CN115212170B - A dense and round drug spherical microcrystal, its preparation method and its application - Google Patents

Abstract

The invention relates to a compact round drug spherical microcrystal, a preparation method and application thereof. The drug microcrystal is a solid spherical microcrystal with compact and round shape, good microcrystal sphericity, high smoothness, uniform particle size distribution, stable and smooth dissolution and release curve, better slow release effect, remarkably improved bioavailability of the drug, accurate control of administration dosage and in-vivo drug release process, reduced administration frequency, improved patient compliance and the like. The preparation method of the drug microcrystal has the advantages of simple operation, high yield, suitability for industrial production and the like.

Description

A dense and round drug spherical microcrystal, its preparation method and its application

Technical field

The invention belongs to the field of medicine, and specifically relates to a dense and round spherical drug crystallite, its preparation method and its application.

Background technique

Sustained-release preparations maintain a constant drug concentration in the blood circulation, reduce or even avoid blood concentration fluctuations caused by repeated administration of ordinary preparations, thereby reducing drug side effects, improving drug safety, and controlling the sustained and constant release of drugs, effectively It can extend the drug action time, significantly reduce the number and frequency of administration, and improve patients' medication compliance, which has broad market potential and development prospects.

Sustained-release oral liquid preparations disperse drug (active ingredient) microcrystals in a liquid medium to form a heterogeneous long-acting preparation, which improves the fluidity of the drug in the suspension and significantly reduces its gastrointestinal irritation, and can be used according to the disease. Treatment requires flexibility in adjusting the oral dosage of medications.

Sustained-release injections prepare drugs (active ingredients) into micron-sized drug crystals (microcrystals for short) and slowly dissolve them into body fluids to delay drug release. They mainly include drug suspensions and drug-loaded microspheres. Injectable drug suspensions directly disperse drug particles in solvents, and have attracted much attention due to their short preparation process, low dosage of excipients, and low cost.

Among FDA-approved sustained-release injection suspensions, Eligard, Sublocade and Atridox use PLGA to achieve sustained drug release; Sustol uses triethylene glycol poly(orthoester) polymer to achieve sustained drug release; paliperidone palmitate and atridox Lipiprazole laurate is made into prodrug microcrystals to delay drug release. The spherical pores, density uniformity, particle size, particle size distribution, and crystallite shape of drug spherical microcrystals affect drug release. The composition and ratio of controlled-release carriers in drug microcrystalline sustained-release suspensions, as well as the spherical pores, density uniformity, particle size, particle size distribution, and crystallite shape of drug spherical microcrystals affect and control the drug (active ingredient). ) release, effectively solving problems such as over-dosage or under-medication, and reducing or even avoiding drug side effects (adverse reactions). For this reason, there is an urgent need to research and develop new drug spherical microcrystals and their preparation methods to accurately control drug release and achieve controllable drug quality to ensure the effectiveness and safety of clinical drugs.

Contents of the invention

The object of the present invention is to provide a kind of drug spherical crystallites, the melting point of the drug is ≥50°C, and the average particle size of the drug spherical crystallites is 0.5 μm-300 μm.

In the preferred technical solution of the present invention, the drug is selected from any one of poorly soluble drugs, easily soluble drugs, soluble drugs, and slightly soluble drugs.

In the preferred technical solution of the present invention, the drug is selected from the group consisting of progesterone, megestrol acetate, moxifloxacin, paliperidone, and curcumin.

In the preferred technical solution of the present invention, the melting point of the drug is 60°C-300°C, preferably 80°C-200°C.

In the preferred technical solution of the present invention, the drug spherical crystallites are solid spheres, preferably dense and round solid spheres.

In the preferred technical solution of the present invention, the average particle size of the drug spherical crystallites is 10 μm-250 μm, preferably 50 μm-200 μm.

In the preferred technical solution of the present invention, the preparation method of the drug spherical microcrystals includes the steps of melting, atomizing and solidifying.

In the preferred technical solution of the present invention, the melting step heats the drug to a molten state under the protection of inert gas.

In a preferred technical solution of the present invention, the inert gas is selected from any one of argon, nitrogen or a combination thereof.

In the preferred technical solution of the present invention, the melting heating temperature is 50°C-300°C, preferably 80°C-250°C.

In the preferred technical solution of the present invention, in the atomization step, under the protection of high-pressure inert gas flow, the molten drug is transported to the atomizer and atomized into spherical droplets.

In the preferred technical solution of the present invention, the atomization pressure is 0.05Mpa-5Mpa, preferably 0.05Mpa-2Mpa.

In the preferred technical solution of the present invention, the atomization flow rate of the drug melt is 1000mL/h-2000mL/h, preferably 1200mL/h-1800mL/h.

In the preferred technical solution of the present invention, the aperture of the atomizer is 0.5mm-5mm, preferably 0.5mm-3mm.

In the preferred technical solution of the present invention, the solidification involves condensation, solidification, drying, and separation of the obtained molten drug droplets to obtain drug microcrystals.

In the preferred technical solution of the present invention, the condensation temperature is -25°C to -80°C, preferably -20°C to -50°C.

In the preferred technical solution of the present invention, the solidification step is performed in a dry environment.

In a preferred technical solution of the present invention, the solidification step is carried out in an air or inert gas environment.

In a preferred technical solution of the present invention, the inert gas is selected from any one of argon, nitrogen or a combination thereof.

In the preferred technical solution of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying or a combination thereof.

In the preferred technical solution of the present invention, the separation is cyclone separation.

In the preferred technical solution of the present invention, a pharmaceutically acceptable carrier is optionally added to the drug spherical microcrystals.

In the preferred technical solution of the present invention, the drug spherical microcrystals can be combined with pharmaceutically acceptable carriers to prepare clinically required pharmaceutical preparations.

Another object of the present invention is to provide a method for preparing pharmaceutical spherical microcrystals, which includes the following steps:

1) Under the protection of inert gas, heat the drug to a molten state;

2) Under the protection of high-pressure inert gas flow, the molten drug is atomized into droplets;

3) Condensate, solidify and dry the obtained mist droplets to obtain drug spherical microcrystals.

In a preferred technical solution of the present invention, the inert gas is selected from any one of argon, nitrogen or a combination thereof.

In the preferred technical solution of the present invention, the melting heating temperature is 50°C-300°C, preferably 80°C-250°C.

In the preferred technical solution of the present invention, in the atomization step, under the protection of high-pressure inert gas flow, the molten drug is transported to the atomizer and atomized into spherical droplets.

In the preferred technical solution of the present invention, the atomization pressure is 0.05Mpa-5Mpa, preferably 0.05Mpa-2Mpa.

In the preferred technical solution of the present invention, the atomization flow rate of the drug melt is 1000mL/h-2000mL/h, preferably 1200mL/h-1800mL/h.

In the preferred technical solution of the present invention, the aperture of the atomizer is 0.5mm-5mm, preferably 0.5mm-3mm.

In the preferred technical solution of the present invention, the solidification involves condensation, solidification, drying, and separation of the obtained molten drug droplets to obtain drug microcrystals.

In the preferred technical solution of the present invention, the condensation temperature is -25°C to -80°C, preferably -20°C to -50°C.

In the preferred technical solution of the present invention, the solidification step is performed in a dry environment.

In a preferred technical solution of the present invention, the solidification step is carried out in an air or inert gas environment.

In a preferred technical solution of the present invention, the inert gas is selected from any one of argon, nitrogen or a combination thereof.

In the preferred technical solution of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying or a combination thereof.

In the preferred technical solution of the present invention, the separation is cyclone separation.

In the preferred technical solution of the present invention, the drug is selected from any one of poorly soluble drugs, easily soluble drugs, soluble drugs, and slightly soluble drugs.

In the preferred technical solution of the present invention, the drug is selected from the group consisting of progesterone, megestrol acetate, moxifloxacin, paliperidone, and curcumin.

In the preferred technical solution of the present invention, the melting point of the drug is 60°C-300°C, preferably 80°C-200°C.

In the preferred technical solution of the present invention, the drug spherical crystallites are solid spheres, preferably dense and round solid spheres.

In the preferred technical solution of the present invention, the average particle size of the drug spherical crystallites is 10 μm-250 μm, preferably 50 μm-200 μm.

In the preferred technical solution of the present invention, a pharmaceutically acceptable carrier is optionally added to the drug spherical microcrystals.

Another object of the present invention is to provide a pharmaceutical microcrystalline preparation, which contains the pharmaceutical microcrystalline of the present invention and a pharmaceutically acceptable carrier.

In the preferred technical solution of the present invention, the drug is selected from any one of poorly soluble drugs, easily soluble drugs, soluble drugs, and slightly soluble drugs.

In the preferred technical solution of the present invention, the drug is selected from the group consisting of progesterone, megestrol acetate, moxifloxacin, paliperidone, and curcumin.

In the preferred technical solution of the present invention, the melting point of the drug is 60°C-300°C, preferably 80°C-200°C.

In the preferred technical solution of the present invention, the drug spherical crystallites are solid spheres, preferably dense and round solid spheres.

In the preferred technical solution of the present invention, the average particle size of the drug spherical crystallites is 10 μm-250 μm, preferably 50 μm-200 μm.

In the preferred technical solution of the present invention, the preparation is any one of a normal preparation, a sustained-release preparation, and a controlled-release preparation.

In the preferred technical solution of the present invention, the sustained-release preparation is selected from the group consisting of sustained-release injections and sustained-release oral preparations.

In the preferred technical solution of the present invention, the preparation dosage form is selected from any one of injections, tablets, capsules, pills, granules, and patches.

In the preferred technical solution of the present invention, the pharmaceutically acceptable carrier is selected from the group consisting of surfactants, suspending agents, isotonic agents, preservatives, fillers, disintegrants, binders, lubricants, and flavoring agents. any one or combination thereof.

The object of the present invention is to provide a progesterone microcrystalline sustained-release suspension, which disperses progesterone microcrystals with a particle size of 20-200 μm in an aqueous matrix, wherein the aqueous matrix is composed of The solvent is composed of any one selected from surfactants, suspending agents, isotonic agents, preservatives or a combination thereof.

In the preferred technical solution of the present invention, the progesterone microcrystalline particle size is 30-100 μm, preferably 35-90 μm.

In the preferred technical solution of the present invention, the progesterone is selected from the group consisting of amorphous progesterone, progesterone crystals, and progesterone microcrystals.

In the preferred technical solution of the present invention, the content of progesterone microcrystals in the sustained-release suspension is 5%-40% (w/v), preferably 10-30% (w/v).

In the preferred technical solution of the present invention, the surfactant content in the sustained-release suspension is 0.01%-3% (w/v), preferably 0.02-2% (w/v).

In the preferred technical solution of the present invention, the surfactant is selected from one of Tween 20, Tween 80, polysorbate, glyceryl monostearate, poloxamer, Span, Maize, and Benzene. species or combination thereof.

In the preferred technical solution of the present invention, the content of the suspending agent in the sustained-release suspension is 0.03%-3% (w/v), preferably 0.05-2% (w/v).

In the preferred technical solution of the present invention, the suspending agent is selected from any one of sodium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium alginate or a combination thereof.

In the preferred technical solution of the present invention, the content of the isotonicity agent in the sustained-release suspension is 1%-10% (w/v), preferably 4-6% (w/v).

In the preferred technical solution of the present invention, the isotonicity agent is selected from any one of mannitol, glucose, sodium chloride, trehalose, sucrose or a combination thereof.

In the preferred technical solution of the present invention, the preservative content in the sustained-release suspension is 0.05%-3% (w/v), preferably 0.10-2% (w/v).

In the preferred technical solution of the present invention, the preservative is selected from methyl paraben, propyl paraben, benzoic acid or its salt, sorbic acid or its salt, paraben, sodium metabisulfite, chlorhexidine, Any one of sodium citrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, ethylenediaminetetraacetic acid, propyl gallate, quaternary ammonium compounds or a combination thereof.

In the preferred technical solution of the present invention, the solvent is selected from water for injection and sodium chloride solution.

In the preferred technical solution of the present invention, the sustained-release suspension contains progesterone microcrystal content of 5%-40% (w/v), surfactant content of 0.01%-3% (w/v), suspension aid The content of the agent is 0.03%-3% (w/v), the content of the isotonic agent is 1%-10% (w/v), and the content of the preservative is 0.05%-3% (w/v).

In the preferred technical solution of the present invention, the sustained-release suspension contains progesterone microcrystal content of 10-30% (w/v), surfactant content of 0.02-2% (w/v), and suspending agent content. The content of isotonic agent is 0.05-2% (w/v), the content of isotonic agent is 4-6% (w/v), and the content of preservative is 0.10-2% (w/v).

In the preferred technical solution of the present invention, the sustained-release suspension contains progesterone microcrystals 10-30% (w/v), Tween 80 content 0.02-2% (w/v), sodium carboxymethyl cellulose The content is 0.05-2% (w/v), the mannitol content is 4-6% (w/v), and the total content of methyl paraben and propyl paraben is 0.10-2% (w/v).

In the preferred technical solution of the present invention, the content of progesterone microcrystals in the sustained-release suspension is 10% (w/v), the content of Tween 80 is 0.02% (w/v), and the content of carboxymethylcellulose sodium is 0.07 % (w/v), mannitol content is 4.44% (w/v), methyl paraben content is 0.13% (w/v), and propyl paraben content is 0.10% (w/v).

The object of the present invention is to provide a moxifloxacin microcrystalline sustained-release tablet, which is prepared by mixing, granulating, and drying moxifloxacin microcrystals with a particle size of 1-200 μm and a pharmaceutically acceptable carrier. , tableting is obtained, wherein the pharmaceutically acceptable carrier is selected from any one of fillers, disintegrants, binders, lubricants or a combination thereof.

In the preferred technical solution of the present invention, the moxifloxacin crystallite size is 5-100 μm, preferably 5-60 μm.

In the preferred technical solution of the present invention, the moxifloxacin is selected from the group consisting of amorphous, crystalline, and microcrystalline.

In the preferred technical solution of the present invention, the content of moxifloxacin microcrystals in the sustained-release tablet is 5%-40% (w/w), preferably 10-30% (w/w).

In the preferred technical solution of the present invention, the filler content in the sustained-release tablet is 30%-90% (w/w), preferably 50%-80% (w/w).

In the preferred technical solution of the present invention, the filler is selected from any one of lactose, microcrystalline cellulose, sucrose, dextrin, sorbitol, mannitol, starch, maltitol or a combination thereof.

In the preferred technical solution of the present invention, the disintegrant content in the sustained-release tablet is 2%-15% (w/w), preferably 3%-12% (w/w).

In the preferred technical solution of the present invention, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, crospovidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch Methylcellulose calcium any one or a combination thereof.

In the preferred technical solution of the present invention, the binder content in the sustained-release tablet is 0.5%-10% (w/w), preferably 0.8%-4% (w/w).

In the preferred technical solution of the present invention, the binder is selected from sodium carboxymethylcellulose, starch slurry, pregelatinized starch, povidone, hypromellose, methylcellulose, and hydroxypropylcellulose. , any one of sodium alginate, ethylcellulose, gelatin, polyethylene glycol or a combination thereof.

In the preferred technical solution of the present invention, the lubricant content in the sustained-release tablet is 0.5%-10% (w/w), preferably 0.8%-4% (w/w).

In a preferred technical solution of the present invention, the lubricant is one or more selected from the group consisting of magnesium stearate, silicon dioxide and talc, or a combination thereof.

In the preferred technical solution of the present invention, the sustained-release tablet contains moxifloxacin microcrystals with a content of 5%-40% (w/w), a filler content of 30%-90% (w/w), and a disintegrant. The content is 2%-15% (w/w), the binder content is 0.5%-10% (w/w), and the lubricant content is 0.5%-10% (w/w).

In the preferred technical solution of the present invention, the sustained-release tablet contains moxifloxacin microcrystal content of 10-30% (w/w), filler content of 50%-80% (w/w), and disintegrant content. The content is 3%-12% (w/w), the binder content is 0.8%-4% (w/w), and the lubricant content is 0.8%-4% (w/w).

The object of the present invention is to provide a megestrol acetate microcrystalline sustained-release suspension, which disperses megestrol acetate microcrystals with a particle size of 5-200 μm in a pharmaceutically acceptable Among the carriers, the pharmaceutically acceptable carrier is selected from any one of surfactants, suspending agents, flavoring agents, preservatives or a combination thereof.

In the preferred technical solution of the present invention, the megestrol acetate crystallite size is 5-50 μm, preferably 1-30 μm.

In the preferred technical solution of the present invention, the megestrol acetate is selected from any one of amorphous, crystalline and microcrystalline.

In the preferred technical solution of the present invention, the surfactant is selected from any one of polysorbate, glyceryl monostearate, sodium lauryl sulfate, poloxamer, Span, Maize, and Benzyl sulfate. or combination thereof.

In the preferred technical solution of the present invention, the suspending agent is selected from any one of carbomer, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, or a combination thereof.

In the preferred technical solution of the present invention, the flavoring agent is selected from any one of sucrose, aspartame, strawberry flavor, vanilla flavor, orange flavor, banana flavor or a combination thereof.

In the preferred technical solution of the present invention, the preservative is selected from benzoic acid or its salt, sorbic acid or its salt, paraben, sodium metabisulfite, chlorhexidine, sodium citrate, butylated hydroxytoluene (BHT) ), butylated hydroxyanisole (BHA), tocopherol, ethylenediaminetetraacetic acid, propyl gallate, quaternary ammonium compounds, or any combination thereof.

The present invention uses laser diffraction method to detect the particle size distribution of spherical crystals: Mastersizer 2000Mu laser particle size analyzer (Malvern Company, UK), using water as the dispersion medium, the pump speed of the sample pool is set to 2200 rpm, and the analysis mode selects the general mode. After the light and background measurements are completed, stir the suspension evenly and add it to the injector until the opacity stabilizes at 10±1%, and then start particle size measurement.

In the present invention, a JSM-7900F thermal field emission scanning electron microscope (Japanese JEOL Company) is used to observe the surface morphology of the product to be tested. After gold spraying treatment, the scanning voltage is 30kV.

The present invention uses a D/MAX2000 rotating target anode X-ray diffractometer (Japanese Rigaku Company) to measure the crystal form of the product to be tested. The product to be tested is placed in the X-ray powder diffractometer so that the sample is in the X-ray optical path and rotates along a fixed axis. , change the angle of θ and record data at the same time. Test conditions: copper target, high voltage intensity: 40kV, tube flow: 40mA, scanning speed: 5°/min, scanning range: 3-190°, scintillation detector.

Unless otherwise stated, when the present invention relates to the percentage between liquid and liquid, the percentage is volume/volume percentage; when the present invention relates to the percentage between liquid and solid, the percentage is volume/weight percentage; the present invention When referring to percentages between solids and liquids, the percentages are weight/volume; the remainder are weight/weight.

Compared with the prior art, the present invention has the following beneficial technical effects:

1. The drug microcrystals of the present invention are solid spherical microcrystals that are dense and round, have good microcrystal sphericity, high smoothness, and uniform particle size distribution (average particle size is 0.5-200 μm). Their dissolution release curve is stable, smooth and sustained-release. The effect is better, the bioavailability of the drug is significantly improved, and it is conducive to accurately controlling the release rate of the drug and selecting the required drug crystal particle size and particle size distribution according to the medication needs, ensuring the quality, effectiveness and safety of the drug.

2. The drug microcrystals of the present invention are dispersed in an aqueous matrix for the preparation of sustained-release suspensions or sustained-release tablets and used for oral administration or injection administration, reducing or even avoiding adverse reactions such as local irritation at the injection site, and the drug The rounded shape of the microcrystalline sphere facilitates good needle passage and delays drug release, significantly improves the bioavailability, effectiveness and safety of the drug, significantly reduces the number of times the patient takes the drug and reduces the toxic and side effects of the drug.

3. The pharmaceutical microcrystal preparation method of the present invention has the characteristics of simple operation, high overall yield, and is conducive to industrial production.

Description of the drawings

Figure 1a-1b Scanning electron microscope imaging results of irregular microcrystals of progesterone prepared in Comparative Example 1;

Figure 2a-2b is a scanning electron microscope imaging result of progesterone spherical microcrystals prepared in Comparative Example 2;

Figures 3a-3b are scanning electron microscope imaging results of progesterone spherical microcrystals prepared in Comparative Example 3;

Figure 4a-4b Scanning electron microscope imaging results of progesterone spherical microcrystals prepared in Example 1;

Figure 5 shows the particle size distribution of progesterone spherical crystallites prepared in Example 1;

Figure 6 Study on the external release of progesterone drug microcrystals;

Figure 7 In vitro release study of progesterone sustained-release suspension;

Figure 8 In vivo release study of progesterone sustained-release suspension.

Detailed ways

Some specific examples are listed below to illustrate the present invention. It is necessary to point out that the following specific examples are only used to further illustrate the present invention and do not mean to limit the scope of protection of the present invention. Some non-essential modifications and adjustments made by others based on the present invention still belong to the protection scope of the present invention.

Comparative Example 1 Preparation of irregular progesterone microcrystals

Under stirring conditions, according to the mass ratio of progesterone ethanol solution: distilled water is 1:12, add the progesterone ethanol solution with a concentration of 40mg/ml into the cold distilled water, precipitate, and obtain a progesterone micron suspension, continue After stirring for 30 minutes, filter it through a Buchner funnel, place it in a vacuum drying box, and dry it at 40°C for 24 hours to obtain progesterone microcrystals. The scanning electron microscope results are shown in Figure 1a-1b.

Comparative Example 2 Preparation of progesterone spherical microcrystals

Heat the progesterone to 135°C until it is completely melted, transport the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200mL/h, and introduce the resulting progesterone atomization liquid into liquid nitrogen. The progesterone microspheres are cooled, solidified and crystallized in the condensation chamber. After the progesterone microspheres are separated by cyclone, the progesterone microcrystals with the required particle size and particle size distribution are collected. The scanning electron microscope results are shown in Figure 2a-2b.

Comparative Example 3 Preparation of progesterone spherical microcrystals

Heat the progesterone to 135°C until it is completely melted, transport the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200 mL/h, and introduce the resulting progesterone atomized liquid into air for condensation. The progesterone microspheres are cooled, solidified and crystallized in the chamber. After the progesterone microspheres are separated by cyclone, the progesterone microcrystals with the required particle size and particle size distribution are collected. The scanning electron microscope results are shown in Figure 3a-3b.

Example 1 Preparation of progesterone spherical microcrystals

Heat the progesterone to 135°C until it is completely melted, transport the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200mL/h, and introduce the resulting progesterone atomization liquid into -20 The progesterone microspheres are cooled, solidified and crystallized in a dry air condensation chamber at ℃. After the prepared progesterone microspheres are separated by cyclone, the progesterone microcrystals are collected. The scanning electron microscope results are shown in Figures 4a-4b, and the particle size distribution is shown in Figure 5.

Example 2 Preparation of progesterone sustained-release suspension

Composition of progesterone extended-release suspension:

The preparation method of progesterone suspension long-acting injection includes the following steps:

1) Weigh the required amount of methyl paraben, propyl paraben and mannitol, dissolve them in water for injection, then add the required amount of sodium carboxymethylcellulose and Tween 80, and incubate in a 60°C water bath Heating under the conditions, stirring until completely dispersed, then cooling to room temperature to prepare 200 ml of aqueous carrier;

2) Precisely weigh 20g of the progesterone drug microcrystals prepared in Example 1 and disperse them into the aqueous carrier prepared in step 1) to obtain a progesterone suspension long-acting injection.

Test Example 1 Study on the in vitro release of progesterone drug microcrystals

A sampling separation method was used to detect the in vitro release degree of the progesterone drug microcrystals prepared in Comparative Example 1 and Example 1:

Release medium: PBS buffer with 0.5% Tween 80

Temperature: 37±0.5℃

Speed: 100rpm

Take 10 mg of progesterone microcrystals prepared in Comparative Example 1 and Example 1 respectively, add them to the release medium (PBS buffer containing 0.5% Tween 80) and adjust the volume to 400 mL, at 1h, 2h, 3h, respectively. Sample 1.5mL at 4h, 6h, 8h, 10h, 12h, 24h, 48h, and 72h. After high-speed centrifugation, take 1mL of supernatant, add release medium and adjust the volume to 1.5mL. Shake and pour back into the cone shape. in a bottle. The test results are shown in Figure 6.

Calculation formula: X _accumulation =X _i +(X ₁ +X ₂ +......+X _i-1 )*V ₂ /V ₁

_{Among them , _} volume number.

Test Example 2 In vitro release study of progesterone sustained-release suspension

Use the sampling separation method to detect the in vitro release of progesterone sustained-release suspension:

Release medium: PBS buffer with 0.5% Tween 80

Temperature: 37±0.5℃

Speed: 100rpm

Use a pipette to remove 100 μL of commercially available sustained-release suspension (trade name: prosphere, Carnot Laboratories) and the progesterone sustained-release suspension prepared in Example 2, and add them to the release medium (containing 0.5% Tween 80 PBS buffer) and dilute to 400 ml, take 1.5 mL samples at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, and 72h respectively. After sampling, centrifuge at high speed and measure the supernatant. Add 1 mL of solution, add release medium and adjust the volume to 1.5 mL, shake and pour back into the Erlenmeyer flask. The test results are shown in Figure 7.

(Calculation formula: X _accumulation =X _i +(X ₁ +X ₂ +...+X _i-1 )*V _{2 /} V ₁ ; degree, Xi _accumulation is the relative cumulative percentage release degree of the i-th time, V ₁ is the total volume of the release medium, and V ₂ is the volume added after each sampling.

Test Example 3: Study on in vivo release of progesterone sustained-release suspension

Twelve male SD rats weighing 190-200 g were raised in a standard experimental environment with free access to water and food. The test animals were randomly divided into 2 groups (6 animals in each group), and the progesterone commercially available oil injection (Zhejiang Xianju Pharmaceutical Co., Ltd.) and the progesterone sustained-release suspension prepared in Example 2 were intramuscularly injected respectively. The dose is 50mg/kg. 150μL of blood is collected from the fundus venous plexus before and 10min, 30min, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 3d, 4d, 6d, 8d and 10d after administration. Place the blood sample in an EP tube containing heparin, set the centrifuge speed to 3000 rpm, and centrifuge for 10 minutes. Take 150 μL of plasma and measure its blood drug concentration. The results are shown in Figure 8.

The results show that the average residence time in the body of the progesterone sustained-release suspension prepared by the present invention is significantly longer than that of commercially available progesterone oil injection, and the sustained-release performance is excellent.

Example 3 Preparation of Moxifloxacin Spherical Microcrystals

Heat moxifloxacin to 195°C until it is completely melted, transport the molten moxifloxacin to an atomizer with a flow rate of 2000mL/h and atomize it at a pressure of 4MPa, and introduce the resulting moxifloxacin atomization liquid. Cool, solidify and crystallize in a dry air condensation chamber at -20°C. The prepared moxifloxacin microspheres are separated by a cyclone to collect moxifloxacin microcrystals with the required particle size and particle size distribution.

Example 4 Preparation of megestrol acetate spherical microcrystals

Megestrol acetate is heated to 215°C until it is completely melted, and the molten megestrol acetate is transported to an atomizer with an atomization pressure of 1MPa at a flow rate of 2000mL/h for atomization, and the resulting megestrol acetate is atomized. The progesterone atomized liquid is introduced into a dry air condensation chamber at -20°C for cooling, solidification, and crystallization. The prepared megestrol acetate microcrystals are separated by a cyclone, and the megestrol acetate microcrystals with the required particle size and particle size distribution are collected. .

The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or deformations according to the present invention. As long as they do not deviate from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims (5)

1. A spherical microcrystal of a drug selected from any one of progesterone, megestrol acetate, moxifloxacin; the drug spherical microcrystals are compact and round solid spheres; the average grain diameter of the spherical microcrystals of the medicine is 50-200 mu m;

the preparation method of the spherical microcrystal comprises the following steps:

1) Heating the medicine to a molten state under the protection of inert gas, wherein the melting heating temperature is 80-250 ℃;

2) Atomizing the molten medicine into mist drops under the protection of high-pressure inert gas flow, wherein the inert gas is selected from any one or combination of argon and nitrogen; the atomizing step is to convey the molten medicine into an atomizer to be atomized into spherical fog drops under the protection of high-pressure inert gas flow; the atomization pressure is 0.05Mpa-2Mpa; the aperture of the atomizer is 0.5mm-3mm; the atomizing flow rate of the medicine melt is 1200mL/h-1800mL/h;

3) Condensing, solidifying, drying and separating the obtained fog drops to obtain spherical microcrystals of the medicine, wherein the condensing temperature is-20-50 ℃; the solidification step is carried out in a dry environment; the solidification step is carried out under air;

the drying is selected from any one or combination of reduced pressure drying and vacuum drying; the separation is cyclone separation.

2. A sustained release suspension of progesterone crystallites according to claim 1 dispersed in an aqueous matrix, wherein the aqueous matrix consists of a solvent and any one or combination selected from the group consisting of surfactants, suspending agents, isotonic agents, preservatives;

the grain diameter of the progesterone microcrystal is 35-90 mu m;

the suspension contains 5% -40% (w/v) of progesterone microcrystal, 0.01% -3% (w/v) of surfactant, 0.03% -3% (w/v) of suspending agent, 1% -10% (w/v) of isotonic agent and 0.05% -3% (w/v) of preservative.

3. The sustained-release suspension according to claim 2, wherein the sustained-release suspension comprises a spherical microcrystal of progesterone in an amount of 10-30% (w/v), a surfactant in an amount of 0.02-2% (w/v), a suspending agent in an amount of 0.05-2% (w/v), an isotonic agent in an amount of 4-6% (w/v), and a preservative in an amount of 0.10-2% (w/v).

4. A sustained-release suspension according to claim 3, wherein the sustained-release suspension comprises 10-30% (w/v) of spherical microcrystals of progesterone, 0.02-2% (w/v) of tween 80, 0.05-2% (w/v) of sodium carboxymethyl cellulose, 4-6% (w/v) of mannitol, and 0.10-2% (w/v) of total of methylparaben and propylparaben.

5. The sustained-release suspension according to claim 4, wherein the content of spherical microcrystals of progesterone is 10% (w/v), the content of tween 80 is 0.02% (w/v), the content of sodium carboxymethylcellulose is 0.07% (w/v), the content of mannitol is 4.44% (w/v), the content of methylparaben is 0.13% (w/v), and the content of propylparaben is 0.10% (w/v).