CN111450064A - Method for preparing sirolimus coated particles based on supercritical anti-solvent method, prepared sirolimus coated particles and application - Google Patents
Method for preparing sirolimus coated particles based on supercritical anti-solvent method, prepared sirolimus coated particles and application Download PDFInfo
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- 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
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
The invention provides a method for preparing sirolimus coated particles based on a supercritical anti-solvent method, the prepared sirolimus coated particles and application thereof, and relates to the technical field of novel medicament preparation. In the method, in a supercritical state, a supercritical fluid is used as an antisolvent to precipitate the sirolimus particles in the sirolimus solution, and then the precipitated sirolimus particles react with the particle carrier to coat the sirolimus particles on the surface of the particle carrier, so that the sirolimus-coated particles are prepared. The sirolimus coated particle prepared by the preparation method greatly improves the solubility of sirolimus in water, and meanwhile, the sirolimus coated particle prepared by the method has good coating rate, so that the problems that the sirolimus prepared by the existing medium grinding method has large energy consumption and easy product inactivation, and the existing method for improving the solubility of sirolimus is not beneficial to industrial production are effectively solved.
Description
Technical Field
The invention relates to the technical field of preparation of novel medicaments, in particular to a method for preparing sirolimus coated particles based on a supercritical anti-solvent method, the prepared sirolimus coated particles and application thereof.
Background
Compared with cyclosporine and tacrolimus, the sirolimus oral preparation has high curative effect and low toxicity, and draws attention of people, however, the existing sirolimus oral preparation has low solubility in water, the solubility in water is only about 2.6 mu g/ml, the oral bioavailability is very low, and is only 14-31%, so the improvement of the solubility and the dissolution performance and the improvement of the bioavailability become the key of the research on the existing sirolimus medicaments.
The preparation form of sirolimus on the market at the present stage is mainly tablets prepared by a medium grinding method, but the medium grinding method has certain defects and shortcomings, for example, the energy consumption is larger, the steps of subsequent treatment are complicated, the medicine can be inactivated by high temperature possibly generated by grinding, and the like.
Therefore, on the basis, research and development of a method which has a simple preparation process and low energy consumption and can remarkably improve the solubility of sirolimus in water and further improve the oral bioavailability of sirolimus are necessary and urgent to solve the problems that the existing medium grinding method for preparing sirolimus consumes more energy and the grinding high temperature may cause drug inactivation and the existing method for improving the solubility of sirolimus has complicated subsequent treatment steps and is not beneficial to industrial production.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first object of the present invention is to provide a method for preparing sirolimus-coated particles based on the supercritical anti-solvent method, which comprises precipitating sirolimus fine particles in a sirolimus solution using a supercritical fluid as an anti-solvent, and subsequently reacting the precipitated sirolimus fine particles with a particle carrier to coat the sirolimus fine particles on the surface of the particle carrier, thereby preparing sirolimus-coated particles. The sirolimus particles precipitated by the supercritical anti-solvent method have smaller particle size, so that the solubility of sirolimus in water is greatly improved, and meanwhile, the sirolimus coated particles prepared by the method have good coating rate.
A second object of the present invention is to provide sirolimus-coated particles prepared by the above method.
The third objective of the present invention is to provide an application of the sirolimus coated particle, wherein the sirolimus coated particle can be widely applied to the preparation of immunosuppressive drugs.
The invention provides a method for preparing sirolimus coated particles based on a supercritical anti-solvent method, which comprises the following steps:
in a supercritical state, firstly mixing a sirolimus solution with a supercritical fluid to precipitate sirolimus particles, and then reacting the precipitated sirolimus particles with a particle carrier to coat the sirolimus particles on the surface of the particle carrier, thereby obtaining sirolimus-coated particles.
Further, the solvent of the sirolimus solution is an organic solvent;
preferably, the organic solvent comprises any one of methanol, ethanol or acetone, preferably acetone;
preferably, the concentration of the sirolimus solution is 1-5 mg/ml, and preferably 1 mg/ml.
Further, the supercritical state satisfies at least one of the following: the temperature of the supercritical state comprises 40-50 ℃, and the pressure of the supercritical state comprises 7-9 MPa;
preferably, the supercritical state satisfies at least one of the following: the temperature in the supercritical state comprises 45 ℃ and the pressure in the supercritical state comprises 8 MPa.
Further, the supercritical fluid includes carbon dioxide.
Further, when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the supercritical fluid is 17-50 g/min, preferably 32 g/min;
preferably, when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the sirolimus solution is 0.4 to 0.6ml/min, and preferably 0.5 ml/min.
Further, the particulate carrier comprises at least one of microcrystalline cellulose, lactose, sucrose, mannitol, or xylitol, preferably microcrystalline cellulose;
preferably, the particle size of the particle carrier is 200-400 μm, preferably 200 μm.
Further, the preparation method comprises the following steps:
(a) dissolving sirolimus in an organic solvent to obtain a solution A with the concentration of 1-5 mg/ml;
(b) in a supercritical reaction device, adjusting the supercritical state to 40-50 ℃, adjusting the pressure to 7-9 MPa, and adjusting the flow of the supercritical fluid to 17-50 g/min;
(c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing the solution A with a supercritical fluid at a flow rate of 0.4-0.6 ml/min to precipitate sirolimus particles, blowing a particle carrier into the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surface of the particle carrier to obtain sirolimus coated particles;
preferably, the preparation method further comprises step (d): and (c) after the sirolimus-coated nanoparticles are prepared in the step (c), introducing the same organic solvent as that in the step (a) into a supercritical reaction device to clean the organic solvent remained after the sirolimus microparticles are precipitated from the solution A.
The invention provides sirolimus coated particles prepared according to the method.
The invention provides an application of the sirolimus coated particles in preparation of immunosuppressive drugs.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a method for preparing sirolimus coated particles based on a supercritical anti-solvent method. The sirolimus particles precipitated by the supercritical anti-solvent method have smaller particle size of 0.1-1 mu m, so that the solubility of sirolimus in water is greatly improved, and meanwhile, the sirolimus coated particles prepared by the method have good coating rate. Therefore, the sirolimus coated particle prepared by the preparation method effectively improves the utilization rate of sirolimus, and solves the problems that the energy consumption is high and the grinding high temperature can cause the inactivation of the medicine when the sirolimus is prepared by the existing medium grinding method, and the problems that the subsequent treatment steps are complicated and the industrialized production is not facilitated when the existing method for improving the solubility of sirolimus is adopted.
The sirolimus coated particle provided by the invention is prepared by the method, and the outer layer of the particle carrier is coated with nano-grade sirolimus particles, and meanwhile, the coated particle has high coating rate; therefore, the sirolimus-coated particles have good solubility in water.
The sirolimus coated particle provided by the invention can be widely applied to the preparation of immunosuppressive drugs.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph showing the measurement of the dissolution rate in water of sirolimus-coated particles prepared in examples 1, 2, 3, 10, 11, 12, 13, 15, 16, 17, 18 and 21 according to Experimental example 1 of the present invention;
FIG. 2 is an electron microscope comparing the sirolimus coated particles prepared in example 1 of the present invention with the lactose particle carrier without sirolimus microparticles in example 1;
FIG. 3 is an electron microscope comparison of sirolimus coated particles prepared in example 24 and provided in Experimental example 1 of the present invention with microcrystalline cellulose particle carriers of example 24 which are not coated with sirolimus particles;
FIG. 4 is an electron microscope comparing the sirolimus coated particles prepared in example 13 and the sucrose particle carrier without sirolimus particles in example 13 provided in Experimental example 1 of the present invention;
FIG. 5 is an electron microscope image of sirolimus prepared by a conventional media milling method according to Experimental example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
According to one aspect of the present invention, a method for preparing sirolimus-coated particles based on a supercritical anti-solvent process, the preparation method comprising the steps of:
in a supercritical state, firstly mixing a sirolimus solution with a supercritical fluid to precipitate sirolimus particles, and then reacting the precipitated sirolimus particles with a particle carrier to coat the sirolimus particles on the surface of the particle carrier, thereby obtaining sirolimus-coated particles.
The invention provides a method for preparing sirolimus coated particles based on a supercritical anti-solvent method. The sirolimus particles precipitated by the supercritical anti-solvent method have smaller particle size of 0.1-1 μm, which greatly improves the solubility of sirolimus in water, and meanwhile, the sirolimus coated particles prepared by the method have higher coating rate. Therefore, the sirolimus coated particle prepared by the preparation method effectively improves the utilization rate of sirolimus, and solves the problems that the energy consumption is high and the grinding high temperature can cause the inactivation of the medicine when the sirolimus is prepared by the existing medium grinding method, and the problems that the subsequent treatment steps are complicated and the industrialized production is not facilitated when the existing method for improving the solubility of sirolimus is adopted.
In a preferred embodiment of the present invention, the solvent of the sirolimus solution is an organic solvent;
in the above preferred embodiment, the organic solvent includes any one of methanol, ethanol, or acetone, preferably acetone;
in a preferred embodiment, the organic solvent includes acetone.
In a preferred embodiment of the invention, the concentration of the sirolimus solution is 1 to 5mg/ml, preferably 1 mg/ml.
Typical but non-limiting preferred embodiments of the concentration of solution a described above are: 1mg/ml, 2mg/ml, 3mg/ml, 4mg/ml and 5 mg/ml.
In a preferred embodiment of the present invention, the supercritical state satisfies at least one of the following: the temperature of the supercritical state comprises 40-50 ℃, and the pressure of the supercritical state comprises 7-9 MPa;
in a preferred embodiment, the temperature in the supercritical state is 45 ℃ and the pressure in the supercritical state comprises 8 MPa.
Typical but non-limiting preferred embodiments of the above-mentioned temperature in the supercritical state are: 40 deg.C, 42 deg.C, 45 deg.C, 48 deg.C and 50 deg.C; typical but non-limiting preferred embodiments of the above-mentioned pressure in the supercritical state are: 7MPa, 7.5MPa, 8MPa, 8.5MPa and 9 MPa.
Preferably, the supercritical state satisfies at least one of the following: the temperature in the supercritical state comprises 45 ℃ and the pressure in the supercritical state comprises 8 MPa.
In a preferred embodiment of the invention, when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the supercritical fluid is 17-50 g/min, preferably 32 g/min;
in a preferred embodiment, the flow rate of the supercritical fluid is maintained at 10g/min or more and higher than the initial fluidization velocity.
Typical but non-limiting preferred embodiments of the above-described flow rates of supercritical fluids are: 17g/min, 20g/min, 25g/min, 30g/min, 32g/min, 35g/min, 40g/min, 45g/min, 48g/min and 50 g/min.
In a preferred embodiment of the present invention, when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the sirolimus solution is 0.4 to 0.6ml/min, preferably 0.5 ml/min.
In a preferred embodiment of the invention, the particulate carrier comprises at least one of microcrystalline cellulose, lactose, sucrose, mannitol, or xylitol, preferably microcrystalline cellulose;
in the preferred embodiment, the particle size of the particulate carrier is 200 to 400 μm, preferably 200 μm.
Typical but non-limiting preferred embodiments of the particle size of the particulate carrier described above are: 200 μm, 250 μm, 300 μm, 350 μm and 400 μm.
In a preferred embodiment of the present invention, the preparation method comprises the steps of:
(a) dissolving sirolimus in an organic solvent to obtain a solution A with the concentration of 1-5 mg/ml;
(b) in a supercritical reaction device, adjusting the supercritical state to 40-50 ℃, adjusting the pressure to 7-9 MPa, and adjusting the flow of the supercritical fluid to 17-50 g/min;
(c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing the solution A with a supercritical fluid at a flow rate of 0.4-0.6 ml/min to precipitate sirolimus particles, blowing a particle carrier into the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surface of the particle carrier to obtain sirolimus coated particles;
in the above preferred embodiment, the production method further comprises step (d): and (c) after the sirolimus-coated nanoparticles are prepared in the step (c), introducing the same organic solvent as that in the step (a) into a supercritical reaction device to clean the organic solvent remained after the sirolimus microparticles are precipitated from the solution A.
Preferably, the preparation method of the sirolimus coated particle comprises the following steps:
(a) dissolving sirolimus in acetone to obtain a solution A with the concentration of 1-5 mg/ml;
(b) in an HA-II type supercritical anti-solvent fluidization coating device, adjusting the supercritical state to 40-50 ℃, adjusting the pressure to 7-9 MPa, and adjusting the flow of the supercritical fluid to 17-50 g/min;
(c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing 50ml of solution A with a supercritical fluid at a flow rate of 0.4-0.6 ml/min to precipitate sirolimus particles, blowing 2-4 g of particle carriers with the particle size of 200-400 mu m through the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surfaces of the particle carriers to prepare sirolimus coated particles;
(d) pumping 10ml of acetone into the HA-II type supercritical anti-solvent fluidized coating device after the sirolimus coated nano-particles are prepared in the step (c) to clean the acetone remained after the solution A is separated out of sirolimus particles, and then opening the fluidized kettle to collect the sirolimus coated particles.
More preferably, the preparation method of sirolimus coated particles comprises the following steps:
(a) dissolving sirolimus in acetone to obtain a solution A with the concentration of 2.5 mg/ml;
(b) in an HA-II type supercritical anti-solvent fluidization coating device, regulating the supercritical state to 45 ℃, regulating the pressure to 8MPa, and regulating the flow of the supercritical fluid to 30 g/min;
(c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing 50ml of solution A with the supercritical fluid at the flow rate of 0.5ml/min to separate out sirolimus particles, then blowing 3g of lactose particle carrier with the particle size of 200 mu through the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surface of the lactose particle carrier to prepare sirolimus coated particles;
(d) pumping 10ml of acetone into the HA-II type supercritical anti-solvent fluidized coating device after the sirolimus coated nano-particles are prepared in the step (c) to clean the acetone remained after the solution A is separated out of sirolimus particles, and then opening the fluidized kettle to collect the sirolimus coated particles.
According to one aspect of the present invention, a sirolimus coated particle is prepared according to the above-described process.
The sirolimus coated particle provided by the invention is prepared by the method, and the outer layer of the particle carrier is coated with nano-grade sirolimus particles, and meanwhile, the coated particle has high coating rate; therefore, the sirolimus-coated particles have good water solubility in water.
According to one aspect of the invention, the sirolimus coated particle is used for preparing immunosuppressive drugs.
The sirolimus coated particle provided by the invention can be widely applied to the preparation of immunosuppressive drugs.
The technical solution of the present invention will be further described with reference to the following examples.
Example 1
A method of preparing sirolimus coated particles, the method comprising the steps of:
(a) dissolving sirolimus in acetone to obtain a solution A with the concentration of 5 mg/ml;
(b) in an HA-II type supercritical anti-solvent fluidization coating device, regulating the supercritical state to 36 ℃, regulating the pressure to 80MPa, and regulating the flow of the supercritical fluid to 32 g/min;
(c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing 50ml of solution A with supercritical fluid at the flow rate of 0.5ml/min to separate out sirolimus particles, then blowing 2g of particle carriers with the particle size of 200 mu m through the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surface of the particle carriers to prepare sirolimus coated particles;
(d) pumping 10ml of acetone into the HA-II type supercritical anti-solvent fluidized coating device after the sirolimus coated nano-particles are prepared in the step (c) to clean the acetone remained after the solution A is separated out of sirolimus particles, and then opening the fluidized kettle to collect the sirolimus coated particles.
Examples 2 to 24
A sirolimus-coated particle production method, which is similar to example 1 except that the production parameters in the following steps (a) to (c) are different from those in example 1, and specifically includes the following steps:
note: the preparation parameters of example 1 are as follows:
experimental example 1
To show that the sirolimus coated particles prepared by the present application have a better dissolution effect, the applicant performed an experiment for detecting the dissolution rate in water on the sirolimus coated particles prepared in the above examples 1, 2, 3, 10, 11, 12, 13, 15, 16, 17, 18 and 21, and the specific results are shown in fig. 1:
referring to fig. 1, (a) in fig. 1 is the dissolution test results of sirolimus coated particles prepared in examples 1, 2 and 3 and sirolimus prepared by the prior media milling method;
FIG. 1 (b) shows the results of the dissolution test of the sirolimus-coated particles prepared in examples 1, 10 and 11;
FIG. 1 (c) shows the results of the dissolution test of the sirolimus coated particles prepared in examples 1, 15 and 16;
FIG. 1 (d) shows the results of the dissolution test of the sirolimus coated particles prepared in examples 1, 17 and 18;
FIG. 1 (e) shows the results of the dissolution test of the sirolimus-coated particles prepared in examples 1 and 21;
FIG. 1 (f) shows the results of the dissolution test of the sirolimus-coated particles prepared in examples 1, 12 and 13;
as can be seen from fig. 1, the sirolimus coated particles prepared by the above example have substantially no great difference in dissolution rate, the dissolution rate is much faster than that of sirolimus prepared by the prior media milling method in fig. 1 (a), the dissolution is substantially completed within 10min, and the results prove that the preparation method of the present application is advantageous for improving the dissolution rate of sirolimus drug particles, and the process conditions have little influence on the dissolution rate of sirolimus coated particles.
Further, the applicant carried out a test for detecting the coating rate of the sirolimus-coated particles prepared in examples 1 to 24, and the specific results were as follows:
as can be seen from the above table, the sirolimus coated particles prepared by the process parameters of examples 23 and 24 have a better coating rate, wherein the coating rate of example 24 is the best, and reaches 74.1%.
Meanwhile, in order to obtain more preferable preparation process parameters, the applicant selects the effects of the "supercritical temperature", "supercritical pressure" and "concentration of the solution a" as orthogonal three factors on the coating rate of the sirolimus-coated particles, and performs an orthogonal experiment, and the preparation methods of the embodiments 25 to 33 are the same as the embodiment 1 except that the above 3 factors are different, and the three factor variables are as follows:
the specific experimental results are as follows:
from the above orthogonal experiments k 1-k 3, it was found that the solution A had the best coating effect at a concentration of 1mg/ml, and that the sirolimus-coated particles had the better coating rate at a supercritical state of 45 ℃ and 80 bar.
In addition, in order to more intuitively detect the sirolimus coated particles of the present application, the applicant performed electron microscope observation of the sirolimus coated particles prepared in example 1 and example 24 under a 5000-fold electron microscope, and the specific results are as follows:
FIG. 2 is an electron micrograph of sirolimus coated particles prepared in example 1 and lactose particle carriers of example 1 without sirolimus microparticles coating, wherein:
FIG. 2 (a) is an electron micrograph of sirolimus-coated particles prepared in example 1;
FIG. 2 (b) is an electron micrograph of a lactose particle carrier uncoated with sirolimus fine particles in example 1;
as can be seen from FIG. 2, crystalline sirolimus is uniformly coated on the surface of the carrier, and the particle size is about 1 μm.
FIG. 3 is an electron microscope comparison of sirolimus coated particles prepared in example 24 with microcrystalline cellulose particle carriers of example 24 in which the sirolimus particles are not coated, wherein:
FIG. 3 (c) is an electron micrograph of sirolimus-coated particles prepared in example 24;
FIG. 3 (d) is an electron micrograph of a carrier of microcrystalline cellulose particles in example 24, which carrier is not coated with sirolimus fine particles;
FIG. 4 is an electron micrograph of sirolimus coated particles prepared in example 13 compared to a sucrose particle carrier of example 13 that is not coated with sirolimus microparticles wherein:
FIG. 4 (e) is an electron micrograph of sirolimus-coated particles prepared in example 13;
FIG. 4 (f) is an electron micrograph of a sucrose particle carrier uncoated with sirolimus fine particles in example 13;
FIG. 5 is an electron microscope image of sirolimus prepared by a conventional media milling method.
As can be seen from fig. 3, 4 and 5, the bulk drug of sirolimus is a rhombohedral crystal with a large particle size, and the coated particles prepared by the SASFB technique have a significantly reduced particle size and a reduced crystallinity with only a small amount of microcrystals.
In conclusion, according to the method for preparing sirolimus coated particles based on the supercritical anti-solvent method, the sirolimus particles which are precipitated by the supercritical anti-solvent method and coated on the surface of the particle carrier have smaller particle size, so that the solubility of sirolimus in water is greatly improved, and meanwhile, the sirolimus coated particles prepared by the method have good coating rate. Therefore, the sirolimus coated particle prepared by the preparation method effectively improves the utilization rate of sirolimus, and solves the problems that the energy consumption is high and the grinding high temperature can cause the inactivation of the medicine when the sirolimus is prepared by the existing medium grinding method, and the problems that the subsequent treatment steps are complicated and the industrialized production is not facilitated when the existing method for improving the solubility of sirolimus is adopted.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for preparing sirolimus coated particles based on a supercritical anti-solvent method is characterized by comprising the following steps:
in a supercritical state, firstly mixing a sirolimus solution with a supercritical fluid to precipitate sirolimus particles, and then reacting the precipitated sirolimus particles with a particle carrier to coat the sirolimus particles on the surface of the particle carrier, thereby obtaining sirolimus-coated particles.
2. The process according to claim 1, wherein the solvent of the sirolimus solution is an organic solvent;
preferably, the organic solvent comprises any one of methanol, ethanol or acetone, preferably acetone.
3. The method according to claim 1, wherein the concentration of the sirolimus solution is 1-5 mg/ml, preferably 1 mg/ml;
preferably, the particle size of the precipitated sirolimus fine particles is 0.1 to 1 μm.
4. The method of claim 1, wherein the supercritical state satisfies at least one of: the temperature of the supercritical state comprises 40-50 ℃, and the pressure of the supercritical state comprises 7-9 MPa;
preferably, the supercritical state satisfies at least one of the following: the temperature in the supercritical state comprises 45 ℃ and the pressure in the supercritical state comprises 8 MPa.
5. The method of claim 1, wherein the supercritical fluid comprises carbon dioxide.
6. The method according to claim 1, wherein when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the supercritical fluid is 17-50 g/min, preferably 32 g/min;
preferably, when the sirolimus solution is mixed with the supercritical fluid, the flow rate of the sirolimus solution is 0.4 to 0.6ml/min, and preferably 0.5 ml/min.
7. The method of claim 1, wherein the particulate carrier comprises at least one of microcrystalline cellulose, lactose, sucrose, mannitol, or xylitol, preferably microcrystalline cellulose;
preferably, the particle size of the particle carrier is 200-400 μm, preferably 200 μm.
8. The method according to claim 1, wherein the preparation method comprises the steps of:
(a) dissolving sirolimus in an organic solvent to obtain a solution A with the concentration of 1-5 mg/ml;
(b) in a supercritical reaction device, adjusting the supercritical state to 40-50 ℃, adjusting the pressure to 7-9 MPa, and adjusting the flow of the supercritical fluid to 17-50 g/min;
(c) and (c) under the condition that the reaction conditions in the step (b) are kept unchanged, mixing the solution A with a supercritical fluid at a flow rate of 0.4-0.6 ml/min to precipitate sirolimus particles, blowing the particle carrier into the supercritical fluid to react with the sirolimus particles, and coating the sirolimus particles on the surface of the particle carrier to obtain sirolimus coated particles.
9. Sirolimus coated particles prepared according to the process of any one of claims 1 to 8.
10. Use of the sirolimus coated particle of claim 9 in the preparation of an immunosuppressive drug.
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