary clinics, and has good antibacterial effects on a variety of Gram-positive and Gram-negative bacteria. However, existing doxycycline hydrochloride preparations are mainly in the form of injections, soluble powders, tablets or capsules. Injections have a safety hazard of large muscle irritation, while soluble powders, tablets, capsules, etc. may cause swallowing difficulties for some pets (such as dogs and cats), especially young or old pets.

[0003] Therefore, it is of great practical significance to develop a doxycycline hydrochloride preparation that is highly stable, easy to take, has significant efficacy, and has little gastrointestinal irritation. Summary of the invention

[0004] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a doxycycline hydrochloride internal paste and a preparation method thereof. The doxycycline hydrochloride internal paste of the present invention has stable properties, low irritation, significant drug efficacy, high bioavailability, is easy to take, and the preparation method is simple, which is suitable for large-scale production needs.

[0005] In a first aspect, the present invention provides a doxycycline hydrochloride internal paste, comprising the following components: doxycycline hydrochloride, a complexing agent, a capsule material, a pharmaceutical excipient and purified water.

[0006] In some embodiments, the complexing agent includes a zinc compound.

[0007] Compared with other metal ion complexing agents, zinc compounds and doxycycline hydrochloride can form complexes that are highly stable to high temperature, high humidity and light.

[0008] In some embodiments, the zinc compound is selected from one or more of zinc acetate, zinc sulfate, zinc chloride, amino acid chelated zinc, zinc gluconate and zinc oxide.

[0009] In some embodiments, the capsule material is selected from one or more of gelatin, gum arabic, sodium alginate, chitosan, polylysine, albumin, and the like.

[0010] In some embodiments, the pharmaceutical excipient is selected from one or more of fish oil, soybean oil, corn oil, vitamin E oil, olive oil, maltose syrup, whey protein powder, polyethylene glycol, an emulsifier or a thickener.

[0011] In some embodiments, the emulsifier is selected from egg yolk lecithin.

[0012] In some embodiments, the thickener is selected from sodium carboxymethyl cellulose and / or sodium alginate.

[0013] In some embodiments, the molar ratio of the complexing agent to the doxycycline hydrochloride is 0.1-2, for example, 0.2, 0.5, 0.8, 1.1, 1.4, 1.7, 2 or any value therebetween.

[0014] In some embodiments, the ratio of the mass of the capsule material to the sum of the masses of the doxycycline hydrochloride and the complexing agent is 1:2-2:1, for example, 1:2, 1:1.5, 1:1, 1.5:1, 2:1 or any value therebetween.

[0015] In some embodiments, the doxycycline hydrochloride composition comprises 80-200 parts of doxycycline hydrochloride, 30-150 parts of a complexing agent, and 10-60 parts of a capsule material, by weight.

[0016] In some embodiments, the doxycycline hydrochloride composition comprises 80 parts, 100 parts, 120 parts, 140 parts, 160 parts, 180 parts, 200 parts of doxycycline hydrochloride or any value therebetween, by weight.

[0017] In some embodiments, the doxycycline hydrochloride composition comprises 30 parts, 50 parts, 70 parts, 90 parts, 110 parts, 130 parts, 150 parts or any value therebetween of the complexing agent by weight.

[0018] In some embodiments, the doxycycline hydrochloride composition comprises 10 parts, 20 parts, 30 parts, 40 parts, 50 parts, 60 parts of capsule material or any value therebetween, by weight.

[0019] In some embodiments, the mass ratio of the doxycycline hydrochloride composition to the pharmaceutical excipient is 5:1-1:5, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or any value therebetween.

[0020] In some embodiments, the doxycycline hydrochloride internal paste further comprises a flavoring agent and / or a preservative.

[0021] In some embodiments, the flavoring agent is selected from one or more mixtures of sucrose, fructose, maltose syrup, cane molasses, edible flavoring, chicken liver powder, pork liver powder, beef powder or chicken powder.

[0022] In some embodiments, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, sodium benzoate or potassium sorbate.

[0023] In a second aspect, the present invention provides a method for preparing the doxycycline hydrochloride oral paste according to the first aspect of the present invention, comprising the following steps:

[0024] (1) preparing microcapsules using a suspension comprising a doxycycline hydrochloride complex, a capsule material and purified water; solidifying the microcapsules to obtain doxycycline hydrochloride complex microcapsules;

[0025] (2) Mixing the doxycycline hydrochloride complex microcapsules with pharmaceutical excipients to obtain the doxycycline hydrochloride oral paste.

[0026] In some embodiments, the mass ratio of the capsule material to the complex of doxycycline hydrochloride is 1:2-2:1, for example, 1:2, 1:1.5, 1:1, 1.5:1, 2:1 or any value therebetween.

[0027] The mass ratio of the doxycycline hydrochloride complex microcapsules to the pharmaceutical excipients is 5:1-1:5, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or any value therebetween.

[0028] In some embodiments, the method for preparing the doxycycline hydrochloride complex comprises: complexing an aqueous solution of doxycycline hydrochloride with an aqueous solution of a complexing agent, and drying after the complexation is complete.

[0029] In some embodiments, the drying may be spray drying.

[0030] In some embodiments, the complexing is performed at a pH of 4.0-6.5.

[0031] In some embodiments, the pH of complexation is 4.0, 4.2, 4.5, 4.8, 5.0, 5.2, 5.5, 5.7, 6.0, 6.2, 6.5, or any value therebetween.

[0032] In some embodiments, the complexing is performed at a pH of 5.0-6.5.

[0033] In some embodiments, the pH of the complexation is adjusted with sodium bicarbonate solution.

[0034] In some embodiments, the mass concentration of the sodium bicarbonate solution is 0.1-2%, for example, 0.2%, 0.5%, 0.8%, 1.1%, 1.4%, 1.7%, 2% or any value therebetween.

[0035] In some embodiments, the concentration of the sodium bicarbonate solution is 1%.

[0036] In some embodiments, the method for preparing doxycycline hydrochloride complex microcapsules comprises:

[0037] S1, mixing the doxycycline hydrochloride complex with the capsule material aqueous solution to obtain a suspension;

[0038] S2, adjusting the pH of the suspension to 3.0-5.0 to form microcapsules;

[0039] S3, solidifying the microcapsules to obtain the doxycycline hydrochloride complex microcapsules.

[0040] In some embodiments, in step S1, the mixing temperature is 40-60°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C or any value therebetween.

[0041] In some embodiments, in step S1, the mixing temperature is 40-50°C.

[0042] In some embodiments, the mass concentration of the capsule material aqueous solution is 1-10%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or any value therebetween.

[0043] In some embodiments, in step S2, the pH is adjusted using an acetic acid solution.

[0044] In some embodiments, in step S3, the curing temperature is 0-30°C, for example, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C or any value therebetween.

[0045] In some embodiments, in step S3, the solidifying solvent is a formaldehyde solution.

[0046] In some embodiments, the mass concentration of the formaldehyde solution is 20-45%, for example, 20%, 25%, 30%, 35%, 40%, 45% or any value therebetween.

[0047] In some embodiments, the solidification is performed at a pH of 8-9.

[0048] In some embodiments, the pH is adjusted using sodium hydroxide solution.

[0049] In some embodiments, the mass concentration of the sodium hydroxide solution is 10-30%, for example, 10%, 15%, 20%, 25%, 30% or any value therebetween.

[0050] In some embodiments, the method for preparing the doxycycline hydrochloride internal paste comprises the following steps:

[0051] (A) preparing a complex: complexing a doxycycline hydrochloride solution with a zinc compound solution at a pH value of 4.0-6.5, and spray drying after the complexation is complete to obtain a doxycycline hydrochloride-zinc complex;

[0052] (B) Preparation of microcapsules: taking purified water and heating it to 40-60° C., adding capsule materials to prepare a solution of appropriate concentration, adding doxycycline hydrochloride-zinc complex, stirring evenly to obtain a suspension, adding acetic acid solution, adjusting the pH value to 3.0-5.0, continuing to stir until microcapsules are formed, adding water to dilute the microcapsules to precipitate, adding formaldehyde solution to solidify, and finally washing with water until there is no formaldehyde to obtain doxycycline hydrochloride-zinc complex microcapsules;

[0053] (C) Preparation of paste: Add the emulsifier, thickener, excipients and water in the pharmaceutical excipients into an emulsifying pot, homogenize and emulsify, then add the doxycycline hydrochloride-zinc complex microcapsules, flavoring agents and preservatives, homogenize and stir evenly to eliminate bubbles, and after passing the inspection, fill and package to obtain the paste.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] (1) The complex formed by doxycycline hydrochloride and the complexing agent has high stability to high temperature, high humidity and light;

[0056] (2) Using microcapsule materials to encapsulate and oxidatively isolate the doxycycline hydrochloride complex to achieve dual stabilization and reduce gastrointestinal irritation;

[0057] (3) The nutrient paste is prepared by combining with a flavoring agent with good palatability and is sealed in a quantitative container, which is easy for pets such as dogs and cats to take, thereby solving the shortcomings of other doxycycline hydrochloride preparations (such as injections, soluble powders, tablets, and capsules) such as poor stability, high irritation, and difficulty in swallowing. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 Graphs showing high temperature test results of doxycycline hydrochloride and the doxycycline hydrochloride internal paste obtained in Example 10;

[0059] Figure 2 This is a diagram showing the results of a strong light irradiation experiment of doxycycline hydrochloride and the doxycycline hydrochloride internal paste obtained in Example 10;

[0060] Figure 3 It is a graph showing the results of accelerated tests on doxycycline hydrochloride and the doxycycline hydrochloride paste for oral administration obtained in Example 10;

[0061] Figure 4 The content change diagram of doxycycline hydrochloride and the doxycycline hydrochloride internal paste obtained in Example 10 after being placed for different time periods;

[0062] Figure 5The figure is a graph showing the changes in the contents of related substances in doxycycline hydrochloride and the doxycycline hydrochloride oral paste obtained in Example 10 after being placed for different periods of time. DETAILED DESCRIPTION

[0063] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments and drawings. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

[0064] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0065] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments and equipment used in the following examples, etc., can all be purchased on the market or can be obtained by existing methods; the reagent amounts, unless otherwise specified, are the reagent amounts used in conventional experimental operations; the experimental methods, unless otherwise specified, are all conventional methods.

[0066] The oral paste described in the present invention refers to a semi-solid paste preparation, which actually refers to an ointment containing a large amount of powder.

[0067] The microcapsule described in the present invention refers to a microcapsule formed by encapsulating the powder of the doxycycline hydrochloride complex in a capsule material.

[0068] The room temperature in the present invention refers to 10-30°C.

[0069] 1. Complex Preparation

[0070] Example 1

[0071] Take 100 g of doxycycline hydrochloride, add 1000 mL of purified water and stir until dissolved; take 120 g of zinc sulfate heptahydrate, add 1000 mL of purified water and stir until dissolved; mix the two liquids, adjust the pH to 6.0-6.3 with 1% sodium bicarbonate, stir for 2 hours to complete the complexation, centrifuge at 3000 rpm for 20 minutes, discard the supernatant, and spray-dry the lower layer of the separated product into powder, i.e., doxycycline hydrochloride-zinc complex powder.

[0072] Example 2

[0073] Take 150 g of doxycycline hydrochloride, add 1000 mL of purified water and stir until dissolved; take 85 g of zinc chloride, add 1000 mL of purified water and stir until dissolved; mix the two liquids, adjust the pH value to 5.0-5.5 with 0.1% sodium hydroxide, continue stirring for 2 hours to complete the complexation, centrifuge at 3500 rpm for 25 minutes, discard the supernatant, and spray-dry the lower layer of the separated product to obtain a component powder, i.e., doxycycline hydrochloride-zinc complex powder.

[0074] Example 3

[0075] Take 100 g of doxycycline hydrochloride, add 1000 mL of purified water and stir until dissolved; take 34 g of zinc oxide, add 1000 mL of purified water and stir to form a suspension; mix the two liquids, adjust the pH value to 5.6-6.0 with 0.1% sodium carbonate, continue stirring for 3 hours to complete the complexation, add dilute hydrochloric acid to adjust the pH value to 1.5-2.0, stir evenly, centrifuge at 3000 rpm for 25 minutes, discard the supernatant, and spray-dry the lower layer of the separated product into powder, i.e., doxycycline hydrochloride-zinc complex powder.

[0076] Example 4

[0077] Take 100 g of doxycycline hydrochloride, add 1000 mL of purified water and stir until dissolved; take 55 g of copper sulfate pentahydrate, add 1000 mL of purified water and stir until dissolved; mix the two liquids, adjust the pH to 6.0-6.3 with 1% sodium bicarbonate, stir for 2 hours to complete the complexation, centrifuge at 3000 rpm for 20 minutes, discard the supernatant, and spray-dry the lower layer of the separated product into powder, i.e., doxycycline hydrochloride-copper complex powder.

[0078] Example 5

[0079] Take 100 g of doxycycline hydrochloride, add 1000 mL of purified water and stir until dissolved; take 35 g of aluminum hydroxide, add 1000 mL of purified water and stir until evenly dispersed; mix the two liquids, adjust the pH to 6.0-6.3 with 1% sodium bicarbonate or dilute hydrochloric acid, stir for 2 hours to complete the complexation, centrifuge at 3000 rpm for 20 minutes, discard the supernatant, and spray-dry the lower layer of the separated product into powder, i.e., doxycycline hydrochloride-aluminum complex powder.

[0080] 2. Microcapsule Preparation

[0081] Example 6

[0082] 1000 mL of purified water was heated to 45° C., divided into two portions, 500 mL each, and 15 g of gum arabic and 15 g of gelatin were added respectively, stirred until dissolved, to obtain a 3% gum arabic solution and a 3% gelatin solution; 15 g of the doxycycline hydrochloride-zinc complex powder obtained in Example 1 was added to the 3% gum arabic solution, homogenized for 15 minutes to form a suspension, and the prepared 3% gelatin solution was added, the gelatin solution was kept at about 45° C., stirring was continued, and the pH value was adjusted to 4.1-4.3 with 5% acetic acid solution, and stirring was continued until microcapsules were formed. After the capsules were formed, 2000 mL of purified water with a slightly lower temperature was added, and stirring was continued. When the temperature dropped to below 30° C., it was moved to an ice bath (below 5° C.) and stirring was continued, and 10 mL of 37% formaldehyde solution was added, and stirring was performed to solidify and set the shape, and the pH value was adjusted to 8.0-8.5 with 10% sodium hydroxide to reduce the pores of the gel, and stirring was continued for 30 minutes. Add 40 mL of 10% raw starch suspension, stir at about 10° C. for another hour, collect the microcapsules by suction filtration, wash with water until there is no formaldehyde, and set aside.

[0083] Example 7

[0084] Take 30g of gelatin and add purified water to make a 5% solution; take 20g of the doxycycline hydrochloride-zinc complex obtained in Example 2, add 1000mL of 5% gelatin solution, heat to 40-45°C, stir to form a suspension, adjust the pH value to 3.5-3.8 with 10% acetic acid solution, add 60% sodium sulfate solution, continue stirring to form microcapsules, add 2000mL of purified water after capsule formation, continue stirring, after the temperature drops to room temperature, move to an ice bath (below 5°C) and continue stirring, add 15mL of 37% formaldehyde solution, stir to solidify and fix, and adjust the pH from the solution to 8.0-8.8 with 20% sodium hydroxide, continue stirring for 30 minutes, return to the temperature to about 10°C and stir for another hour, collect the microcapsules by suction filtration, wash with water until there is no formaldehyde, and set aside.

[0085] Example 8

[0086] 1000 mL of purified water was heated to 45° C., divided into two portions, 500 mL each, and 15 g of gum arabic and 15 g of gelatin were added respectively, stirred until dissolved, to obtain a 3% gum arabic solution and a 3% gelatin solution; 15 g of the doxycycline hydrochloride-copper complex powder obtained in Example 4 was added to the 3% gum arabic solution, homogenized for 15 minutes to form a suspension, and the prepared 3% gelatin solution was added, the gelatin solution was kept at about 45° C., and stirring was continued, and the pH value was adjusted to 4.1-4.3 with 5% acetic acid solution, and stirred until microcapsules were formed. After the capsules were formed, 2000 mL of purified water with a slightly lower temperature was added, and stirring was continued. When the temperature dropped to below 30° C., it was moved to an ice bath (below 5° C.) and stirring was continued, and 10 mL of 37% formaldehyde solution was added, and stirring was performed to solidify and set the shape, and the pH value was adjusted to 8.0-8.5 with 10% sodium hydroxide to reduce the pores of the gel, and stirring was continued for 30 minutes. Add 40 mL of 10% raw starch suspension, stir at about 10° C. for another hour, collect the microcapsules by suction filtration, wash with water until there is no formaldehyde, and set aside.

[0087] Example 9

[0088] 1000 mL of purified water was heated to 45° C., divided into two portions, 500 mL each, and 15 g of gum arabic and 15 g of gelatin were added respectively, stirred until dissolved, to obtain a 3% gum arabic solution and a 3% gelatin solution; 15 g of the doxycycline hydrochloride-aluminum complex powder obtained in Example 5 was added to the 3% gum arabic solution, homogenized for 15 minutes to form a suspension, and the prepared 3% gelatin solution was added, the gelatin solution was kept at about 45° C., and stirring was continued, and the pH value was adjusted to 4.1-4.3 with 5% acetic acid solution, and stirred until microcapsules were formed. After the capsules were formed, 2000 mL of purified water with a slightly lower temperature was added, and stirring was continued. When the temperature dropped to below 30° C., it was moved to an ice bath (below 5° C.) and stirring was continued, and 10 mL of 37% formaldehyde solution was added, and stirring was performed to solidify and set the shape, and the pH value was adjusted to 8.0-8.5 with 10% sodium hydroxide to reduce the pores of the gel, and stirring was continued for 30 minutes. Add 40 mL of 10% raw starch suspension, stir at about 10° C. for another hour, collect the microcapsules by suction filtration, wash with water until there is no formaldehyde, and set aside.

[0089] 3. Paste Preparation

[0090] Example 10

[0091] Take 3g of egg yolk lecithin, 2g of sodium carboxymethyl cellulose, 2g of sodium alginate, 8g of fish oil, 5g of vitamin E oil, 30g of whey protein powder, 25g of maltose syrup and 25g of purified water, add them into an emulsifying pot and mix and stir, homogenize and emulsify at 70-75°C for 15-30 minutes to obtain a matrix, then add 50g of the microcapsules collected in Example 6, 2g of chicken flavor, 8g of chicken liver powder, 2g of methylparaben and 2g of sodium benzoate, stir and homogenize for 10-15 minutes, cool to room temperature, and pot.

[0092] Embodiment 11

[0093] Take 3g of egg yolk lecithin, 2g of sodium carboxymethyl cellulose, 2g of sodium alginate, 8g of edible soybean oil, 5g of vitamin E oil, 30g of polyethylene glycol 4000, 25g of cane molasses and 25g of purified water, add them into an emulsifying pot and mix and stir, homogenize and emulsify at 70-75°C for 25-30 minutes to obtain a matrix, then add 50g of the microcapsules collected in Example 7, 2g of pork flavor, 8g of pig liver powder, 1g of methylparaben and 1g of ethylparaben, stir and homogenize for 10-15 minutes, cool to room temperature, and potting to obtain.

[0094] Example 12

[0095] Take 3g of egg yolk lecithin, 2g of sodium carboxymethyl cellulose, 2g of sodium alginate, 8g of fish oil, 5g of vitamin E oil, 30g of whey protein powder, 25g of maltose syrup and 25g of purified water, add them into an emulsifying pot and mix and stir, homogenize and emulsify at 70-75°C for 15-30 minutes to obtain a matrix, then add 50g of the microcapsules collected in Example 8, 2g of chicken flavor, 8g of chicken liver powder, 2g of methylparaben and 2g of sodium benzoate, stir and homogenize for 10-15 minutes, cool to room temperature, and pot.

[0096] Embodiment 13

[0097] Take 3g of egg yolk lecithin, 2g of sodium carboxymethyl cellulose, 2g of sodium alginate, 8g of fish oil, 5g of vitamin E oil, 30g of whey protein powder, 25g of maltose syrup and 25g of purified water, add them into an emulsifying pot and mix and stir, homogenize and emulsify at 70-75°C for 15-30 minutes to obtain a matrix, then add 50g of the microcapsules collected in Example 9, 2g of chicken flavor, 8g of chicken liver powder, 2g of methyl paraben and 2g of sodium benzoate, stir and homogenize for 10-15 minutes, cool to room temperature, and potting to obtain.

[0098] Comparative Example 1 Doxycycline hydrochloride injection (Specification: 10mL:1g, Batch: 1000mL)

[0099] Take 50g of magnesium chloride, 2g of sodium bisulfite, and 3g of sodium formaldehyde sulfoxylate, add them to 200mL of water for injection and stir until dissolved, add 200g of polyethylene glycol 300 and 400g of glycerol formal, stir evenly, raise the temperature to 40-45°C, add 120g of doxycycline hydrochloride and stir until dissolved, continue to keep warm and stir for 30 minutes, add enough water for injection (1000mL), stir evenly, cool to below 30°C, adjust the pH value to 3.5-4.0 with ethanolamine, filter through 0.22μm micropore, fill the ampoule, and sterilize with circulating steam at 105°C for 30 minutes to obtain the product.

[0100] Comparative Example 2 Doxycycline hydrochloride tablets (Specification: 50 mg, tablet weight: 0.2 g, batch: 1000 tablets)

[0101] Take 50g of doxycycline hydrochloride, 44g of microcrystalline cellulose, 53g of corn starch, and 40g of lactose, respectively, and add them to a trough mixer after passing through a 60-mesh sieve, mix for 30 minutes, add 100g of 10% PVP ethanol solution to make a soft material, pass through an 18-mesh sieve to make wet granules, transfer to a hot air circulation oven, dry at 60°C to a moisture content of ≤2%, sieve through a 20-mesh sieve to size the granules, finally add 1g of colloidal silicon dioxide and 1g of magnesium stearate, mix evenly, compress into tablets, coat with a gastric-soluble coating premix to increase the weight by 3%, and prepare blisters.

[0102] Comparative Example 3

[0103] The preparation method of the doxycycline hydrochloride injection of this comparative example, taking 100 mL as an example, is as follows: take 20 mL of water, add 0.5 g of sodium formaldehyde sulfoxylate, dissolve it completely, add 2 g of zinc oxide, 1 g of co-solvent vitamin C or ammonium chloride, dissolve it completely, then add 50 g of α-pyrrolidone and PEG-200 with a mass ratio of 4:1, stir evenly, add 20 g of sodium sulfate and trimethoprim with a mass ratio of 1:3, dissolve it completely, then add 20 g of doxycycline hydrochloride, stir evenly, heat to 55°C, slowly add 7 g of triethanolamine to dissolve and complex the doxycycline hydrochloride, cool to room temperature, adjust the pH value to 4.5-6.5, add water for injection to 100 mL, filter with a 0.22-0.45 μm organic filter membrane, package, fill, and sterilize at 105°C for 30 minutes.

[0104] 4. Stability test

[0105] (I) Complex stability

[0106] 1.1 Instruments

[0107] AUW-120D electronic analytical balance (Shimadzu, Japan), SHH-400SD drug stability test chamber (Chongqing Yongsheng Instrument), SHH-250SD intelligent constant temperature and humidity chamber (Chongqing Yongsheng Instrument), SHH-200GD-2F drug strong light irradiation test chamber (Chongqing Yongsheng Instrument), U-1800 UV spectrophotometer (Shanghai Jinghua), pHS-3C acidity meter (Anting, Shanghai), ultrapure water system, KQ-100DE ultrasonic cleaner (Kunshan, Shanghai), clean bench (Suzhou Purification), LC-16 high performance liquid chromatograph (Suzhou Shimadzu)

[0108] 1.2. Content determination

[0109] Take 10.0 mg of each of doxycycline hydrochloride, doxycycline hydrochloride paste for oral administration obtained in Example 10, Example 12 and Example 13, accurately weigh, place in 10 mL brown volumetric flasks, dissolve with DMSO, and shake well. Accurately pipette 1.0 mL of this solution into 50 mL brown volumetric flasks, dilute to scale with water, and shake well. Use water (containing 0.5% DMSO) as a blank reference solution, and perform ultraviolet spectrum scanning at a wavelength of 200-400 nm.

[0110] 1.3 High temperature test

[0111] Doxycycline hydrochloride and the doxycycline hydrochloride pastes obtained in Examples 10, 12 and 13 were respectively prepared into aqueous solutions with a concentration of 20 μg / mL, placed in a drug stability test chamber, and placed at 60°C for 10 days. Samples were taken for testing on the 5th and 10th days. The results are shown in Table 1. Figure 1 .

[0112] Table 1 High temperature test results of doxycycline hydrochloride and doxycycline hydrochloride paste for oral administration

[0113]

[0114] From Table 1 and Figure 1 It can be seen from the data in that at a high temperature of 60°C, the doxycycline hydrochloride oral paste obtained in Example 10 has higher stability than doxycycline hydrochloride, Example 12 (doxycycline hydrochloride-copper complex) and Example 13 (doxycycline hydrochloride-aluminum complex).

[0115] 1.4 Strong light exposure test

[0116] Doxycycline hydrochloride, and the doxycycline hydrochloride pastes obtained in Example 10, Example 12, and Example 13 were prepared into aqueous solutions with a concentration of 20 μg / mL, placed in a drug stability test chamber, and placed under an illumination of 4500±500 Lx for 10 days, and samples were taken on the 5th and 10th days. The results are shown in Table 2. Figure 2 .

[0117] Table 2 Results of strong light irradiation experiment of doxycycline hydrochloride and doxycycline hydrochloride paste for oral administration

[0118]

[0119] From Table 2 and Figure 2 It can be seen from the data in that under strong light irradiation, the doxycycline hydrochloride oral paste obtained in Example 10 is more stable than doxycycline hydrochloride, Example 12 (doxycycline hydrochloride-copper complex), and Example 13 (doxycycline hydrochloride-aluminum complex).

[0120] 1.5 Accelerated testing

[0121] Doxycycline hydrochloride, and the doxycycline hydrochloride pastes obtained in Example 10, Example 12, and Example 13 were prepared into aqueous solutions with a concentration of 20 μg / mL, placed in a constant temperature and humidity chamber at 40±2°C and a relative humidity of 75±5% for 6 months, and samples were taken at the end of the first, second, third, and sixth months to investigate changes in their contents. The results are shown in Table 3. Figure 3 .

[0122] Table 3 Doxycycline hydrochloride and doxycycline hydrochloride paste accelerated test results

[0123]

[0124] from Figure 3 As shown in Table 3, the stability of the doxycycline hydrochloride paste is significantly improved compared with that of doxycycline hydrochloride. Furthermore, the paste for oral administration obtained by using a zinc complexing agent in Example 10 is more stable than that in Example 12 (doxycycline hydrochloride-copper complex) and Example 13 (doxycycline hydrochloride-aluminum complex).

[0125] 1.6. Accelerated test of paste

[0126] Doxycycline hydrochloride, Example 10, Example 12 and Example 13 obtained by oral administration of doxycycline hydrochloride paste were respectively configured into aqueous solutions with a concentration of 20 μg / mL, and the doxycycline hydrochloride injection (10mL / piece, ampoule bottle) of Comparative Example 1, the doxycycline hydrochloride tablets (50mg / tablet, aluminum-plastic blister) of Comparative Example 2 were placed in a constant temperature and humidity chamber in their original packaging at 40±2°C and a relative humidity of 75±5% for 6 months. Samples were taken at the end of the first month, second month, third month and sixth month, and the content and changes of related substances were investigated according to the relevant substances and their content detection methods under the doxycycline hydrochloride item of the 2020 edition of the Chinese Veterinary Pharmacopoeia. The results are shown in Table 4. Figure 4 , Figure 5 .

[0127] Table 4 Doxycycline hydrochloride and doxycycline hydrochloride paste accelerated test results

[0128]

[0129]

[0130] The contents in Table 4 are indicated amounts.

[0131] From Table 4 and Figure 4 , 5It can be seen that the doxycycline hydrochloride oral paste obtained in Example 10 has better stability than doxycycline hydrochloride, the doxycycline hydrochloride injection obtained in Comparative Examples 1 and 3, Example 12 (doxycycline hydrochloride-copper complex), and Example 13 (doxycycline hydrochloride-aluminum complex), and is equivalent to the stability of the doxycycline hydrochloride tablets in Comparative Example 2.

[0132] (II) Palatability test

[0133] Test method:

[0134] (1) First choice test method: Two food bowls were provided for the experimental cats at the same time. An equal amount of basic complete cat food and basic complete cat food + 2g doxycycline hydrochloride oral paste were placed in the food bowls respectively. The first choice of each cat was observed and recorded. See Table 5 for the average number of cats who chose the first choice per day.

[0135] (2) Double bowl test: Provide two food bowls for the experimental cats at the same time, and put equal amounts of basic complete cat food and basic complete cat food + 2g doxycycline hydrochloride paste in the food bowls respectively. Weigh and record the consumption of the two cat foods during one feeding process, and calculate the consumption rate. See Table 5 for the average daily consumption rate. (Switch the food bowls every other day)

[0136] Note: 30 cats with similar characteristics and weights were selected for each group of the preferred test method and the double basin test method, and the test time was 20 days. The test results are shown in Table 5. The experimental group is the test data of the basic complete cat food + 2g doxycycline hydrochloride oral paste, and the control group is the test data of the general basic complete cat food.

[0137] Table 5 Palatability test results

[0138]

[0139]

[0140] The injections of Comparative Example 1 and Comparative Example 3 are not suitable for oral administration but for injection administration, so no comparison of palatability is made.

[0141] It can be seen from the data in the figure that the doxycycline hydrochloride oral paste prepared by the method of the embodiment of the present invention has good palatability, can better stimulate the appetite of pets, and has a larger consumption amount.

[0142] In summary, the present invention has the following beneficial effects:

[0143] (1) by complexing doxycycline hydrochloride with zinc, magnesium, aluminum, copper and other ions and observing under high temperature, high humidity and light conditions, a doxycycline hydrochloride-zinc complex with high stability to high temperature, high humidity and light was screened out as the starting material for doxycycline hydrochloride oral paste;

[0144] (2) Using microcapsule materials to encapsulate and oxidatively isolate the doxycycline hydrochloride zinc complex to achieve dual stabilization and reduce gastrointestinal irritation;

[0145] (3) The nutrient paste is prepared by adding a flavoring agent with good palatability and encapsulating it in a quantitative container, which is easy for pets such as dogs and cats to take. In short, the doxycycline hydrochloride oral paste solves the shortcomings of other doxycycline hydrochloride preparations (such as injections, soluble powders, tablets, and capsules) such as poor stability, high irritation, and difficulty in swallowing.

[0146] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A doxycycline hydrochloride paste for oral administration, comprising the following components: doxycycline hydrochloride, a complexing agent, a capsule material, a pharmaceutical excipient and purified water.

2. The doxycycline hydrochloride paste for internal use according to claim 1, characterized in that The complexing agent includes a zinc compound; Preferably, the zinc compound is selected from one or more of zinc acetate, zinc sulfate, zinc chloride, amino acid chelated zinc, zinc gluconate and zinc oxide.

3. The doxycycline hydrochloride paste for internal use according to claim 1 or 2, characterized in that: The capsule material is selected from one or more of gelatin, gum arabic, sodium alginate, chitosan, polylysine, albumin and the like.

4. The doxycycline hydrochloride paste for internal use according to claim 1 or 2, characterized in that: The pharmaceutical excipient is selected from one or more of fish oil, soybean oil, corn oil, vitamin E oil, olive oil, maltose syrup, whey protein powder, polyethylene glycol, emulsifier or thickener; Preferably, the emulsifier is selected from egg yolk lecithin; Preferably, the thickener is selected from sodium carboxymethyl cellulose and / or sodium alginate.

5. The doxycycline hydrochloride paste for internal use according to any one of claims 1 to 4, characterized in that: The molar ratio of the complexing agent to the doxycycline hydrochloride is 0.1-2; and / or The ratio of the mass of the capsule material to the sum of the mass of the doxycycline hydrochloride and the complexing agent is 1:2-2:1; and / or The doxycycline hydrochloride composition comprises 80-200 parts of doxycycline hydrochloride, 30-150 parts of a complexing agent and 10-60 parts of a capsule material in parts by weight; Preferably, the mass ratio of the doxycycline hydrochloride composition to the pharmaceutical excipient is 5:1-1:

5.

6. The doxycycline hydrochloride paste for internal use according to any one of claims 1 to 5, characterized in that: The doxycycline hydrochloride paste for internal use further comprises a flavoring agent and / or a preservative; Preferably, the flavoring agent is selected from one or more mixtures of sucrose, fructose, maltose syrup, cane molasses, edible flavoring, chicken liver powder, pork liver powder, beef powder or chicken powder; Preferably, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, sodium benzoate or potassium sorbate.

7. A method for preparing the doxycycline hydrochloride oral paste according to any one of claims 1 to 6, comprising the following steps: (1) preparing microcapsules using a suspension comprising a complex of doxycycline hydrochloride, a capsule material and purified water; solidifying the microcapsules to obtain doxycycline hydrochloride composite microcapsules; (2) mixing the doxycycline hydrochloride complex microcapsules with pharmaceutical excipients to obtain the doxycycline hydrochloride oral paste; Preferably, the mass ratio of the capsule material to the complex of doxycycline hydrochloride is 1:2-2:1; and / or The mass ratio of the doxycycline hydrochloride composite microcapsules to the pharmaceutical excipients is 5:1-1:

5.

8. The preparation method according to claim 7, characterized in that: The preparation method of the doxycycline hydrochloride complex comprises: complexing the doxycycline hydrochloride aqueous solution with the complexing agent aqueous solution, and drying after the complexing is complete; Preferably, the complexation is carried out at a pH of 4.0-6.

5.

9. The preparation method according to claim 7, characterized in that: The method for preparing doxycycline hydrochloride complex microcapsules comprises: S1, mixing the doxycycline hydrochloride complex with the capsule material aqueous solution to obtain a suspension; S2, adjusting the pH of the suspension to 3.0-5.0 to form microcapsules; S3, solidifying the microcapsules to obtain the doxycycline hydrochloride complex microcapsules.

10. The preparation method according to claim 9, characterized in that: In step S1, the mixing temperature is 40-60°C; and / or The mass concentration of the capsule material aqueous solution is 1-10%; In step S2, the pH is adjusted using acetic acid solution. In step S3, the solidification solvent is a formaldehyde solution; Preferably, the mass concentration of the formaldehyde solution is 20-45%; The solidification is carried out at a pH of 8-9; Preferably, the pH is adjusted using sodium hydroxide solution.

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