CN115212170B - Compact and round drug spherical microcrystal, and preparation method and application thereof - Google Patents
Compact and round drug spherical microcrystal, and preparation method and application thereof Download PDFInfo
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- CN115212170B CN115212170B CN202110417837.6A CN202110417837A CN115212170B CN 115212170 B CN115212170 B CN 115212170B CN 202110417837 A CN202110417837 A CN 202110417837A CN 115212170 B CN115212170 B CN 115212170B
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- progesterone
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
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
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compact and round spherical drug microcrystal, a preparation method and application thereof.
Background
The sustained and controlled release preparation maintains constant drug concentration in blood circulation, reduces or even avoids the fluctuation of blood concentration caused by repeated administration of common preparations, further reduces the side effect of the drugs, improves the medication safety, controls the sustained and constant-speed release of the drugs, effectively prolongs the action time of the drugs, obviously reduces the administration times and the administration frequency, improves the medication compliance of patients, and has wide market potential and development prospect.
The slow-release oral liquid preparation disperses the drug (active ingredient) microcrystals in a liquid medium to form a heterogeneous long-acting preparation, improves the mobility of the drug in suspension, obviously reduces the irritation to the gastrointestinal tract, and can flexibly select and adjust the oral dosage of the drug according to the treatment requirement of diseases.
The slow release injection prepares the medicine (active ingredient) into micron-sized medicine crystals (microcrystals for short) and slowly dissolves the medicine crystals into body fluid to delay the release of the medicine, and mainly comprises two major categories of medicine suspension and medicine carrying microspheres. The injection drug suspension directly disperses the drug particles in the solvent, and has the advantages of short preparation process, less auxiliary material consumption, low cost and the like, thus being valued by people.
Eligard, sublocade and Atridox achieve drug release using PLGA in FDA approved sustained release injection suspensions; sustol uses triethylene glycol poly (orthoester) polymer to achieve drug release; paliperidone palmitate and aripiprazole laurate were then formed into prodrug crystallites to delay drug release. The spherical pores, density uniformity, particle size distribution, crystallite shape, etc. of the spherical crystallites of the drug affect drug release. The composition and the proportion of a controlled release carrier in the drug microcrystalline sustained-release suspension, as well as the effects of sphere pores, density uniformity, particle size distribution, microcrystalline shape and the like of the drug spherical microcrystalline, control the release of the drug (active ingredient), effectively solve the problems of overdose or insufficient drug administration and the like, and reduce or even avoid the side effects (adverse reactions) of the drug. Therefore, research and development of new spherical microcrystals of drugs and a preparation method thereof are needed to accurately control drug release and realize controllable drug quality so as to ensure the effectiveness and safety of clinical medication.
Disclosure of Invention
The invention aims to provide a drug spherical microcrystal, the melting point of the drug is more than or equal to 50 ℃, and the average grain diameter of the drug spherical microcrystal is 0.5-300 mu m.
In a preferred embodiment of the present invention, the drug is selected from any one of poorly soluble drug, easily soluble drug, and slightly soluble drug.
In a preferred embodiment of the present invention, the drug is selected from any one of progesterone, megestrol acetate, moxifloxacin, paliperidone, curcumin.
In a preferred embodiment of the present invention, the melting point of the drug is 60 ℃ to 300 ℃, preferably 80 ℃ to 200 ℃.
In a preferred technical scheme of the invention, the drug spherical microcrystals are solid spheres, preferably compact and round solid spheres.
In a preferred embodiment of the present invention, the average particle size of the spherical crystallites of the drug is from 10 μm to 250. Mu.m, preferably from 50 μm to 200. Mu.m.
In a preferred technical scheme of the invention, the preparation method of the spherical drug microcrystal comprises the steps of melting, atomizing and solidifying.
In a preferred embodiment of the present invention, the melting step heats the drug to a molten state under the protection of an inert gas.
In a preferred embodiment of the present invention, the inert gas is selected from any one of argon and nitrogen, or a combination thereof.
In a preferred embodiment of the present invention, the melting heating temperature is 50 ℃ to 300 ℃, preferably 80 ℃ to 250 ℃.
In a preferred embodiment of the present invention, the atomizing step delivers the molten drug to an atomizer under the protection of a high pressure inert gas flow to atomize the molten drug into spherical droplets.
In a preferred embodiment of the present invention, the atomization pressure is 0.05Mpa-5Mpa, preferably 0.05Mpa-2Mpa.
In a preferred technical scheme of the invention, the atomizing flow rate of the drug melt is 1000mL/h-2000mL/h, preferably 1200mL/h-1800mL/h.
In a preferred embodiment of the present invention, the pore diameter of the atomizer is 0.5mm-5mm, preferably 0.5mm-3mm.
In the preferred technical scheme of the invention, the obtained drug melt mist drops are condensed, solidified, dried and separated by solidification to prepare drug microcrystals.
In a preferred embodiment of the present invention, the condensation temperature is-25℃to-80℃and preferably-20℃to-50 ℃.
In a preferred embodiment of the present invention, the solidification step is performed in a dry environment.
In a preferred embodiment of the present invention, the solidification step is performed in an air or inert gas atmosphere.
In a preferred embodiment of the present invention, the inert gas is selected from any one of argon and nitrogen, or a combination thereof.
In a preferred embodiment of the present invention, the drying is selected from any one of reduced pressure drying and vacuum drying, or a combination thereof.
In a preferred embodiment of the invention, the separation is cyclone separation.
In a preferred embodiment of the present invention, a pharmaceutically acceptable carrier is optionally added to the spherical microcrystals of the drug.
In a preferred technical scheme of the invention, the spherical microcrystals of the medicine can be used for preparing clinically-required medicine preparations with pharmaceutically-acceptable carriers.
Another object of the present invention is to provide a method for preparing spherical microcrystals of a drug, comprising the steps of:
1) Heating the drug to a molten state under the protection of inert gas;
2) Atomizing the molten medicine into mist drops under the protection of high-pressure inert gas flow;
3) Condensing, solidifying and drying the obtained fog drops to obtain the spherical microcrystal of the medicine.
In a preferred embodiment of the present invention, the inert gas is selected from any one of argon and nitrogen, or a combination thereof.
In a preferred embodiment of the present invention, the melting heating temperature is 50 ℃ to 300 ℃, preferably 80 ℃ to 250 ℃.
In a preferred embodiment of the present invention, the atomizing step delivers the molten drug to an atomizer under the protection of a high pressure inert gas flow to atomize the molten drug into spherical droplets.
In a preferred embodiment of the present invention, the atomization pressure is 0.05Mpa-5Mpa, preferably 0.05Mpa-2Mpa.
In a preferred technical scheme of the invention, the atomizing flow rate of the drug melt is 1000mL/h-2000mL/h, preferably 1200mL/h-1800mL/h.
In a preferred embodiment of the present invention, the pore diameter of the atomizer is 0.5mm-5mm, preferably 0.5mm-3mm.
In the preferred technical scheme of the invention, the obtained drug melt mist drops are condensed, solidified, dried and separated by solidification to prepare drug microcrystals.
In a preferred embodiment of the present invention, the condensation temperature is-25℃to-80℃and preferably-20℃to-50 ℃.
In a preferred embodiment of the present invention, the solidification step is performed in a dry environment.
In a preferred embodiment of the present invention, the solidification step is performed in an air or inert gas atmosphere.
In a preferred embodiment of the present invention, the inert gas is selected from any one of argon and nitrogen, or a combination thereof.
In a preferred embodiment of the present invention, the drying is selected from any one of reduced pressure drying and vacuum drying, or a combination thereof.
In a preferred embodiment of the invention, the separation is cyclone separation.
In a preferred embodiment of the present invention, the drug is selected from any one of poorly soluble drug, easily soluble drug, and slightly soluble drug.
In a preferred embodiment of the present invention, the drug is selected from any one of progesterone, megestrol acetate, moxifloxacin, paliperidone, curcumin.
In a preferred embodiment of the present invention, the melting point of the drug is 60 ℃ to 300 ℃, preferably 80 ℃ to 200 ℃.
In a preferred technical scheme of the invention, the drug spherical microcrystals are solid spheres, preferably compact and round solid spheres.
In a preferred embodiment of the present invention, the average particle size of the spherical crystallites of the drug is from 10 μm to 250. Mu.m, preferably from 50 μm to 200. Mu.m.
In a preferred embodiment of the present invention, a pharmaceutically acceptable carrier is optionally added to the spherical microcrystals of the drug.
Another object of the present invention is to provide a pharmaceutical microcrystalline preparation comprising the pharmaceutical microcrystalline according to the present invention and a pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the drug is selected from any one of poorly soluble drug, easily soluble drug, and slightly soluble drug.
In a preferred embodiment of the present invention, the drug is selected from any one of progesterone, megestrol acetate, moxifloxacin, paliperidone, curcumin.
In a preferred embodiment of the present invention, the melting point of the drug is 60 ℃ to 300 ℃, preferably 80 ℃ to 200 ℃.
In a preferred technical scheme of the invention, the drug spherical microcrystals are solid spheres, preferably compact and round solid spheres.
In a preferred embodiment of the present invention, the average particle size of the spherical crystallites of the drug is from 10 μm to 250. Mu.m, preferably from 50 μm to 200. Mu.m.
In the preferred technical scheme of the invention, the preparation is any one of a common preparation, a slow release preparation and a controlled release preparation.
In a preferred technical scheme of the invention, the slow release preparation is selected from any one of slow release injection and slow release oral preparation.
In a preferred embodiment of the present invention, the formulation is selected from any one of injection, tablet, capsule, pill, granule, and patch.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or a combination of surfactants, suspending agents, isotonic agents, preservatives, fillers, disintegrants, binders, lubricants, flavoring agents.
The invention aims to provide a progesterone microcrystal slow-release suspension, which disperses progesterone microcrystals with the particle size of 20-200 μm in an aqueous matrix, wherein the aqueous matrix consists of a solvent and any one or combination of a surfactant, a suspending agent, an isotonic agent and a preservative.
In a preferred embodiment of the present invention, the progesterone crystallites have a particle size of 30-100. Mu.m, preferably 35-90. Mu.m.
In a preferred embodiment of the present invention, the progestin is selected from any one of amorphous progestin, progestin crystals, and progestin crystallites.
In a preferred embodiment of the present invention, the content of progesterone crystallites in the slow release suspension is 5-40% (w/v), preferably 10-30% (w/v).
In a preferred embodiment of the present invention, the slow release suspension comprises 0.01% -3% (w/v), preferably 0.02-2% (w/v) of surfactant.
In a preferred embodiment of the present invention, the surfactant is selected from one or a combination of tween 20, tween 80, polysorbate, glyceryl monostearate, poloxamer, span, frazier, and benzyl.
In a preferred embodiment of the present invention, the sustained-release suspension comprises a suspending agent in an amount of 0.03% -3% (w/v), preferably 0.05-2% (w/v).
In a preferred embodiment of the present invention, the suspending agent is selected from any one or a combination of sodium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, methylcellulose, and sodium alginate.
In a preferred embodiment of the present invention, the sustained-release suspension contains 1% -10% (w/v), preferably 4-6% (w/v) of isotonic agent.
In a preferred embodiment of the present invention, the isotonic agent is selected from any one of mannitol, glucose, sodium chloride, trehalose, sucrose, or a combination thereof.
In a preferred embodiment of the present invention, the slow release suspension comprises 0.05% -3% (w/v), preferably 0.10-2% (w/v) of preservative.
In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of methylparaben, propylparaben, benzoic acid or a salt thereof, sorbic acid or a salt thereof, paraben, sodium metabisulfite, chlorhexidine, sodium citrate, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, and a quaternary ammonium compound.
In a preferred embodiment of the present invention, the solvent is selected from any one of water for injection and sodium chloride solution.
In the preferred technical scheme of the invention, the slow-release 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.
In the preferred technical scheme of the invention, the sustained-release suspension contains 10-30% (w/v) of progesterone microcrystals, 0.02-2% (w/v) of surfactant, 0.05-2% (w/v) of suspending agent, 4-6% (w/v) of isotonic agent and 0.10-2% (w/v) of preservative.
In the preferred technical scheme of the invention, the sustained-release suspension contains 10-30% (w/v) of progesterone microcrystal, 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 content of methylparaben and propylparaben.
In a preferred technical scheme of the invention, the slow-release suspension comprises flavone microcrystals with the content of 10% (w/v), tween 80 with the content of 0.02% (w/v), sodium carboxymethylcellulose with the content of 0.07% (w/v), mannitol with the content of 4.44% (w/v), methylparaben with the content of 0.13% (w/v) and propylparaben with the content of 0.10% (w/v).
The invention aims to provide a moxifloxacin microcrystalline sustained-release tablet, which is prepared by mixing moxifloxacin microcrystalline with the particle size of 1-200 mu m with a pharmaceutically acceptable carrier, granulating, drying and tabletting, wherein the pharmaceutically acceptable carrier is selected from any one or combination of a filler, a disintegrating agent, an adhesive and a lubricant.
In a preferred technical scheme of the invention, the grain size of the moxifloxacin microcrystals is 5-100 mu m, preferably 5-60 mu m.
In a preferred technical scheme of the invention, the moxifloxacin is selected from any one of amorphous, crystalline and microcrystalline.
In a preferred embodiment of the present invention, the moxifloxacin microcrystals are present in the sustained release tablet in an amount of 5% to 40% (w/w), preferably 10% to 30% (w/w).
In a preferred embodiment of the present invention, the filler content of the sustained release tablet is 30% -90% (w/w), preferably 50% -80% (w/w).
In a preferred embodiment 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 a preferred embodiment of the present invention, the content of disintegrant in the sustained release tablet is 2% -15% (w/w), preferably 3% -12% (w/w).
In a preferred embodiment of the present invention, the disintegrating agent is selected from any one of sodium carboxymethyl starch, crospovidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and calcium carboxymethyl cellulose, or a combination thereof.
In a preferred embodiment of the present invention, the binder content of the sustained release tablet is 0.5% -10% (w/w), preferably 0.8% -4% (w/w).
In a preferred embodiment of the present invention, the binder is selected from any one of sodium carboxymethyl cellulose, starch slurry, pregelatinized starch, povidone, hypromellose, methylcellulose, hydroxypropyl cellulose, sodium alginate, ethylcellulose, gelatin, polyethylene glycol, or a combination thereof.
In a preferred embodiment of the present invention, the lubricant content of the sustained release tablet is 0.5% -10% (w/w), preferably 0.8% -4% (w/w).
In a preferred embodiment of the present invention, the lubricant is one or more selected from magnesium stearate, silica and talc, or a combination thereof.
In the preferred technical scheme of the invention, the sustained release tablet contains 5-40% (w/w) of moxifloxacin microcrystal, 30-90% (w/w) of filler, 2-15% (w/w) of disintegrating agent, 0.5-10% (w/w) of adhesive and 0.5-10% (w/w) of lubricant.
In the preferred technical scheme of the invention, the sustained release tablet contains 10-30% (w/w) of moxifloxacin microcrystal, 50-80% (w/w) of filler, 3-12% (w/w) of disintegrating agent, 0.8-4% (w/w) of adhesive and 0.8-4% (w/w) of lubricant.
The invention aims to provide a megestrol acetate microcrystal slow-release suspension, which disperses megestrol acetate microcrystal with the grain diameter of 5-200 μm in a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is selected from any one or combination of a surfactant, a suspending agent, a flavoring agent and a preservative.
In a preferred embodiment of the present invention, the megestrol acetate crystallites have a particle size of 5-50 μm, preferably 1-30 μm.
In a preferred embodiment of the present invention, the megestrol acetate is selected from any one of amorphous, crystalline, and microcrystalline.
In a preferred embodiment of the present invention, the surfactant is selected from any one or a combination of polysorbate, glyceryl monostearate, sodium lauryl sulfate, poloxamer, span, frazier, and benzyl.
In a preferred embodiment of the present invention, the suspending agent is selected from any one or a combination of carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and acacia.
In a preferred technical scheme of the invention, the flavoring agent is selected from any one or combination of sucrose, aspartame, strawberry essence, vanilla essence, orange essence and banana essence.
In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of benzoic acid or a salt thereof, sorbic acid or a salt thereof, parabens, sodium metabisulfite, chlorhexidine, sodium citrate, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, and quaternary ammonium compounds.
The invention adopts a laser diffraction method to detect the particle size distribution of spherical crystals: the Mastersizer 2000Mu laser particle sizer (Malvern, uk) uses water as the dispersion medium, the pump speed of the cell is set to 2200rpm, and the analysis mode selects the universal mode. After the light and background measurement is completed, the suspension is taken and stirred uniformly and added into a sample injector until the shading degree is stabilized at 10+/-1%, and the particle size measurement is started.
The invention adopts a JSM-7900F thermal field emission scanning electron microscope (JEOL corporation) to observe the surface morphology of the to-be-detected sample, and the scanning voltage is 30kV after the gold spraying treatment.
The invention adopts a D/MAX2000 rotary target anode X-ray diffractometer (Rigaku corporation of Japan) to measure the crystal form of the to-be-measured product, the to-be-measured product is placed in the X-ray powder diffractometer, the sample is positioned in an X-ray light path, and rotates along a fixed shaft, the angle of theta is changed, and meanwhile, the data is recorded. Test conditions: copper target, high pressure intensity: 40kV, tube flow: 40mA, scanning speed: 5 °/min, scan range: 3-190 deg., scintillation detector.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the drug microcrystal is a solid spherical microcrystal which is compact, round, good in microcrystal sphericity, high in smoothness and even in particle size distribution (the average particle size is 0.5-200 mu m), has a stable and smooth dissolution and release curve and a better slow release effect, remarkably improves the bioavailability of the drug, is beneficial to precisely controlling the release rate of the drug, and ensures the quality, the effectiveness and the safety of the drug by selecting the needed drug microcrystal particle size and the particle size distribution according to the drug requirement.
2. The drug microcrystal is dispersed in an aqueous matrix for preparing a sustained-release suspension or a sustained-release tablet and for oral administration or injection administration, so that adverse reactions such as local irritation at an injection position are reduced or even avoided, and the drug microcrystal is round and round, thereby being beneficial to well dredging needles and delaying drug release, remarkably improving the bioavailability and the effectiveness and the safety of the drug, remarkably reducing the administration times of patients and reducing the toxic and side effects of the drug.
3. The preparation method of the medicine microcrystal has the characteristics of simple and convenient operation, high total yield, contribution to realizing industrial production and the like.
Drawings
FIGS. 1a-1b are graphs showing scanning electron microscope imaging results of irregular microcrystals of progesterone prepared in comparative example 1;
FIGS. 2a-2b scanning electron microscope imaging results of spherical crystallites of progesterone prepared in comparative example 2;
FIGS. 3a-3b scanning electron microscope imaging results of spherical crystallites of progesterone prepared in comparative example 3;
FIGS. 4a-4b are graphs showing the scanning electron microscope imaging results of spherical crystallites of progesterone obtained in example 1;
FIG. 5 the spherical crystallite size distribution of progesterone obtained in example 1;
FIG. 6 in vitro release studies of progesterone drug crystallites;
figure 7 in vitro release studies of progesterone sustained release suspensions;
figure 8 in vivo release studies of progesterone sustained release suspensions.
Detailed Description
The invention is illustrated by the following examples, which are given solely for the purpose of further illustration and are not intended to limit the scope of the invention. Some insubstantial modifications and adaptations of the invention by others are within the scope of the invention.
Comparative example 1 preparation of irregular progesterone crystallites
Under stirring, the ethanol solution of progesterone is prepared by the following steps: the mass ratio of distilled water is 1:12, adding 40mg/ml of progesterone ethanol solution into cold distilled water, precipitating to obtain progesterone micron-sized suspension, continuously stirring for 30min, filtering by a Buchner funnel, placing into a vacuum drying oven, and drying at 40 ℃ for 24h to obtain progesterone microcrystals. The scanning electron microscope results are shown in fig. 1a-1b.
Comparative example 2 preparation of spherical microcrystals of progesterone
And heating the progesterone to 135 ℃ until the progesterone is completely melted, conveying the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200mL/h for atomization, introducing the obtained progesterone atomized liquid into a liquid nitrogen condensing chamber for cooling, solidifying and crystallizing, and collecting progesterone microcrystals with required particle size and particle size distribution after cyclone separation of the prepared progesterone microballoons. The scanning electron microscope results are shown in fig. 2a-2b.
Comparative example 3 preparation of spherical microcrystals of progesterone
And heating the progesterone to 135 ℃ until the progesterone is completely melted, conveying the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200mL/h for atomization, introducing the obtained progesterone atomized liquid into an air condensing chamber for cooling, solidifying and crystallizing, and collecting progesterone microcrystals with required particle size and particle size distribution after cyclone separation of the prepared progesterone microspheres. The scanning electron microscope results are shown in FIGS. 3a-3b.
EXAMPLE 1 preparation of spherical microcrystals of progesterone
And heating the progesterone to 135 ℃ until the progesterone is completely melted, conveying the molten progesterone to an atomizer with an atomization pressure of 0.1MPa at a flow rate of 1200mL/h for atomization, introducing the obtained progesterone atomized liquid into a dry air condensing chamber with the temperature of minus 20 ℃ for cooling, solidifying and crystallizing, and collecting progesterone microcrystals after cyclone separation of the progesterone microspheres. The scanning electron microscope results are shown in fig. 4a-4b, and the particle size distribution is shown in fig. 5.
EXAMPLE 2 preparation of Progesterone sustained-release suspension
Composition of the progesterone sustained-release suspension:
the preparation method of the progesterone suspension type long-acting injection comprises the following steps:
1) Weighing required amounts of methylparaben, propylparaben and mannitol, dissolving in water for injection, adding required amounts of sodium carboxymethylcellulose and Tween 80, heating in water bath at 60deg.C, stirring until dispersion is complete, and cooling to room temperature to obtain 200ml of aqueous carrier;
2) Precisely weighing 20g of the progesterone drug microcrystal prepared in the example 1, dispersing the microcrystal into the aqueous carrier prepared in the step 1), and obtaining the progesterone suspension long-acting injection.
Test example 1 in vitro Release study of Progesterone drug microcrystals
The in vitro release rate of the progesterone drug microcrystals prepared in comparative example 1 and example 1 was measured by a sampling separation method:
release medium: PBS buffer containing 0.5% Tween 80
Temperature: 37+ -0.5 DEG C
Rotational speed: 100rpm
10mg of progesterone microcrystals prepared in comparative example 1 and example 1 were taken respectively, added to a release medium (PBS buffer containing 0.5% Tween 80) and fixed to 400mL, 1.5mL were sampled at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h and 72h respectively, centrifuged at high speed, 1mL of supernatant was taken, the release medium was supplemented and fixed to 1.5mL, and the mixture was poured into a conical flask after shaking. The detection results are shown in FIG. 6.
The calculation formula is as follows: x is X Accumulation of ＝X i +(X 1 +X 2 +......+X i-1 )*V 2 /V 1
Wherein X is i For the ith actual measured relative percent release, X i accumulation For the ith relative cumulative percent release, V 1 To release the total volume of the medium, V 2 The number of volumes replenished after each sampling.
Experimental example 2 in vitro release profile study of progesterone sustained release suspensions
In vitro release of progesterone sustained-release suspension was detected by sampling separation:
release medium: PBS buffer containing 0.5% Tween 80
Temperature: 37+ -0.5 DEG C
Rotational speed: 100rpm
100. Mu.L of a commercially available sustained-release suspension (trade name: prosphere, carnot laboratory) and the progesterone sustained-release suspension prepared in example 2 were removed by a pipette, added to a release medium (PBS buffer containing 0.5% Tween 80) and fixed to 400mL, 1.5mL was sampled at 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h, respectively, and after high-speed centrifugation of the samples, 1mL of the supernatant was measured, the release medium was supplemented and fixed to 1.5mL, and the mixture was poured into a conical flask after shaking. The detection results are shown in FIG. 7.
(calculation formula: X) Accumulation of ＝X i +(X 1 +X 2 +......+X i-1 )*V 2 /V 1 ；X i For the ith actual measured relative percent release, X i accumulation For the ith relative cumulative percent release, V 1 To release the total volume of the medium, V 2 The number of volumes replenished after each sampling.
Test example 3 in vivo Release study of Progesterone sustained-release suspension
Male SD rats 12 weighing 190-200g were kept under standard test conditions, freely fed with water and ingested. The test animals were randomly divided into 2 groups (6 animals per group), and each group was intramuscular injected with a commercial oil needle of progesterone (manufactured by Zhejiang Xian He pharmaceutical Co., ltd.) at a dose of 50mg/kg, and the plasma concentration was measured by taking 150. Mu.L of blood sample from the fundus venous plexus, placing the blood sample in an EP tube containing heparin, setting the rotational speed of the centrifuge at 3000rpm, centrifuging for 10min, and taking 150. Mu.L of plasma, and measuring the blood concentration of the blood sample 10min, 30min, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 3d, 4d, 6d, 8d, and 10d, respectively, as shown in FIG. 8.
The result shows that the in-vivo average residence time of the progesterone sustained-release suspension prepared by the invention is obviously longer than that of a commercial progesterone oil needle, and the sustained-release performance is excellent.
EXAMPLE 3 preparation of spherical microcrystals of moxifloxacin
And heating moxifloxacin to 195 ℃ until the moxifloxacin is completely melted, conveying the molten moxifloxacin to an atomizer with an atomization pressure of 4MPa at a flow rate of 2000mL/h for atomization, introducing the obtained moxifloxacin atomized liquid into a dry air condensing chamber with the temperature of minus 20 ℃ for cooling, solidifying and crystallizing, and collecting moxifloxacin microcrystals with the required particle size and particle size distribution after cyclone separation of the prepared moxifloxacin microspheres.
EXAMPLE 4 preparation of megestrol acetate spherical microcrystals
The megestrol acetate is heated to 215 ℃ until the megestrol acetate is completely melted, the molten megestrol acetate is conveyed to an atomizer with the atomization pressure of 1MPa at the flow rate of 2000mL/h for atomization, the obtained megestrol acetate atomized liquid is guided into a drying air condensing chamber with the temperature of minus 20 ℃ for cooling, solidification and crystallization, and after cyclone separation, the prepared megestrol acetate microcrystal is collected to obtain the megestrol acetate microcrystal with the required grain diameter and grain diameter distribution.
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope 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).
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