Clathration synergistic type doxycycline hydrochloride soluble powder and preparation method thereof

Abstract

The invention relates to inclusion synergistic type doxycycline hydrochloride soluble powder. 100kg of the soluble powder is mainly prepared from the following raw materials in a weight ratio: 10 to 30kg of doxycycline hydrochloride, 20 to 40kg of beta-cyclodextrin, 3 to 8kg of lauryl sodium sulfate, 0.8 to 1.2 kg of lysozyme freeze-dried powder, 2 to 3kg of sodium ascorbate, 8 to 12kg of microcrystalline cellulose and 15 to 45kg of lactose. The soluble powder can effectively avoid inactivation caused by direct contact between lysozyme and an organic solvent, improves the slow release performance of drugs, and meets the national policy requirements of resistance reduction.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of veterinary drug preparations, and particularly relates to a package inclusion synergistic doxycycline hydrochloride soluble powder and a preparation method thereof. BACKGROUND

[0002] Doxycycline hydrochloride, as a broad-spectrum antibiotic of tetracyclines, is widely used in the prevention and treatment of common infectious diseases such as streptococcosis of pigs and colibacillosis of chickens. However, in view of the current challenge of reducing the dosage of veterinary antibiotics, the traditional preparation has a high dosage dependence, and the bioavailability of the ordinary soluble powder is only 40%-50%, so that the clinical drug dosage generally exceeds 100 mg / kg of body weight, resulting in that the residues of livestock and poultry products exceed the standard and are in conflict with the No. 194 "antibiotic reduction order" of the Ministry of Agriculture and Rural Affairs.

[0003] In addition, the existing production process has a low package inclusion rate, a large fluctuation of blood drug concentration, and cannot achieve the goal of reducing the dosage, and lacks antibacterial synergistic components, so that it cannot meet the rapid mixing and drinking demand of large-scale farms.

[0004] Based on this, the present application is developed. SUMMARY

[0005] The present application aims to overcome the defects of the prior art and provide a package inclusion synergistic doxycycline hydrochloride soluble powder. The soluble powder can effectively avoid the inactivation caused by the direct contact of lysozyme and organic solvent, improve the drug release performance, and meet the requirements of the national "antibiotic reduction" policy.

[0006] Another object of the present application is to provide a preparation method of the above-mentioned package inclusion synergistic doxycycline hydrochloride soluble powder.

[0007] A third object of the present application is to provide laboratory tests and clinical test analysis of the above-mentioned preparation.

[0008] To achieve the above-mentioned objects, the present application adopts the following technical solutions: A package inclusion synergistic doxycycline hydrochloride soluble powder, wherein 100 kg of the soluble powder is mainly composed of the following raw materials in a weight ratio: 10-30 kg of doxycycline hydrochloride, 20-40 kg of beta-cyclodextrin, 3-8 kg of sodium dodecyl sulfate, 0.8-1.2 kg of lysozyme freeze-dried powder, 2-3 kg of vitamin C sodium, 8-12 kg of microcrystalline cellulose, and 15-45 kg of lactose.

[0009] As a preferred embodiment of the above-mentioned package inclusion synergistic doxycycline hydrochloride soluble powder, 100 kg of the soluble powder is mainly composed of the following raw materials in a weight ratio: 10 kg of doxycycline hydrochloride, 30 kg of beta-cyclodextrin, 3 kg of sodium dodecyl sulfate, 1.2 kg of lysozyme freeze-dried powder, 3 kg of vitamin C sodium, 8 kg of microcrystalline cellulose, and 44.8 kg of lactose.

[0010] The above-mentioned inclusion synergistic doxycycline hydrochloride soluble powder, as a preferred embodiment, 100 kg of the soluble powder is mainly composed of the following raw materials in the following weight ratio: Doxycycline hydrochloride 20 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate 5 kg, lysozyme freeze-dried powder 0.8 kg, vitamin C sodium 2.5 kg, microcrystalline cellulose 10 kg, lactose 31.7 kg.

[0011] The above-mentioned inclusion synergistic doxycycline hydrochloride soluble powder, as a preferred embodiment, 100 kg of the soluble powder is mainly composed of the following raw materials in the following weight ratio: Doxycycline hydrochloride 30 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate 8 kg, lysozyme freeze-dried powder 1.2 kg, vitamin C sodium 2 kg, microcrystalline cellulose 12 kg, lactose 16.8 kg.

[0012] The present application provides a preparation method of the above-mentioned inclusion synergistic doxycycline hydrochloride soluble powder, which comprises the following steps: 1) Weigh doxycycline hydrochloride and dissolve it in an ethanol aqueous solution to prepare a drug solution with a concentration of 40-60 mg / ml; 2) Add β-cyclodextrin to purified water, and stir in a water bath at 50-60°C to form a β-cyclodextrin saturated solution; 3) Add the drug solution obtained in step 1) to the β-cyclodextrin saturated solution obtained in step 2) (flow rate control is 15-30 ml / min), and maintain the system temperature at 50±2°C during the process, and continuously stir (rotation speed is 200-400 rpm) for 3-5 hours; 4) Transfer the reaction solution to a 2-6°C refrigerator and stand for 18-24 hours, and then separate the crystalline precipitate from the liquid, wash the filter cake with ethanol, and obtain the inclusion compound filter cake; 5) Mix lactose and microcrystalline cellulose in a mixer, and then add lysozyme freeze-dried powder, vitamin C sodium and sodium dodecyl sulfate to obtain a premixed excipient; 6) Add the inclusion compound filter cake obtained in step 4) to purified water to prepare a suspension with a solid content of 20-30%, and then treat it with a colloid mill until the particle size D90 is ≤50 μm, and then add the premixed excipient obtained in step 5) to the suspension and homogenize for 3-5 minutes, and then perform low-temperature spray drying granulation; 7) Use a fluidized bed airflow pulverizer to pulverize the spray drying granulation product, and the particle size D50 of the powder after pulverization is 30-40 μm.

[0013] Specifically, in step 1), the volume concentration of the ethanol aqueous solution can be 50-70%.

[0014] Specifically, in step 3), the pH value of the reaction solution is monitored by a pH meter to maintain at 6.5-7.0 to ensure the formation of stable molecular inclusion compounds.

[0015] Specifically, in step 5), dry nitrogen gas is introduced into the mixing machine bin, and the relative humidity is ≤30% to prevent the inactivation of lysozyme due to moisture absorption.

[0016] Specifically, in step 6), during homogenization, the stirring speed can be 80-150 rpm, and the homogenization pressure can be 35-60 MPa. Further, in step 6), during spray drying, the inlet air temperature is 120±5℃, the outlet air temperature is 70±3℃, and the atomizer speed can be 15000-20000 rpm.

[0017] Specifically, in step 7), the compressed air pressure during crushing can be 0.6-1.0 MPa.

[0018] Compared with the prior art, the present application has the following advantages and beneficial effects: 1) The present application uses a low-temperature inclusion (2-6℃ cold storage standing crystallization) and low-temperature spray drying (120±5℃ inlet air) combined application of low-temperature synergistic technology to solve the problem of heat sensitivity of doxycycline; 2) The present application uses a two-mixing method of “inclusion first and excipient second” to avoid the inactivation of lysozyme caused by direct contact with organic solvents; 3) The present application uses a low-temperature crystallization process to form a stable inclusion compound with a porosity of 15% higher than that of conventional freeze-drying method, which improves the sustained-release performance of the drug; 4) The process used in the present application only requires a conventional mixer, a spray drying tower and a crusher, which has low equipment investment cost, is suitable for rapid transformation of the production line of veterinary drug enterprises, has high industrialization adaptability, and meets the requirements of the national “antibiotic reduction” policy. DETAILED DESCRIPTION

[0019] The technical solutions of the present application are further described in detail below, but the scope of protection of the present application is not limited thereto.

[0020] In the following examples, the raw materials used are ordinary commercially available products that can be purchased directly or prepared by conventional techniques in the art. For example, lysozyme freeze-dried powder is purchased from Nanning Dongheng Huadao Biology (enzyme activity ≥500,000 U / g, DH-DFLY-50W). Microcrystalline cellulose is purchased from Xi'an Xinfengda Pharmaceutical (particle size D50=100μm).

[0021] Example 1 A kind of inclusion synergistic type doxycycline hydrochloride soluble powder 10% 100kg inclusion synergistic type doxycycline hydrochloride soluble powder is mainly composed of the following weight ratio of raw materials: Doxycycline hydrochloride 10 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate (SDS) 3 kg, lysozyme freeze-dried powder 1.2 kg, vitamin C sodium 3 kg, microcrystalline cellulose 8 kg, lactose 44.8 kg.

[0022] Preparation method: 1. The doxycycline hydrochloride raw material was weighed and added to a 60% ethanol aqueous solution to prepare a drug solution with a concentration of 50 mg / ml, which was heated to 45°C and stirred until completely dissolved.

[0023] 2. The β-cyclodextrin was added to purified water, and a β-cyclodextrin saturated solution was formed by stirring in a 60°C water bath.

[0024] 3. The drug solution was slowly added to the β-cyclodextrin saturated solution (flow rate controlled at 20 ml / min), and the system temperature was maintained at 50±2°C during the process, and magnetic stirring (speed 300 rpm) was continued for 4 hours.

[0025] 4. The reaction solution was transferred to a 4°C refrigerator and left for 22 hours, and a crystalline precipitate was separated out. Vacuum suction filtration (filter paper pore size 0.45 μm) was performed through a Buchner funnel, and the filter cake was washed with 0-4°C cold ethanol 3 times to remove free drugs, and a clathrate filter cake was obtained.

[0026] 5. Lactose and microcrystalline cellulose were put into a mixer, pre-mixed for 10 minutes, and then lysozyme freeze-dried powder, vitamin C sodium and SDS were added in sequence, mixed for 20 minutes, and a pre-mixed excipient was obtained.

[0027] 6. The clathrate filter cake of step 4 was added to purified water to prepare a suspension with a solid content of 25%, and the suspension was treated by a colloid mill to a particle size D90≤50 μm. The pre-mixed excipient of step 5 was gradually added to the suspension for homogenization treatment for 4 minutes (stirring speed 100 rpm, homogenization pressure 50 MPa). Then low-temperature spray drying granulation was performed (inlet air temperature 120±5°C, outlet air temperature 70±3°C, atomizer speed 18000 rpm).

[0028] 7. The spray-dried powder was crushed using a fluidized bed air jet pulverizer, with compressed air pressure 0.8 MPa, and the crushed powder had a particle size D50=35 μm, thus obtaining the product of the present application.

[0029] 1. In step 3, the pH of the reaction solution was monitored using a pH meter to maintain a pH of 6.5-7.0 to ensure the formation of stable molecular inclusion complexes. Phosphate-citrate buffer was added for pH adjustment (buffer preparation method: Na2HPO4·2H2O 3.56 g + citric acid 2.10 g was dissolved in 1 L purified water), and the same was used for subsequent pH adjustment.

[0030] 2. In step 5, dry nitrogen was introduced into the mixing machine bin, with a relative humidity of ≤30%, to prevent lysozyme from being deactivated due to moisture absorption.

[0031] Example 2 A kind of inclusion synergistic doxycycline hydrochloride soluble powder 20% 100 kg inclusion synergistic doxycycline hydrochloride soluble powder is mainly composed of the following weight ratio of raw materials: Doxycycline hydrochloride 20 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate (SDS) 5 kg, lysozyme freeze-dried powder 0.8 kg, vitamin C sodium 2.5 kg, microcrystalline cellulose 10 kg, lactose 31.7 kg.

[0032] Preparation method: 1, the doxycycline hydrochloride raw material is weighed and added to 60% ethanol aqueous solution, and a drug solution with a concentration of 50 mg / ml is prepared, heated to 45 DEG C and stirred until completely dissolved.

[0033] 2, β-cyclodextrin is added to purified water, and a β-cyclodextrin saturated solution is formed by stirring in a 60 DEG C water bath.

[0034] 3, the drug solution is slowly added to the β-cyclodextrin saturated solution (flow rate control is 20 ml / min), and the system temperature is maintained at 50±2 DEG C during the period, and the magnetic stirring (speed 300 rpm) is continued for 4 hours.

[0035] 4, the reaction solution is transferred to a 4 DEG C refrigerator and placed for 22 hours, and the crystalline precipitate is separated out, and the filter cake is washed with 0-4 DEG C cold ethanol for 3 times to remove free drugs, and the inclusion compound filter cake is obtained.

[0036] 5, the lactose and microcrystalline cellulose are put into a mixer, and the lysozyme freeze-dried powder, vitamin C sodium and SDS are sequentially added after pre-mixing for 10 minutes, and the mixture is mixed for 20 minutes to obtain a pre-mixed excipient.

[0037] 6, the inclusion compound filter cake of step 4 is added to purified water to prepare a 25% solid content suspension, which is treated by a colloid mill for 3 times until the particle size D90≤50 μm, and the pre-mixed excipient of step 5 is gradually added to the suspension for homogenization treatment for 4 minutes (stirring speed 100 rpm, homogenization pressure 50 MPa). Then low-temperature spray drying granulation (inlet air temperature 120±5 DEG C, outlet air temperature 70±3 DEG C, atomizer speed 18000 rpm) is carried out.

[0038] 7, the spray-dried powder is crushed using a fluidized bed air jet pulverizer, and the compressed air pressure is 0.8 MPa. After crushing, the powder particle size D50=35 μm, and the product of the application is obtained.

[0039] Wherein: 1, in step 3, the pH meter is used to monitor the pH value of the reaction solution to maintain 6.5-7.0, to ensure the formation of stable molecular inclusion compounds.

[0040] 2. In step 5, dry nitrogen is introduced into the mixing bin, with a relative humidity of ≤30%, to prevent the lysozyme from being inactivated due to moisture absorption.

[0041] Example 3 A solubility powder of 30% of the inclusion synergistic doxycycline hydrochloride 100 kg of the solubility powder of the inclusion synergistic doxycycline hydrochloride is mainly composed of the following raw materials in the following proportions by weight: 30 kg of doxycycline hydrochloride, 30 kg of β-cyclodextrin, 8 kg of sodium dodecyl sulfate (SDS), 1.2 kg of lysozyme freeze-dried powder, 2 kg of vitamin C sodium, 12 kg of microcrystalline cellulose, and 16.8 kg of lactose.

[0042] Preparation method: 1. The doxycycline hydrochloride raw material is weighed and added to a 60% ethanol aqueous solution to prepare a drug solution with a concentration of 50 mg / ml, which is heated to 45°C and stirred until completely dissolved.

[0043] 2. The β-cyclodextrin is added to purified water, and a β-cyclodextrin saturated solution is formed by stirring in a 60°C water bath.

[0044] 3. The drug solution is slowly added to the β-cyclodextrin saturated solution (flow rate controlled at 20 ml / min), and the system temperature is maintained at 50±2°C during the process, with continuous magnetic stirring (rotation speed 300 rpm) for 4 hours.

[0045] 4. The reaction solution is transferred to a 4°C refrigerator and left to stand for 22 hours, and the crystalline precipitate is separated out. The filter cake is washed with 0-4°C cold ethanol 3 times to remove free drugs, and the inclusion complex filter cake is obtained.

[0046] 5. The lactose and microcrystalline cellulose are put into a mixer, and after 10 minutes of premixing, the lysozyme freeze-dried powder, vitamin C sodium, and SDS are added in sequence, and mixed for 20 minutes to obtain the premixed excipients.

[0047] 6. The inclusion complex filter cake of step 4 is added to purified water to prepare a suspension with a solid content of 25%, which is treated by a colloid mill for 3 cycles until the particle size D90≤50μm. The premixed excipients of step 5 are gradually added to the suspension for homogenization treatment for 4 minutes (stirring speed 100 rpm, homogenization pressure 50 MPa). Then, low-temperature spray drying granulation is performed (inlet air temperature 120±5°C, outlet air temperature 70±3°C, atomizer rotation speed 18000 rpm).

[0048] 7. The spray-dried powder is crushed using a fluidized bed jet mill, with a compressed air pressure of 0.8 MPa. After crushing, the powder particle size D50=35μm, and the product of the present application is obtained.

[0049] Wherein: 1, in step 3, use pH meter to monitor the pH value of the reaction solution to maintain 6.5-7.0, to ensure the formation of stable molecular inclusion.

[0050] 2, in step 5, dry nitrogen is introduced into the mixing chamber, the relative humidity is ≤30%, to prevent lysozyme from being inactivated by moisture absorption.

[0051] Comparative Example 1: A commercially available brand of doxycycline hydrochloride soluble powder Traditional process, doxycycline hydrochloride 10% + lactose 90%, direct dry mixing.

[0052] Comparative Example 2: Remove low-temperature spray drying granulation process

Process adjustment

[0053] The composition and the weight of the raw materials used for 100 kg of finished product are: doxycycline hydrochloride 20 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate (SDS) 5 kg, lysozyme freeze-dried powder 0.8 kg, vitamin C sodium 2.5 kg, microcrystalline cellulose 10 kg, lactose 31.7 kg.

[0054] Preparation method: 1. Weigh the doxycycline hydrochloride raw material and add it to a 60% ethanol aqueous solution to prepare a drug solution with a concentration of 50 mg / ml. Heat to 45°C and stir until completely dissolved.

[0055] 2. Add β-cyclodextrin to purified water and stir in a 60°C water bath to form a β-cyclodextrin saturated solution.

[0056] 3. Slowly add the drug solution to the β-cyclodextrin saturated solution (flow rate 30 ml / min), maintain the system temperature at 50±2°C, constant temperature stirring reaction for 6 hours, the reaction solution pH naturally fluctuates (measured 5.8-6.5).

[0057] 4. Hot filtration of the reaction solution (Buchner funnel, 0.65 μm filter membrane), the filtrate is transferred to -20°C for 12 hours, the frozen material is vacuum freeze-dried (cold trap temperature -45°C, vacuum degree 10 Pa, 24 hours), to get loose inclusion complex.

[0058] 5. Put the dried doxycycline hydrochloride loose inclusion complex, lactose, and microcrystalline cellulose into a mixer, pre-mix for 10 minutes, then add lysozyme freeze-dried powder, vitamin C sodium and SDS in sequence, mix for 20 minutes, to get the product.

[0059] Wherein: 1, in step 5, dry nitrogen is introduced into the mixing chamber, the relative humidity is ≤30%, to prevent lysozyme from being inactivated by moisture absorption.

[0060] Comparative Example 3: High temperature inclusion + ordinary physical mixing

Process adjustment

[0061] The composition and the weight of raw materials used for 100 kg of finished product are: doxycycline hydrochloride 30 kg, β-cyclodextrin 30 kg, sodium dodecyl sulfate (SDS) 8 kg, lysozyme freeze-dried powder 1.2 kg, vitamin C sodium 2 kg, microcrystalline cellulose 12 kg, lactose 16.8 kg.

[0062] Preparation method: 1. The doxycycline hydrochloride raw material is weighed and added to a 60% ethanol aqueous solution to prepare a drug solution with a concentration of 50 mg / ml. Heat to 45℃ and stir until completely dissolved.

[0063] 2. Add β-cyclodextrin to purified water and stir in a 60℃ water bath to form a β-cyclodextrin saturated solution.

[0064] 3. Slowly add the drug solution to the β-cyclodextrin saturated solution (flow rate controlled at 20 ml / min), and stir at a constant temperature of 60℃ for 7 hours.

[0065] 4. Hot filtration of the reaction solution (Buchner funnel, 0.65 μm filter membrane), transfer the filtrate to -20℃ for 12 hours, and vacuum freeze-drying (cold trap temperature -45℃, vacuum degree 10 Pa, 24 hours) to obtain the inclusion compound.

[0066] 5. Put the inclusion compound, lactose, and microcrystalline cellulose into a mixer, pre-mix for 10 minutes, then add lysozyme freeze-dried powder, vitamin C sodium, and SDS in sequence, mix for 20 minutes, and the product is obtained.

[0067] Among them: 1. In step 5, dry nitrogen is introduced into the mixing machine bin, with a relative humidity of ≤30%, to prevent lysozyme from being inactivated due to moisture absorption.

[0068] Test example 1. Test materials Products prepared in Examples 1, 2, and 3.

[0069] Comparative Example 1: A commercially available brand of doxycycline hydrochloride soluble powder.

[0070] Comparative Example 2: Remove the low temperature spray drying granulation process.

[0071] Comparative Example 3: High temperature inclusion + ordinary physical mixing.

[0072] Reference preparation: Doxycycline hydrochloride soluble powder 10% (veterinary drug word 150256011), Qilu Animal Health Products Co., Ltd.

[0073] 2. Test method 2.1 Dissolution test: China Veterinary Drug Criteria 2020 method, rotation speed 75 rpm.

[0074] Simulated gastric fluid (pH 3.0 hydrochloric acid buffer + 0.2% SDS).

[0075] Simulated intestinal fluid (pH 6.8 phosphate buffer).

[0076] 2.2 Bioavailability test: 6 healthy weaned piglets (variety: long white x white hybrid) with a body weight of 25±2 kg were selected, and were free of mycoplasma, circovirus and other infections after quarantine and were pre-fed for 7 days to adapt to the environment. A single dose of 40 mg / kg (calculated as doxycycline) was administered by gavage, and the animals were fasted for 12 hours before administration, allowed to drink water freely, and were fed again 4 hours after administration. Blood samples (4 ml each time) were collected from the jugular vein of the pigs at 0.5, 1, 2, 4, 8, 12 and 24 hours after administration, and were injected into heparin sodium anticoagulant tubes. The blood plasma was separated by centrifugation at 4°C and 3000 rpm for 10 min, and was stored at -80°C. The blood drug concentration was detected by HPLC-MS / MS, and the relative bioavailability (F%) was calculated as follows: F% = (AUC test / AUCᵣ ef ) x 100%.

[0077] AUC 0-24 : The area under the plasma concentration-time curve from 0 to 24 hours was calculated by the trapezoidal method.

[0078] AUCᵣ ef : AUC value of the reference preparation.

[0079] C max , T max : Direct observation value.

[0080] 2.3 Reduction test: 200 healthy 1-day-old Hyline Brown egg chickens were selected, with a body weight of 35±5 g, and were evenly divided into 4 groups. The chickens were pre-fed until 14 days of age, and 0.2 ml of O78 type chicken-derived E. coli (5x10 8 CFU / mL) was injected into the thoracic air sac of each chicken. The chickens were administered 2 hours after the challenge, and the administration scheme (calculated as doxycycline) was as follows: Example 2: 60 mg / kg, once a day x 5 days; Comparative Example 1: 100 mg / kg, once a day x 5 days; Comparative Example 2: 100 mg / kg, once a day x 5 days; Comparative Example 3: 100 mg / kg, once a day x 5 days.

[0081] The cure rate was recorded: the symptoms disappeared and the animals survived within 7 days after the challenge, and the cure rate = (number of cured animals / number of surviving animals) x 100%.

[0082] Fecal residue: tested on the day of the end of administration, test method HPLC-MS / MS.

[0083] Fecal residue refers to the total residue of doxycycline hydrochloride and its main metabolites in feces, indicating drug absorption efficiency and drug resistance pressure. The smaller the residue, the higher the drug absorption rate and the lower the drug resistance.

[0084] 2.4 Formulation performance: angle of repose, dissolution time.

[0085] 3. Test results 3.1 Dissolution and bioavailability (pig model, n = 6) Table 1 Dissolution and bioavailability data As can be seen from Table 1, the 45min dissolution of Examples 1, 2 and 3 is increased by 43.4%, 20.0% and 25.5% respectively compared with Comparative Examples 1, 2 and 3, and the 45min relative bioavailability of Examples 1, 2 and 3 is increased by 104.2%, 48.9% and 46.6% respectively compared with Comparative Examples 1, 2 and 3, and the peak time is shorter than that of Comparative Examples 1, 2 and 3.

[0086] It can be seen that the product of the application can significantly improve the dissolution and bioavailability by using low-temperature inclusion and spray drying granulation process.

[0087] 3.2 Drug resistance reduction effect (chicken E. coli challenge test, n = 50) Table 2 Comparison of drug resistance reduction data As can be seen from Table 2, the cure rate of Example 2 is increased by 30.6%, 16.0% and 23.7% respectively compared with Comparative Examples 1, 2 and 3, and the fecal residue of doxycycline hydrochloride of Example 2 is reduced by 84.4%, 65.1% and 81.9% respectively compared with Comparative Examples 1, 2 and 3.

[0088] It can be seen that the cure rate of the product of the application is still higher than that of the traditional process under "40% reduction", which also indicates that the drug resistance is low and the absorption rate is high.

[0089] 3.3 Formulation performance comparison Table 3 Comparison of angle of repose and dissolution time data As can be seen from Table 3, the angle of repose of Comparative Examples 2 and 3 is increased by 28.3% and 48.6% respectively compared with Example 2, and the dissolution time is significantly increased, and the dissolution time of Example 2 is only 45 seconds, and the dissolution time of the comparative examples needs to be more than 90 seconds.

[0090] Therefore, the patent process can improve the liquidity and dissolution speed of the medicine.

Claims

1. A soluble powder containing synergistic doxycycline hydrochloride, characterized in that, 100kg of soluble powder is mainly composed of the following raw materials in the indicated weight ratios: Doxycycline hydrochloride 10-30kg, β-cyclodextrin 20-40kg, sodium dodecyl sulfate 3-8kg, lysozyme lyophilized powder 0.8-1.2kg, sodium vitamin C 2-3kg, microcrystalline cellulose 8-12kg, lactose 15-45kg.

2. The inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, 100kg of soluble powder is mainly composed of the following raw materials in the indicated weight ratios: 10 kg of doxycycline hydrochloride, 30 kg of β-cyclodextrin, 3 kg of sodium lauryl sulfate, 1.2 kg of lysozyme lyophilized powder, 3 kg of sodium vitamin C, 8 kg of microcrystalline cellulose, and 44.8 kg of lactose.

3. The inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, 100kg of soluble powder is mainly composed of the following raw materials in the indicated weight ratios: 20 kg of doxycycline hydrochloride, 30 kg of β-cyclodextrin, 5 kg of sodium lauryl sulfate, 0.8 kg of lysozyme lyophilized powder, 2.5 kg of sodium vitamin C, 10 kg of microcrystalline cellulose, and 31.7 kg of lactose.

4. The inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, 100kg of soluble powder is mainly composed of the following raw materials in the indicated weight ratios: 30 kg of doxycycline hydrochloride, 30 kg of β-cyclodextrin, 8 kg of sodium dodecyl sulfate, 1.2 kg of lysozyme lyophilized powder, 2 kg of sodium vitamin C, 12 kg of microcrystalline cellulose, and 16.8 kg of lactose.

5. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder according to any one of claims 1 to 4, characterized in that, Includes the following steps: 1) Weigh out doxycycline hydrochloride and dissolve it in an ethanol aqueous solution to prepare a drug solution with a concentration of 40-60 mg / ml; 2) Add β-cyclodextrin to purified water and stir in a water bath at 50-60℃ to form a saturated β-cyclodextrin solution; 3) Add the drug solution obtained in step 1) to the saturated β-cyclodextrin solution obtained in step 2), and maintain the system temperature at 50±2℃ during the process, and continuously stir magnetically for 3-5 hours; 4) Transfer the reaction solution to a cold storage at 2-6℃ and let it stand for 18-24 hours to precipitate crystals. Separate the solid and liquid, wash the filter cake with ethanol, and obtain the inclusion complex filter cake. 5) Add lactose and microcrystalline cellulose into a mixer and mix, then add lysozyme lyophilized powder, sodium vitamin C and sodium lauryl sulfate and mix to obtain a premixed excipient; 6) Add the inclusion compound filter cake obtained in step 4) to purified water to prepare a suspension with a solid content of 20-30%, and process it through a colloid mill until the particle size D90≤50μm. Then add the premixed excipients obtained in step 5) to the suspension for homogenization, and then spray dry granulation. 7) The spray-dried granulated product is pulverized using a fluidized bed jet mill. The pulverized powder has a particle size D50 of 30-40μm.

6. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 5, characterized in that, In step 1), the volume concentration of the ethanol aqueous solution is 50-70%.

7. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 5, characterized in that, In step 3), a pH meter is used to monitor the pH of the reaction solution and maintain it at 6.5-7.0 to ensure the formation of stable molecular inclusion complexes.

8. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 5, characterized in that, In step 5), dry nitrogen gas is introduced into the mixing chamber, with a relative humidity of ≤30%.

9. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 5, characterized in that, In step 6), during homogenization, the stirring speed is 80-150 rpm and the homogenization pressure is 35-60 MPa.

10. The method for preparing the inclusion-synergistic doxycycline hydrochloride soluble powder as described in claim 5, characterized in that, In step 6), during spray drying, the inlet air temperature is 120±5℃, the outlet air temperature is 70±3℃, and the atomizer speed is 15000-20000rpm; in step 7), the compressed air pressure during pulverization is 0.6-1.0 MPa.

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