CN107049963B - Sirolimus nano-drug composition and preparation method thereof - Google Patents
Sirolimus nano-drug composition and preparation method thereof Download PDFInfo
- Publication number
- CN107049963B CN107049963B CN201710487872.9A CN201710487872A CN107049963B CN 107049963 B CN107049963 B CN 107049963B CN 201710487872 A CN201710487872 A CN 201710487872A CN 107049963 B CN107049963 B CN 107049963B
- Authority
- CN
- China
- Prior art keywords
- sirolimus
- nano
- drug
- solution
- auxiliary material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/4353—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
-
- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a sirolimus nano-drug composition, which comprises the following raw materials in percentage by weight: 10-30 wt% of sirolimus, 10-50 wt% of auxiliary materials and 20-80% of protective agents. Also discloses a preparation method of the sirolimus nano-drug composition. The nano-drug composition has small particle size, narrow distribution, particle size of 50-400nm, good dispersibility and wide application range, and can be applied to the preparation of tablets, capsules and oral solution; the dissolution rate of the medicine is not less than 85% in 5 min.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a sirolimus nano preparation and a preparation method thereof.
Background
Sirolimus (Sirolimus), chemical name (3S, 6R,7E, 9R, 10R, 12R, 14S, 15E,17E,19E, 21S, 23S, 26R, 27R, 34aS) -9, 10, 12, 13, 14, 21, 22, 23, 24, 25, 26,27,32, 33, 34, 34 a-hexadecahydro-9, 27-dihydroxy-3- [ (1R) -2- [ (1S, 3R, 4R) -4-hydroxy-3-methoxycyclohexyl]-1-methylethyl group]-10, 21-dimethoxy-6, 8,12,14, 20, 26-hexamethyl-23, 27-epoxy-3H-pyrido [2,1-c ]][1,4]Oxaazatriundecylene-1, 5,11,28,29(4H, 6H, 31H) -pentanone. Molecular formula C51H79NO13The relative molecular mass is 914.19, the melting point is between 183-185 ℃, and the molecular structural formula is as follows:
sirolimus (SRL) is a novel, potent macrolide immunosuppressant, mainly used for the treatment of rejection after organ transplantation, and is commercially available under the name Rapamycin. Sirolimus, as a third-generation immunosuppressant, is a immunosuppressant which has low toxicity and great potential discovered so far, and is becoming a basic drug for long-term immunosuppressive treatment of kidney transplant patients. Sirolimus responds to stimulation by antigens and cytokines (IL-2, IL-4) by a different mechanism than other immunosuppressive agents to T lymphocyte activation and proliferation. In cells, sirolimus binds to the immunoprotein, FK-binding protein-12 (FKBP-12), to produce an immunosuppressive complex. Sirolimus blocks the intermediate and late stages of the cell cycle progression in the G1 phase, inhibiting IL-2-dependent and IL-4-dependent lymphob cell proliferation, inhibiting the production of immunoglobulins A, M and G, thereby preventing the activation of the immune system and the conduction of organ rejection signals, achieving immunosuppressive effects.
Sirolimus is poorly water soluble, is nearly insoluble in water (2.6. mu.g/mL), and belongs to the class II BCS (bifunctional screening system) class II drugs, i.e., low solubility and high permeability, whose absorption rate depends on the dissolution rate. Because sirolimus is poor in water solubility and the absorption rate of the drug depends on the dissolution rate, the drug is limited to act in the human body, and the bioavailability of the drug preparation is low.
In order to increase the dissolution rate of sirolimus drugs, the prior art discloses a large number of relevant documents. For example, chinese patent application publication No. CN103655486A discloses sirolimus microemulsion particles, and a preparation method and an application thereof, wherein the sirolimus microemulsion particles are prepared by a heating and melting method, so that the stability and the dissolution rate of the preparation can be improved. In the invention, a high-pressure homogenization mode is used, and fine drug particles are homogenized by means of mechanical external force to form the drug nanoparticles. In the chinese patent application publication No. CN103239399A, a method for preparing a sirolimus nanosuspension is disclosed, in which an ethanol solution of sirolimus and copovidone is dropped into a copovidone aqueous solution to prepare a nanosuspension. The Chinese patent application with publication number CN105640886A discloses a preparation method of a sirolimus self-microemulsion preparation, wherein the method comprises the steps of adding sirolimus into an oil phase, dissolving in an emulsifier, adding other raw materials, and uniformly mixing to obtain the microemulsion preparation. However, these methods have the disadvantages of complicated preparation process, high production cost, etc., or the prepared particle size is large, and thus they are not suitable for large-scale industrial continuous production.
Therefore, in view of the above problems, there is a need to provide a new method for preparing sirolimus nano-drug composition.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide a sirolimus nano-drug composition. The nano-drug composition has the average particle size of 50-400nm, narrow distribution, good dispersibility and wide application range, and can be applied to the preparation of tablets, capsules and oral solution; the drug dissolution rate of the nano drug composition particles is not less than 85% in 5 min.
The second technical problem to be solved by the invention is to provide a preparation method of the sirolimus nano-drug composition. The prepared sirolimus nano-drug particles have small particle size (50-400 nm) and narrow particle size distribution.
In order to solve the first technical problem, the invention adopts the following technical scheme:
a sirolimus nano-drug composition comprises the following raw materials in percentage by weight:
10-30 wt% of sirolimus, 10-50 wt% of auxiliary materials and 20-80% of protective agents.
As a further improvement of the technical scheme, the auxiliary materials are selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl methyl cellulose, mannitol, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, sodium alginate and lactose.
As a further improvement of the technical scheme, the protective agent is selected from one or more of lactose, mannitol, xylitol, sucrose, trehalose, dextran and polyvinyl pyrrolidone.
In order to solve the second technical problem, the invention adopts the following technical scheme:
a preparation method of sirolimus nano-drug composition comprises the following steps:
s01, respectively preparing a sirolimus medicament solution and an auxiliary material aqueous solution;
s02, respectively introducing the sirolimus medicine solution prepared in the step S01 and the auxiliary material water solution into a super-gravity rotating packed bed for mixing, and controlling the system temperature to be 0-40 ℃ to obtain sirolimus nano suspension;
s03, adding spray-drying protective agent into the nano suspension prepared in the step S02, and then carrying out spray-drying treatment to obtain the powdery nano pharmaceutical composition.
In the invention, the supergravity technology is creatively applied to the preparation of sirolimus nano-drug particles, nano-particles with smaller particle size can be prepared by the supergravity technology, the time for drug recrystallization is obviously shortened, and the industrial continuous production is facilitated. The invention mainly controls the particle size distribution of the drug particles by reducing the average particle size of the drug particles so as to promote the dissolution of the drug, thereby improving the dissolution rate of the drug and finally achieving the purpose of improving the bioavailability of the drug. The drug particles prepared by the existing liquid phase precipitation crystallization method have uneven particle size distribution and poor batch-to-batch reproducibility.
In the invention, the control of the system temperature in the hypergravity rotating packed bed plays an important role in the size of the average grain diameter and the grain diameter distribution of the obtained nano-drugs and the drug dissolution rate of the product. The average particle size and the particle size distribution of the nano-drug and the drug dissolution rate of the product are not simply linear relations with the system temperature. Preferably, the temperature of the system in the hypergravity rotating packed bed is 0-40 ℃. The prepared nano-drug has small and uniform particle size and high drug dissolution rate. More preferably, the system temperature in the high-gravity rotating packed bed is 10-25 ℃, and the effect is optimal.
The solvent is preferably a solvent capable of dissolving sirolimus while being less toxic, depending on the solubility properties of sirolimus. Preferably, in step S01, the solvent in the sirolimus pharmaceutical solution is one or more selected from methanol, absolute ethanol, dimethyl sulfoxide, isopropanol, dimethylformamide and acetone.
In the invention, the interaction between the auxiliary material and the medicine sirolimus can finally influence the nucleation rate and the growth rate of the sirolimus, namely the proper auxiliary material is beneficial to increasing the nucleation rate of the medicine and reducing the crystal growth rate, thereby obtaining the medicine particles with small average particle size and uniform particle size distribution.
Preferably, the adjuvant comprises a surfactant and a co-surfactant; the surfactant is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide and hydroxypropyl methyl cellulose; the cosurfactant is selected from one or more of mannitol, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, sodium alginate and lactose; more preferably, the surfactant is polyvinyl pyrrolidone and the co-surfactant is sodium lauryl sulfate.
As a further improvement of the technical scheme, in step S01, the concentration of the sirolimus drug solution is 5g/L to 150 g/L; the concentration of the auxiliary material water solution is 0.5g/L-10 g/L. The bridging phenomenon can occur due to the agglomeration of drug particles when the concentration of the auxiliary material aqueous solution is too high, and the drug nucleation rate cannot be effectively increased and the crystal growth rate can be reduced when the concentration of the auxiliary material aqueous solution is too low. Under the condition, the sirolimus in the sirolimus medicament solution has high solubility, and is helpful for uniform dispersion of medicament particles and crystal growth. More preferably, the concentration of the sirolimus solution is 10g/L to 100 g/L; the concentration of the auxiliary material water solution is 0.5g/L-5.5 g/L.
In the invention, the supersaturation degree is the main driving force for preparing the sirolimus nanoparticles, and the larger supersaturation degree is beneficial to reducing the particle size of the nanoparticles and controlling the particle size distribution. Preferably, in step S01, the volume ratio of the sirolimus medicament solution to the adjuvant aqueous solution is 1:1 to 1: 20.
Preferably, in step S02, the mass ratio of sirolimus in the sirolimus drug solution to the adjuvant in the adjuvant water solution is 1:0.05-1:10, so that the dissolution rate of the preparation can be ensured and the functional requirements of the preparation can be met. More preferably, the aforementioned mass ratio is 1:0.05 to 1: 3; most preferably, the aforementioned mass ratio is 1:0.5 to 1: 1.
In the invention, the particle size and the particle size distribution of the particles in the obtained suspension are influenced by the excessively high or excessively low adding speed of the sirolimus medicament solution and the auxiliary material aqueous solution, and the linear relation is not simple. Preferably, in step S02, the speed of adding the sirolimus drug solution into the high-gravity rotating packed bed is 1mL/min to 10 mL/min; the speed of adding the auxiliary material aqueous solution into the super-gravity rotating packed bed is 20mL/min-300 mL/min.
In the present invention, the rotational speed of the hypergravity rotating packed bed affects the liquid flow state, thereby affecting the nucleation and growth rate of the particles. Preferably, in step S02, the rotating speed of the super-gravity rotating packed bed is 500rpm to 2840rpm, and the particle size of the particles in the obtained suspension is more uniform.
Preferably, the high-gravity rotating packed bed is an external circulation high-gravity rotating packed bed. For example, the structural composition and equipment parameters of the external circulation hypergravity rotating packed bed can be consistent with the literature (Chen J F. et al., IND ENG CHEM RES,2015,54(33): 946-.
Preferably, in step S03, the spray drying protective agent is selected from one or more of lactose, mannitol, xylitol, sucrose, trehalose, dextran and polyvinyl pyrrolidone; the weight ratio of the addition amount of the spray drying protective agent to the weight of the sirolimus medicine is 1-3: 1; the conditions of the spray drying treatment are that the inlet temperature is 100-.
Preferably, the sirolimus nano-drug composition exists in an amorphous form; the average particle size of the sirolimus nano-drug composition is 50-400 nm; more preferably 50-200 nm; most preferably in the range of 80-120nm,
the sirolimus nano-drug composition prepared by the preparation method can be simultaneously combined with one or more pharmaceutically acceptable excipients to be used for preparing tablets, capsules or granular preparations.
According to the sirolimus nano-drug composition, a unified technical scheme is formed by the selection of auxiliary materials, the control of system temperature, the control of raw material concentration, the addition speed of raw material solution and the selection of a drying mode, and the technical characteristics are mutually influenced and matched, so that sirolimus nano-drug composition particles with the average particle size of 50-400nm, uniform particle size distribution and 5min drug dissolution rate of more than or equal to 85% can be obtained.
Any range recited herein is intended to include the endpoints and any number between the endpoints and any subrange subsumed therein or defined therein.
The starting materials of the present invention are commercially available, unless otherwise specified, and the equipment used in the present invention may be any equipment conventionally used in the art or may be any equipment known in the art.
Compared with the prior art, the invention has the following advantages and effects:
1. according to the invention, by utilizing a unified overall technical scheme formed by the supergravity rotary packed bed, the control of the temperature of the supergravity rotary packed bed system, the selection of auxiliary materials, the control of the raw material concentration, the adding speed of the raw material solution and the selection of the drying mode, sirolimus nanoparticles with controllable average particle size, narrow distribution and high stability, which have the average particle size of 50-400nm and uniform particle size distribution, are obtained, and the drug dissolution rate of 5min is not less than 85%.
2. The invention adopts a spray drying treatment method to treat the organic solvent, has simple operation and good organic solvent removal effect. The invention can avoid the cracking and agglomeration of the nano-drug particles in the spray drying process by adding the spray drying protective agent. The slurry is spray dried to obtain dry powder which is convenient to transport and store. The whole preparation process from the slurry to the dry powder can be continuously carried out, and the large-scale production is easy to realize. The nano dispersion can be automatically formed after the spray dry powder meets water, and the particle size is small and the particle size distribution is narrow. After being placed at room temperature for two weeks, the average particle size remained substantially unchanged, showing good stability.
3. The method has the advantages of simple process, easy realization, less energy consumption, high efficiency, low cost and easy amplification, and achieves the aim of industrial production.
Drawings
The following detailed description of embodiments of the invention is provided in connection with the accompanying drawings
Fig. 1 shows a scanning electron micrograph of sirolimus drug substance of example 1.
Fig. 2 shows a scanning electron micrograph of the drug particles in the nanosuspension of example 1.
FIG. 3 shows the scanning electron microscope image of water redispersion of the sirolimus nano-drug composition obtained in example 1.
Fig. 4 shows an X-ray diffraction (XRD) pattern of the sirolimus nano-drug composition, the physically mixed powder, and the sirolimus drug substance prepared in example 1.
Fig. 5 shows the dissolution profiles of the sirolimus nano-drug composition, the physical mixed powder and the sirolimus drug substance prepared in example 1.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus ethanol solution with the concentration of 10mg/mL by using the sirolimus raw material drug (the scanning electron microscope image is shown in figure 1) and ethanol; preparing 200mL of 0.5mg/mL auxiliary material aqueous solution from polyvinylpyrrolidone and deionized water, and simultaneously adding 5mg of lauryl sodium sulfate into the auxiliary material aqueous solution;
s02, starting an external circulation super-gravity rotating packed bed, and adjusting the rotating speed to 2272 rpm; starting a feed pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization reaction, controlling the feeding rate of the sirolimus ethanol solution to be 2mL/min, the feeding rate of the medicine auxiliary material aqueous solution to be 40mL/min, and controlling the temperature of the system to be 20 ℃ to obtain a nano suspension;
s03, adding mannitol and polyvinylpyrrolidone into the obtained nano suspension (the scanning electron microscope image of the drug particles in the suspension is shown in figure 2), and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 200nm, and the particle size distribution is +/-20 nm.
FIG. 3 is the scanning electron microscope image of water redispersion of the obtained sirolimus nano-drug composition, from which it can be seen that the nano-powder obtained by spray drying has good water reduplication and is increased in particle size compared with the particle size in the suspension.
For comparison, sirolimus and the auxiliary material are physically mixed in equal amount to obtain a physically mixed powder.
Fig. 4 is an X-ray diffraction (XRD) pattern of the obtained sirolimus nano-drug composition, the physically mixed powder and the sirolimus raw material. From the figure, it can be seen that sirolimus obtained by the present invention is in an amorphous state.
Dissolution rate test of sirolimus nano-drug composition:
the test method comprises the following steps: respectively taking a certain mass of the obtained sirolimus nano-drug composition, the physical mixed powder and the sirolimus bulk drug, respectively adding the sirolimus nano-drug composition, the physical mixed powder and the sirolimus bulk drug into 300mL of water pH6.8 phosphate buffer solution (added with 0.5% SDS (sodium dodecyl sulfate)), placing the mixture into a water bath at 37 ℃, slowly stirring the mixture at a rotating speed of 100rpm, respectively sampling 4mL at preset time points, filtering the mixture into a centrifuge tube by using a 0.45 micrometer syringe, and adding isothermal equivalent dissolution blank medium after each sampling. In order to obtain absorbance values within the specified range, the clear solution obtained by sampling is diluted by a certain factor with the corresponding blank medium, and the absorbance of the prepared solution is measured at the maximum absorption wavelength. Each sample was assayed in 3 replicates. The above solutions were taken and measured for absorbance at a wavelength of 277.5nm according to spectrophotometry (appendix IV of the second part of the Chinese pharmacopoeia 2010 edition), and the dissolution was calculated.
Fig. 5 shows the dissolution curve of the sirolimus nano-drug composition, the physical mixed powder and the sirolimus drug substance prepared by the above preparation method. From the figure, the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 90%.
Example 2
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus ethanol solution with the concentration of 10mg/mL by the sirolimus raw material medicine and methanol; preparing 200mL of 0.5mg/mL auxiliary material aqueous solution from polyvinylpyrrolidone and deionized water;
s02, starting an external circulation super-gravity rotating packed bed, and adjusting the rotating speed to 2840 rpm; starting a feed pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization reaction, controlling the feeding rate of the sirolimus ethanol solution to be 5mL/min, the feeding rate of the medicine auxiliary material aqueous solution to be 50mL/min, and controlling the temperature of the system to be 20 ℃, thus obtaining the nano suspension;
s03, adding mannitol and polyvinylpyrrolidone into the obtained nano suspension, and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 250nm, and the particle size distribution is +/-30 nm.
According to the same dissolution rate test method of example 1, the results show that the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 87%.
Example 3
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus dimethyl sulfoxide solution with the concentration of 50mg/mL from the sirolimus raw material medicine and dimethyl sulfoxide; preparing 200mL of 8mg/mL auxiliary material aqueous solution from polyvinylpyrrolidone and deionized water;
s02, starting an external circulation hypergravity rotating packed bed, and adjusting the rotating speed to 2250 rpm; starting a feeding pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization reaction, controlling the feeding rate of the sirolimus ethanol solution to be 10mL/min, the feeding rate of the medicine auxiliary material aqueous solution to be 200mL/min, and controlling the temperature of the system to be 20 ℃, thus obtaining the nano suspension;
s03, adding mannitol and polyvinylpyrrolidone into the obtained nano suspension, and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 320nm, and the particle size distribution is +/-20 nm.
According to the same dissolution rate test method of example 1, the results show that the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 88%.
Example 4
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus ethanol solution with the concentration of 100mg/mL by the sirolimus raw material drug and ethanol; preparing polyvinylpyrrolidone and deionized water into 200mL of 5mg/mL auxiliary material aqueous solution, and simultaneously adding 5mg of lauryl sodium sulfate into the auxiliary material aqueous solution;
s02, starting an external circulation super-gravity rotating packed bed, and adjusting the rotating speed to 2272 rpm; starting a feed pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization reaction, controlling the feeding rate of the sirolimus ethanol solution to be 2mL/min, the feeding rate of the medicine auxiliary material aqueous solution to be 40mL/min, and controlling the temperature of the system to be 20 ℃, thus obtaining the nano suspension;
s03, adding mannitol and polyvinylpyrrolidone into the obtained nano suspension, and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 200nm, and the particle size distribution is +/-20 nm.
According to the same dissolution rate test method of example 1, the results show that the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 90%.
Example 5
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus ethanol solution with the concentration of 100mg/mL by the sirolimus raw material drug and ethanol; preparing polyvinylpyrrolidone and deionized water into 200mL of 5mg/mL auxiliary material aqueous solution, and simultaneously adding 5mg of lauryl sodium sulfate into the auxiliary material aqueous solution; starting an external circulation super-gravity rotating packed bed, and adjusting the rotating speed to 2272 rpm;
s02, starting a feeding pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization, controlling the feeding rate of the sirolimus ethanol solution to be 2mL/min, the feeding rate of the medicinal auxiliary material aqueous solution to be 40mL/min, and controlling the temperature of the system to be 20 ℃, thus obtaining the nano suspension;
and S03, adding trehalose into the obtained nano suspension, and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 400nm, and the particle size distribution is +/-25 nm.
According to the same dissolution rate test method of example 1, the results show that the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 85%.
Example 6
A preparation method of sirolimus nano-drug composition comprises the following steps:
s01, preparing 10mL of sirolimus ethanol solution with the concentration of 10mg/mL by the sirolimus raw material medicine and acetone; preparing 200mL of 0.5mg/mL auxiliary material aqueous solution from polyvinylpyrrolidone and deionized water, and simultaneously adding 10mg of lauryl sodium sulfate into the auxiliary material aqueous solution;
s02, starting an external circulation super-gravity rotating packed bed, and adjusting the rotating speed to 1500 rpm; starting a feed pump, simultaneously conveying the sirolimus ethanol solution and the auxiliary material aqueous solution into a super-gravity rotating packed bed for recrystallization reaction, controlling the feeding rate of the sirolimus ethanol solution to be 2mL/min, the feeding rate of the medicine auxiliary material aqueous solution to be 40mL/min, and controlling the temperature of the system to be 10 ℃, thus obtaining the nano suspension;
s03, adding mannitol and lactose into the obtained nano suspension, and then carrying out spray drying to obtain the sirolimus nano-drug composition, wherein the average particle size of the obtained drug particles is about 300nm, and the particle size distribution is +/-20 nm.
According to the same dissolution rate test method of example 1, the results show that the prepared sirolimus nano-drug composition effectively improves the dissolution rate of the drug, and the 5min drug dissolution rate reaches 88%.
Comparative example 1
Example 1 was repeated except that the concentration of the sirolimus drug solution was 1mg/mL, and the other conditions were unchanged, so that the obtained sirolimus nano-drug combination powder had an average particle size of about 120nm and a particle size distribution of. + -. 100 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 75%. Although the average particle size of the pharmaceutical composition of this comparative example was satisfactory, too small a concentration of the drug made it difficult to control the particle size distribution, thereby affecting the dissolution of the drug, and too low a concentration was not practical for industrial production.
Comparative example 2
Example 1 was repeated except that the concentration of the sirolimus drug solution was 160mg/mL, and the other conditions were unchanged, so that the average particle size of the obtained sirolimus nano-drug combination powder was about 450 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 61%.
Comparative example 3
Example 3 is repeated, except that 200mL of 0.3mg/mL adjuvant water solution is prepared from polyvinylpyrrolidone and deionized water, and other conditions are unchanged, so that the average particle size of the prepared sirolimus nano-drug composite powder is about 320nm, and the particle size distribution is +/-120 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 57%. Although the average particle size of the pharmaceutical composition of the comparative example meets the requirement, the particle size distribution is not easy to control due to the excessively low concentration of the aqueous solution of the auxiliary material, thereby influencing the dissolution rate of the drug.
Comparative example 4
Example 3 is repeated, except that polyvinylpyrrolidone and deionized water are mixed to prepare 200mL of auxiliary material aqueous solution of 12mg/mL, other conditions are unchanged, and the average particle size of the prepared sirolimus nano-drug composite powder is about 410 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 44%.
Comparative example 5
The example 1 is repeated, except that the temperature of the reaction system is changed to 60 ℃, the other conditions are not changed, and the average particle size of the prepared sirolimus nano-drug composite powder is about 500 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 75%.
Comparative example 6
The example 1 is repeated, except that the temperature of the reaction system is changed to-5 ℃, the other conditions are not changed, the average particle size of the prepared sirolimus nano-drug composite powder is about 220nm, and the particle size distribution is +/-150 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 59%. Although the average particle size of the pharmaceutical composition of the comparative example meets the requirement, the particle size distribution is not easy to control due to the excessively low temperature of the reaction system, thereby influencing the dissolution rate of the drug.
Comparative example 7
Example 1 was repeated except that, in step S2, the sirolimus drug solution was added to the high-gravity rotating packed bed at a rate of 0.5 mL/min; the speed of adding the auxiliary material aqueous solution into the supergravity rotating packed bed is 15mL/min, the average particle size of the prepared sirolimus nano-drug composite powder is about 270nm, and the particle size distribution is +/-130 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 67%. Although the average particle size of the pharmaceutical composition of this comparative example meets the requirements, the rate of addition of the drug solution to the hypergravity rotating packed bed is too low, which results in poor control of the particle size distribution, thereby affecting the dissolution rate of the drug.
Comparative example 8
Example 1 was repeated except that, in step S2, the sirolimus drug solution was fed into the high-gravity rotating packed bed at a rate of 12 mL/min; the speed of adding the auxiliary material aqueous solution into the supergravity rotating packed bed is 350mL/min, and the average particle size of the prepared sirolimus nano-drug composite powder is about 300nm, and the particle size distribution is +/-150 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 59%. Although the average particle size of the pharmaceutical composition of this comparative example meets the requirements, the rate of addition of the drug solution to the hypergravity rotating packed bed is too low, which results in poor control of the particle size distribution, thereby affecting the dissolution rate of the drug.
Comparative example 9
The example 1 is repeated, except that the drying mode of the nano suspension is changed into freeze drying, the freezing temperature is-74 ℃ to-20 ℃, the other conditions are not changed, and the average particle size of the prepared sirolimus nano-drug composite powder is about 600 nm. The dissolution rate test results are: the drug dissolution rate at 5min is only 45%.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. Not all embodiments are exhaustive. All obvious changes and modifications which are obvious to the technical scheme of the invention are covered by the protection scope of the invention.
Claims (5)
1. The sirolimus nano-drug composition is characterized by comprising the following raw materials in percentage by weight:
10-30 wt% of sirolimus, 10-50 wt% of auxiliary material and 20-80% of protective agent;
the average particle size of the sirolimus nano-drug composition particles is 50-400nm, and the drug dissolution rate of the nano-drug composition particles for 5min is not less than 85%;
the preparation method of the sirolimus nano-drug composition comprises the following steps:
s01, respectively preparing a sirolimus medicament solution and an auxiliary material aqueous solution;
s02, introducing the sirolimus medicine solution prepared in the step S01 and the auxiliary material water solution into a super-gravity rotating packed bed for mixing, and controlling the system temperature to be 10-25 ℃ to obtain sirolimus nano suspension;
s03, adding a spray-drying protective agent into the nano suspension prepared in the step S02, and then carrying out spray-drying treatment to obtain a powdery nano pharmaceutical composition;
the auxiliary material comprises a surfactant and a cosurfactant; the surfactant is selected from polyvinylpyrrolidone; the cosurfactant is selected from sodium dodecyl sulfate;
the protective agent is selected from one or more of lactose, mannitol, xylitol, sucrose, trehalose, dextran and polyvinyl pyrrolidone;
in step S01, the concentration of the sirolimus medicament solution is 10g/L-100 g/L; the concentration of the auxiliary material water solution is 0.5g/L-10 g/L;
in step S01, the solvent in the sirolimus pharmaceutical solution is selected from one or more of methanol, absolute ethanol, dimethyl sulfoxide, isopropanol, dimethylformamide and acetone;
in step S01, the volume ratio of the sirolimus medicament solution to the auxiliary material aqueous solution is 1:1-1: 20;
in step S02, the speed of adding the sirolimus drug solution into the hypergravity rotating packed bed is 2mL/min-10 mL/min; the speed of adding the auxiliary material aqueous solution into the super-gravity rotating packed bed is 40mL/min-200 mL/min;
in step S02, the mass ratio of sirolimus in the sirolimus medicament solution to the auxiliary material in the auxiliary material aqueous solution is 1:0.05-1: 10;
in step S02, the rotating speed of the high-gravity rotating packed bed is 500 rpm-2840 rpm.
2. The preparation method of the sirolimus nano-drug composition of claim 1, wherein: in step S01, the concentration of the adjuvant water solution is 0.5g/L-5.5 g/L.
3. The preparation method of the sirolimus nano-drug composition of claim 1, wherein: in step S02, the mass ratio of sirolimus in the sirolimus medicament solution to the adjuvant in the adjuvant water solution is 1:0.05-1: 3.
4. The preparation method of the sirolimus nano-drug composition of claim 3, wherein: in step S02, the mass ratio of sirolimus in the sirolimus medicament solution to the auxiliary material in the auxiliary material aqueous solution is 1:0.5-1: 1.
5. The preparation method of the sirolimus nano-drug composition of claim 1, wherein: in step S03, the spray-drying protective agent is selected from one or more of lactose, mannitol, xylitol, sucrose, trehalose, dextran, and polyvinyl pyrrolidone; the weight ratio of the addition amount of the spray drying protective agent to the weight of the sirolimus medicine is 1-3: 1; the conditions of the spray drying treatment are that the inlet temperature is 100-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710487872.9A CN107049963B (en) | 2017-06-23 | 2017-06-23 | Sirolimus nano-drug composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710487872.9A CN107049963B (en) | 2017-06-23 | 2017-06-23 | Sirolimus nano-drug composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107049963A CN107049963A (en) | 2017-08-18 |
| CN107049963B true CN107049963B (en) | 2020-11-03 |
Family
ID=59613380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710487872.9A Active CN107049963B (en) | 2017-06-23 | 2017-06-23 | Sirolimus nano-drug composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107049963B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811979A (en) * | 2017-11-08 | 2018-03-20 | 北京化工大学 | A kind of sirolimus nanometer tablet and preparation method thereof |
| CN110339173A (en) * | 2018-04-08 | 2019-10-18 | 北京化工大学 | A kind of Sorafenib Tosylate nanometer tablet |
| CN111166724A (en) * | 2018-11-09 | 2020-05-19 | 北京化工大学 | Regorafenib nano dispersion, tablet and preparation method thereof |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771910A (en) * | 2005-11-02 | 2006-05-17 | 浙江大学 | Nanometer particle of insoluble medicine and its prepn |
| CN1771911A (en) * | 2005-11-10 | 2006-05-17 | 浙江大学 | Re-dispersible nanometer particle of insoluble medicine and its prepn |
| CN101721312A (en) * | 2008-10-10 | 2010-06-09 | 北京化工大学 | Method and device for preparing medicament particles with nano-micro structure |
| CN102614127A (en) * | 2011-01-28 | 2012-08-01 | 北京万生药业有限责任公司 | Resveratrol nanoscale dispersoid and preparation method thereof |
| CN102871966A (en) * | 2012-10-19 | 2013-01-16 | 东南大学 | Nano drug carrier particles for improving bioavailability of rapamycin and preparation method thereof |
| CN103239399A (en) * | 2013-05-30 | 2013-08-14 | 苏州普罗达生物科技有限公司 | Sirolimus nanoparticle suspension agent and preparation method thereof |
| CN103655486A (en) * | 2013-12-12 | 2014-03-26 | 人福医药集团股份公司 | Sirolimus micro-emulsion particles and preparation method and application thereof |
| CN105902496A (en) * | 2016-04-18 | 2016-08-31 | 沈阳药科大学 | A treating method for a nanometer suspension solidification process |
| CN106265542A (en) * | 2016-09-22 | 2017-01-04 | 北京化工大学 | A kind of preparation method of doxorubicin nanometer medicament granule |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090068266A1 (en) * | 2007-09-11 | 2009-03-12 | Raheja Praveen | Sirolimus having specific particle size and pharmaceutical compositions thereof |
-
2017
- 2017-06-23 CN CN201710487872.9A patent/CN107049963B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771910A (en) * | 2005-11-02 | 2006-05-17 | 浙江大学 | Nanometer particle of insoluble medicine and its prepn |
| CN1771911A (en) * | 2005-11-10 | 2006-05-17 | 浙江大学 | Re-dispersible nanometer particle of insoluble medicine and its prepn |
| CN101721312A (en) * | 2008-10-10 | 2010-06-09 | 北京化工大学 | Method and device for preparing medicament particles with nano-micro structure |
| CN102614127A (en) * | 2011-01-28 | 2012-08-01 | 北京万生药业有限责任公司 | Resveratrol nanoscale dispersoid and preparation method thereof |
| CN102871966A (en) * | 2012-10-19 | 2013-01-16 | 东南大学 | Nano drug carrier particles for improving bioavailability of rapamycin and preparation method thereof |
| CN103239399A (en) * | 2013-05-30 | 2013-08-14 | 苏州普罗达生物科技有限公司 | Sirolimus nanoparticle suspension agent and preparation method thereof |
| CN103655486A (en) * | 2013-12-12 | 2014-03-26 | 人福医药集团股份公司 | Sirolimus micro-emulsion particles and preparation method and application thereof |
| CN105902496A (en) * | 2016-04-18 | 2016-08-31 | 沈阳药科大学 | A treating method for a nanometer suspension solidification process |
| CN106265542A (en) * | 2016-09-22 | 2017-01-04 | 北京化工大学 | A kind of preparation method of doxorubicin nanometer medicament granule |
Non-Patent Citations (4)
| Title |
|---|
| Stabilized amorphous glibenclamide nanoparticles by high-gravity technique;Lei Yua，等;《Materials Chemistry and Physics》;20111231(第130期);摘要，第361页左栏第2段-右栏第3段，第362页右栏第3段，第364页左栏第2段-右栏第1段 * |
| 西罗莫司纳米脂质载体固化制剂的制备;吴昊，等;《中国医药工业杂志》;20121231;第43卷(第7期);第562-567页 * |
| 超重力反溶剂沉淀法制备阿霉素纳米药物及其性能研究;董振锋，等;《北京化工大学学报（自然科学版）》;20160920;第43卷(第5期);第8-13页 * |
| 超重力反溶剂法制备超细亲脂性药物颗粒及性能研究;张纪尧，等;《中国博士学位论文全文数据库工程科技Ⅰ辑》;20150315(第3期);第B016-51页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107049963A (en) | 2017-08-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107049963B (en) | Sirolimus nano-drug composition and preparation method thereof | |
| CN102188372B (en) | Medicinal transparent nano dispersant and preparation method thereof | |
| Prajapati et al. | Conventional and alternative pharmaceutical methods to improve oral bioavailability of lipophilic drugs | |
| Yi et al. | The construction of puerarin nanocrystals and its pharmacokinetic and in vivo–in vitro correlation (IVIVC) studies on beagle dog | |
| CN105902496A (en) | A treating method for a nanometer suspension solidification process | |
| CN107320460B (en) | Oral nilotinib nano preparation and preparation method thereof | |
| WO2019137005A1 (en) | Drug-loaded nanoparticle based on tannic acid and preparation method therefor and use thereof | |
| Fan et al. | Nanocrystal technology as a strategy to improve drug bioavailability and antitumor efficacy for the cancer treatment | |
| Yu et al. | Stabilized amorphous glibenclamide nanoparticles by high-gravity technique | |
| CN105796492A (en) | Rivaroxaban nano-suspension and preparation method thereof | |
| Wang et al. | Nano-porous silica aerogels as promising biomaterials for oral drug delivery of paclitaxel | |
| KR101396461B1 (en) | Oxaliplatin nanoparticles and method for preparing same | |
| Nguyen et al. | Encapsulating darunavir nanocrystals within Eudragit L100 using coaxial electrospraying | |
| EP3616688A1 (en) | Preparation of nanosuspension comprising nanocrystals of active pharmaceutical ingredients with little or no stabilizing agents | |
| Han et al. | A new approach to produce drug nanosuspensions CO2-assisted effervescence to produce drug nanosuspensions | |
| Kumar et al. | Drop-by-drop solvent hot antisolvent interaction method for engineering nanocrystallization of sulfamethoxazole to enhanced water solubility and bioavailability | |
| CN110711176A (en) | Cilnidipine nanosuspension and preparation method thereof | |
| CN111759816A (en) | Oral solid nano crystal slow-release composition and preparation method thereof | |
| US20080171687A1 (en) | Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs | |
| Sin Cheow et al. | Towards sustainability: new approaches to nano-drug preparation | |
| WO2012026896A1 (en) | Surface modified micronized tacrolimus crystalline particles and pharmaceutical compositions thereof | |
| CN110787125B (en) | Aprepitant nano preparation and preparation method thereof | |
| Daebis et al. | Formulation and characterization of itraconazole oral nanosuspension: methyl cellulose as promising stabilizer | |
| CN102579373B (en) | Amoitone B nano crystallization preparation and preparation method thereof | |
| CN104800191A (en) | Lyophilized zolmitriptan nanometer powder and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |