CN107049963A - A kind of sirolimus Nano medication composition and preparation method thereof - Google Patents
A kind of sirolimus Nano medication composition and preparation method thereof Download PDFInfo
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- CN107049963A CN107049963A CN201710487872.9A CN201710487872A CN107049963A CN 107049963 A CN107049963 A CN 107049963A CN 201710487872 A CN201710487872 A CN 201710487872A CN 107049963 A CN107049963 A CN 107049963A
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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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K31/4353—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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- 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
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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
Abstract
The invention discloses a kind of sirolimus Nano medication composition, include the raw material of following percentage by weight：The 30wt% of sirolimus 10%, the 50wt% of auxiliary material 10%, protective agent 20% 80%.Also disclose the preparation method of sirolimus Nano medication composition.Nano medication composition particle diameter of the present invention is small and narrowly distributing, and the 400nm of particle diameter 50, good dispersion has wide range of applications, and can be applied to tablet, capsule, the preparation of oral administration solution；5min medicine Rong Chu Du≤85%.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, more particularly, to a kind of sirolimus nanometer formulation and its preparation side
Method.
Background technology
Sirolimus (Sirolimus), chemical name:(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,
21S, 23S, 26R, 27R, 34aS) ten hexahydros of -9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a- -
9,27- dihydroxy -3- [(1R) -2- [(1S, 3R, 4R) -4- hydroxyl -3- methoxies cyclohexyl] -1- Methylethyls] -10,21- diformazans
The cyclenes of oxygen-6,8,12,14,20,26- hexamethyls-23,27- epoxy-3H- pyridos [2,1-c] [1,4] oxazepine 31-
1,5,11,28,29 (4H, 6H, 31H)-pentanones.Molecular formula is C51H79NO13, relative molecular mass is 914.19, and fusing point is in 183-
Between 185 DEG C, its molecular structural formula is as follows：
Sirolimus (Sirolimus, SRL) is a kind of new, potent macrolide immunosuppressants, is mainly used in
Anti- rejection after treating organs transplanting, trade name rapammune (Rapamycin).Sirolimus is used as the immune suppression of the third generation
Preparation, is the less immunodepressant for having a great potential of the toxicity found so far, just exempts from for a long time as renal transplant recipients
The essential drugs of epidemic disease suppression therapy.Sirolimus by the mechanism different from other immunodepressant in response to antigen and cell because
T lymphocyte activations and propagation that sub (IL-2, IL-4) is stimulated and occurred.In cell, sirolimus combination immune protein, FK
Associated proteins -12 (FKBP-12), to produce immunosuppressive compound.In in sirolimus retardance G1 phase cell cycle progressions
Afterwards the period, suppress IL-2 and rely on and IL-4 dependences lymphocytic B cells propagation, suppress immunoglobulin A, M and G generation, so that
Prevent from causing the activation of immune system and the conduction of organ rejection response signal, realize immunosuppressive action.
Sirolimus poorly water-soluble, is practically insoluble in water (2.6 μ g/mL), belongs to BCS (biopharmaceutics
Classification system) II class medicines, i.e. low solubility high osmosis, the absorption rate of such medicine is depending on molten
Go out speed.Due to sirolimus poorly water-soluble, and the absorption rate of medicine depends on dissolution rate, therefore limits it in human body
Inside play a role, so as to cause the bioavilability of the pharmaceutical preparation relatively low.
In order to improve the dissolution rate of sirolimus drug, prior art discloses a large amount of related documents.For example, open
Number for CN103655486A Chinese invention patent application file in, disclose a kind of sirolimus microemulsion particles and its preparation side
Method and application, the invention using heating fusion method prepare sirolimus microemulsion particles, can improve preparation stability and
Dissolution rate.In Publication No. CN1771910A Chinese invention patent application file, a kind of insoluble drug nanometer is disclosed
Grain and preparation method thereof, using the mode that high pressure breast is even in the invention, by means of mechanical external force, makes medicine fine particle by homogeneous
Change, form medicament nano granule.In Publication No. CN103239399A Chinese invention patent application file, a kind of western sieve is disclosed
The preparation method of nano suspension is not taken charge of, it is water-soluble that sirolimus and the ethanol solution of copolyvidone are instilled copolyvidone by this method
In liquid, nanosuspension is made.In Publication No. CN105640886A Chinese invention patent application file, a kind of west is disclosed
The preparation method of Luo Mosi self-micro emulsion formulations, this method by sirolimus add in oil phase, emulsifying agent dissolve after, add other
Raw material is well mixed, and microemulsion formulation is made.But, there is preparation technology complexity, the shortcomings of production cost is high, or system in these methods
Obtain particle diameter larger, be not suitable for heavy industrialization and continuously produce.
Therefore, for problem above, it is desirable to provide a kind of new method for preparing sirolimus Nano medication composition.
The content of the invention
The invention solves the problems that first technical problem be to provide a kind of sirolimus Nano medication composition.This nanometer of medicine
Compositions mean particle size 50-400nm, and narrowly distributing, good dispersion, have wide range of applications, and can be applied to tablet, glue
Capsule, the preparation of oral administration solution；Nano medication composition grain 5min medicine Rong Chu Du≤85%.
The invention solves the problems that second technical problem be to provide a kind of preparation side of sirolimus Nano medication composition
Method.The sirolimus Nano medication grain diameter of preparation is small (50-400nm), and particle diameter distribution is narrow.
To solve above-mentioned first technical problem, the present invention is adopted the following technical scheme that：
A kind of sirolimus Nano medication composition, includes the raw material of following percentage by weight：
Sirolimus 10%-30wt%, auxiliary material 10%-50wt%, protective agent 20%-80%.
As the further improvement of technical scheme, the auxiliary material is selected from polyethylene glycol, poloxamer, polyvinylpyrrolidine
Ketone, polyethylene oxide, polyacrylamide, hydroxypropyl methyl cellulose, mannitol, lauryl sodium sulfate, detergent alkylate
One or more in sodium sulfonate, sodium alginate, lactose.
As the further improvement of technical scheme, the protective agent is selected from lactose, mannitol, xylitol, sucrose, marine alga
One or more in sugar, dextran, PVP.
To solve above-mentioned second technical problem, the present invention is adopted the following technical scheme that：
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, respectively preparation sirolimus drug solution and the auxiliary material aqueous solution；
S02, sirolimus drug solution and the auxiliary material aqueous solution that step S01 preparations are obtained each lead into hypergravity rotation
Packed bed is mixed, and control system temperature is 0-40 DEG C, obtains sirolimus nano suspending liquid；
Spray drying protective agent is added in S03, the nano suspending liquid prepared to step S02, spray drying processing is carried out afterwards, powder is obtained
The Nano medication composition of last shape.
It is creative to be applied to high-gravity technology to prepare sirolimus Nano medication particle in the present invention, by overweight
Power technology can prepare the nano particle compared with small particle, and significantly shorten the time of medicine recrystallization, be easy to industrialization to hold
Continuous production.It is of the invention main by reducing drug particles average grain diameter, the particle diameter distribution of drug particles is controlled, to promote medicine
Dissolving, so as to improve the dissolution rate of medicine, is finally reached the purpose for improving drug bioavailability.And existing liquid-phase precipitation crystallization
Drug particles size distribution prepared by method is uneven, poor reproducibility between batch.
In the present invention, the control of system temperature is for the average grain diameter of obtained Nano medication in high gravity rotating packed bed
Size, the drug-eluting speed of particle diameter distribution and product plays an important role.The average grain diameter of the Nano medication
It is not simple linear relationship between the drug-eluting speed and system temperature of size, particle diameter distribution and product.Preferably,
System temperature is 0-40 DEG C in the high gravity rotating packed bed.The Nano medication particle diameter now prepared is small and homogeneous, medicine
Thing dissolution rate is fast.It is highly preferred that system temperature is 10-25 DEG C, now best results in the high gravity rotating packed bed.
According to the dissolution properties of sirolimus, solvent is preferably able to dissolve sirolimus, while being the relatively low solvent of toxicity.
Preferably, in step S01, solvent in the sirolimus drug solution is selected from methanol, absolute ethyl alcohol, dimethyl sulfoxide (DMSO), different
One or more in propyl alcohol, dimethylformamide and acetone.
In the present invention, the interaction between auxiliary material and the medicine sirolimus, eventually influence sirolimus into
Core speed and growth rate, i.e., suitable auxiliary material help to increase medicine nucleation rate, reduce crystal growth rate, so that
To average grain diameter is small, the uniform drug particles of particle diameter distribution.
Preferably, the auxiliary material includes surfactant and cosurfactant；The surfactant is selected from poly- second two
One kind in alcohol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide and hydroxypropyl methyl cellulose
Or it is several；The cosurfactant be selected from mannitol, lauryl sodium sulfate, neopelex, sodium alginate and
One or more in lactose；It is highly preferred that the surfactant be polyvinylpyrrolidine he, the cosurfactant is
Lauryl sodium sulfate.
As the further improvement of technical scheme, in step S01, the concentration of the sirolimus drug solution is 5g/L-
150g/L；The concentration of the auxiliary material aqueous solution is 0.5g/L-10g/L.Arch formation occurs in the excessive concentration of the auxiliary material aqueous solution
Because its drug particles is reunited, the concentration of the auxiliary material aqueous solution is too low, then can not effectively increase medicine nucleation rate, reduction crystal life
Long speed.On this condition, in sirolimus drug solution sirolimus solubility is high, and contributes to drug particle dispersion equal
Even and crystal growth.It is highly preferred that the concentration of the sirolimus solution is 10g/L-100g/L；The auxiliary material aqueous solution
Concentration is 0.5g/L-5.5g/L.
In the present invention, degree of supersaturation is to prepare sirolimus nano particle chief motivation, and larger degree of super saturation has
Beneficial to reduce nano particle diameter and contribute to control particle size distribution.Preferably, in step S01, the sirolimus
The volume ratio of drug solution and the auxiliary material aqueous solution is 1:1-1:20.
Preferably, in step S02, the sirolimus in the sirolimus drug solution and the auxiliary material in the auxiliary material aqueous solution
Mass ratio be 1:0.05-1:10, it now can guarantee that the dissolution rate of preparation, moreover it is possible to meet the functional requirements of said preparation.More
Preferably, foregoing mass ratio is 1:0.05-1:3；Most preferably, foregoing mass ratio is 1:0.5-1:1.
In the present invention, the adding speed of the sirolimus drug solution and the auxiliary material aqueous solution is excessive or too small can influence
The particle diameter and particle diameter distribution of particle in gained suspension, are not simple linear relationships.Preferably, in step S02, the west
The speed that Luo Mosi drug solutions add high gravity rotating packed bed is 1mL/min-10mL/min；The auxiliary material aqueous solution adds overweight
The speed of power RPB is 20mL/min-300mL/min.
In the present invention, high gravity rotating packed bed rotating speed influence liquid flowing state, so as to influence nucleation and the life of particle
Long speed.Preferably, in step S02, the high gravity rotating packed bed rotating speed is 500rpm~2840rpm, is now obtained
The particle diameter of particle is more homogeneous in suspension.
Preferably, the high gravity rotating packed bed is outer circulation high gravity rotating packed bed.For example, outer circulation hypergravity
The structure composition and device parameter of RPB can with document (Chen J F.et al., IND ENG CHEM RES, 2015,
54(33):It is 946-951.) consistent.
Preferably, in step S03, the spray drying protective agent is selected from lactose, mannitol, xylitol, sucrose, trehalose, the right side
Revolve the one or more in glucosides and PVP；The protectant addition of spray drying is with forming sirolimus drug
Weight ratio be 1-3:1；The condition of spray drying treatment is 100-160 DEG C of inlet temperature, 60-90 DEG C of outlet temperature, charging speed
Spend 2-20mL/min, air velocity 500-800L/min compressed air pressures 0.5-0.7Mpa.
Preferably, the sirolimus Nano medication composition exists in unformed form；The sirolimus nanometer
The average grain diameter of pharmaceutical composition is 50-400nm；More preferably 50-200nm；Most preferably 80-120nm,
The sirolimus Nano medication composition for preparing of preparation method of the present invention can also simultaneously with one or more
Pharmaceutically acceptable excipient is combined, for preparing tablet, capsule or granular preparation.
In the present invention, the selection of auxiliary material, the control to system temperature, the control to material concentration, the addition of material solution
The selection of speed and drying mode constitutes a unified technical scheme, and each technical characteristic influences each other, cooperated,
Average grain diameter 50-400nm can be just obtained, particle diameter distribution is uniform, and the sirolimus of 5min medicine Rong Chu Du≤85% is received
Rice medicament composition granule.
Any scope described in the present invention includes any numerical value and end value or end value between end value and end value
Between any subrange for being constituted of any number.
Unless otherwise specified, each raw material in the present invention can be obtained by commercially available purchase, equipment used in the present invention
The conventional equipment in art or the prior art with reference to art can be used to carry out.
The present invention has the following advantages and effect relative to prior art：
1st, the present invention utilizes high gravity rotating packed bed, control to high gravity rotating packed bed system temperature, auxiliary material
The unified overall technology side that selection, the control of material concentration, the selection of the adding speed of material solution and drying mode are formed
Case, obtains the high sirolimus nano particle of controllable average grain diameter, narrowly distributing, stability -- average grain diameter 50-400nm, particle diameter
It is evenly distributed, and 5min medicine Rong Chu Du≤85%.
2nd, the present invention is using spray drying treatment method processing organic solvent, simple to operate and organic solvent removal effect
It is good.The present invention avoids Nano medication breakage of particles from reuniting by adding spray drying protective agent in spray drying process energy.Slurry is carried out
Spray drying, with regard to the dry powder that can be readily transported and stored.Whole preparation process from slurry to dry powder can be carried out continuously, easily
In amplification and large-scale production.Spray powder can automatically form Nanodispersion after meeting water, and grain diameter is small, particle diameter distribution is narrower.
Place at room temperature after two weeks, average grain diameter is held essentially constant, show good stability.
3rd, present invention process process is simple, easily realizes, less energy consumption, efficiency high, cost is low, and is very easy to amplification, reaches
To the subject invention of industrialized production.
Brief description of the drawings
The embodiment to the present invention is described in further detail below in conjunction with the accompanying drawings
Fig. 1 shows the scanning electron microscope (SEM) photograph of the sirolimus bulk drug of embodiment 1.
Fig. 2 shows the scanning electron microscope (SEM) photograph of drug particles in the nano suspending liquid of embodiment 1.
Fig. 3 shows the scanning electron microscope (SEM) photograph of the gained sirolimus Nano medication composition water redisperse of embodiment 1.
Fig. 4 shows sirolimus Nano medication composition, physical mixed powder and the Xi Luomo that embodiment 1 is prepared
Take charge of X-ray diffraction (XRD) figure of bulk drug.
Fig. 5 shows sirolimus Nano medication composition, physical mixed powder and the sirolimus that embodiment 1 is prepared
The stripping curve figure of bulk drug.
Embodiment
In order to illustrate more clearly of the present invention, with reference to preferred embodiment, the present invention is described further.Ability
Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, and this should not be limited with this
The protection domain of invention.
Embodiment 1
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug (scanning electron microscope (SEM) photograph is as shown in Figure 1) and ethanol are configured into concentration is 10mg/mL's
Sirolimus ethanol solution 10mL；Polyvinylpyrrolidone and deionized water are made into 0.5mg/mL auxiliary material aqueous solution 200mL,
Simultaneously 5mg lauryl sodium sulfate is added to the auxiliary material aqueous solution；
S02, unlatching outer circulation high gravity rotating packed bed, regulation rotating speed to 2272rpm；Feed pump is opened, by Xi Luomo
Department's ethanol solution and the auxiliary material aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls Xi Luomo
Department's ethanol solution feed rate is that 2mL/min, excipient substance aqueous solution feed rate are 40mL/min, and the temperature of control system is
20 DEG C, obtain nano suspending liquid；
S03, by obtained nano suspending liquid (Fig. 2 shows the scanning electron microscope (SEM) photograph of drug particles in suspension) add mannitol
It is spray-dried with after polyvinylpyrrolidone, obtains sirolimus Nano medication composition, gained drug particles is averaged
Particle diameter is 200nm or so, particle diameter distribution ± 20nm.
Fig. 3 is the scanning electron microscope (SEM) photograph of gained sirolimus Nano medication composition water redisperse, as we know from the figure through spraying
Being dried to obtain nano-powder water, point property is good again, has increased compared with grain diameter in suspension.
As a comparison, sirolimus and auxiliary material are subjected to physical mixed by equivalent, obtain physical mixed powder.
Fig. 4 is the X-ray diffraction of gained sirolimus Nano medication composition, physical mixed powder and sirolimus raw material
(XRD) figure.The present invention obtains sirolimus and is in unformed state as we know from the figure.
The dissolution rate test of sirolimus Nano medication composition：
Method of testing is：Sirolimus Nano medication composition obtained above, the physical mixed of certain mass are taken respectively
Powder and sirolimus bulk drug are separately added into 300mL water pH6.8 phosphate buffer solutions (plus 0.5%SDS (dodecyl sulphur
Sour sodium)) in, put in 37 DEG C of water-baths, rotating speed 100rpm is slowly stirred, sample 4mL in predetermined point of time respectively, with 0.45 micron of note
Emitter is filtered into centrifuge tube, and the dissolution blank medium of isothermal equivalent is added after the completion of every sub-sampling.For the extinction for obtaining measure
Angle value samples obtained settled solution and certain multiple is diluted with corresponding blank medium, in absorption maximum in prescribed limit
The absorbance of prepared solution is determined at wavelength.Each sample parallel determination 3 times.Above-mentioned solution is taken according to AAS (China
Two annex IV of pharmacopeia version in 2010), determine absorbance respectively at 277.5nm wavelength, calculate dissolution rate.
Fig. 5 shows sirolimus Nano medication composition, the physical mixed powder prepared using above-mentioned preparation method
With the stripping curve figure of sirolimus bulk drug.The sirolimus Nano medication composition prepared as we know from the figure is effective
Improve the dissolution rate of medicine, 5min drug dissolution reaches 90%.
Embodiment 2
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug and methanol are configured to the sirolimus ethanol solution 10mL that concentration is 10mg/mL；
Polyvinylpyrrolidone and deionized water are made into 0.5mg/mL auxiliary material aqueous solution 200mL；
S02, unlatching outer circulation high gravity rotating packed bed, regulation rotating speed to 2840rpm；Feed pump is opened, by Xi Luomo
Department's ethanol solution and the auxiliary material aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls Xi Luomo
Department's ethanol solution feed rate is that 5mL/min, excipient substance aqueous solution feed rate are 50mL/min, and the temperature of control system is
20 DEG C, obtained nano suspending liquid；
S03, will obtained nano suspending liquid add mannitol and polyvinylpyrrolidone after be spray-dried, obtain west
Luo Mosi Nano medication compositions, the average grain diameter of gained drug particles is 250nm or so, particle diameter distribution ± 30nm.
By the identical dissolution rate method of testing of embodiment 1, as a result show, the sirolimus Nano medication group prepared
Compound effectively improves the dissolution rate of medicine, and 5min drug dissolution reaches 87%.
Embodiment 3
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug and dimethyl sulfoxide (DMSO) are made into the sirolimus dimethyl sulfoxide (DMSO) that concentration is 50mg/mL
Solution 10mL；Polyvinylpyrrolidone and deionized water are made into 8mg/mL auxiliary material aqueous solution 200mL；
S02, unlatching outer circulation high gravity rotating packed bed, regulation rotating speed to 2250rpm；Feed pump is opened, by Xi Luomo
Department's ethanol solution and the auxiliary material aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls Xi Luomo
Department's ethanol solution feed rate is that 10mL/min, excipient substance aqueous solution feed rate are 200mL/min, the temperature of control system
For 20 DEG C, obtained nano suspending liquid；
S03, will obtained nano suspending liquid add mannitol and polyvinylpyrrolidone after be spray-dried, obtain west
Luo Mosi Nano medication compositions, the average grain diameter of gained drug particles is 320nm or so, particle diameter distribution ± 20nm.
By the identical dissolution rate method of testing of embodiment 1, as a result show, the sirolimus Nano medication group prepared
Compound effectively improves the dissolution rate of medicine, and 5min drug dissolution reaches 88%.
Embodiment 4
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug and ethanol are configured to the sirolimus ethanol solution 10mL that concentration is 100mg/mL；
Polyvinylpyrrolidone and deionized water are made into 5mg/mL auxiliary material aqueous solution 200mL, while adding 5mg to the auxiliary material aqueous solution
Lauryl sodium sulfate；
S02, unlatching outer circulation high gravity rotating packed bed, regulation rotating speed to 2272rpm；Feed pump is opened, by Xi Luomo
Department's ethanol solution and the auxiliary material aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls Xi Luomo
Department's ethanol solution feed rate is that 2mL/min, excipient substance aqueous solution feed rate are 40mL/min, and the temperature of control system is
20 DEG C, obtained nano suspending liquid；
S03, will obtained nano suspending liquid add mannitol and polyvinylpyrrolidone after be spray-dried, obtain west
Luo Mosi Nano medication compositions, the average grain diameter of gained drug particles is 200nm or so, particle diameter distribution ± 20nm.
By the identical dissolution rate method of testing of embodiment 1, as a result show, the sirolimus Nano medication group prepared
Compound effectively improves the dissolution rate of medicine, and 5min drug dissolution reaches 90%.
Embodiment 5
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug and ethanol are configured to the sirolimus ethanol solution 10mL that concentration is 100mg/mL；
Polyvinylpyrrolidone and deionized water are made into 5mg/mL auxiliary material aqueous solution 200mL, while adding 5mg to the auxiliary material aqueous solution
Lauryl sodium sulfate；Open outer circulation high gravity rotating packed bed, regulation rotating speed to 2272rpm；
S02, unlatching feed pump, hypergravity rotation filling is delivered to by sirolimus ethanol solution and the auxiliary material aqueous solution simultaneously
Recrystallization reaction is carried out in bed, and controls sirolimus ethanol solution feed rate to be fed for 2mL/min, the excipient substance aqueous solution
Speed is 40mL/min, and the temperature of control system is 20 DEG C, obtained nano suspending liquid；
S03, will obtained nano suspending liquid add trehalose after be spray-dried, obtain sirolimus Nano medication group
Compound, the average grain diameter of gained drug particles is 400nm or so, particle diameter distribution ± 25nm.
By the identical dissolution rate method of testing of embodiment 1, as a result show, the sirolimus Nano medication group prepared
Compound effectively improves the dissolution rate of medicine, and 5min drug dissolution reaches 85%.
Embodiment 6
A kind of preparation method of sirolimus Nano medication composition, comprises the following steps：
S01, sirolimus bulk drug and acetone are configured to the sirolimus ethanol solution 10mL that concentration is 10mg/mL；
Polyvinylpyrrolidone and deionized water are made into 0.5mg/mL auxiliary material aqueous solution 200mL, while being added to the auxiliary material aqueous solution
10mg lauryl sodium sulfate；
S02, unlatching outer circulation high gravity rotating packed bed, regulation rotating speed to 1500rpm；Feed pump is opened, by Xi Luomo
Department's ethanol solution and the auxiliary material aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls Xi Luomo
Department's ethanol solution feed rate is that 2mL/min, excipient substance aqueous solution feed rate are 40mL/min, and the temperature of control system is
10 DEG C, obtained nano suspending liquid；
S03, by obtained nano suspending liquid (Fig. 2 shows the scanning electron microscope (SEM) photograph of drug particles in suspension) add mannitol
With being spray-dried after lactose, sirolimus Nano medication composition is obtained, the average grain diameter of gained drug particles is 300nm
Left and right, particle diameter distribution ± 20nm.
By the identical dissolution rate method of testing of embodiment 1, as a result show, the sirolimus Nano medication group prepared
Compound effectively improves the dissolution rate of medicine, and 5min drug dissolution reaches 88%.
Comparative example 1
Embodiment 1 is repeated, difference is, the concentration of sirolimus drug solution is 1mg/mL, and other conditions are constant, is made
Sirolimus Nano medication combination powder average grain diameter for 120nm or so, particle diameter distribution ± 100nm.Dissolution rate test knot
It is really：5min drug dissolution is only 75%.Although the pharmaceutical composition average grain diameter of this comparative example meets the requirements, medicine
The too small control for causing particle diameter distribution of thing concentration becomes highly difficult, so as to have impact on drug dissolution, and too low concentration is in work
The upper no practical significance of industry metaplasia production.
Comparative example 2
Embodiment 1 is repeated, difference is, the concentration of sirolimus drug solution is 160mg/mL, and other conditions are constant, system
The sirolimus Nano medication combination powder average grain diameter obtained is 450nm or so.Dissolution rate test result is：5min medicine
Dissolution rate is only 61%.
Comparative example 3
Embodiment 3 is repeated, difference is, the auxiliary material that polyvinylpyrrolidone and deionized water are made into 0.3mg/mL is water-soluble
Liquid 200mL, other conditions are constant, and obtained sirolimus Nano medication combination powder average grain diameter is 320nm or so, particle diameter point
Cloth ± 120nm.Dissolution rate test result is：5min drug dissolution is only 57%.Although the drug regimen of this comparative example
Thing average grain diameter meets the requirements, but auxiliary material concentration of aqueous solution is too small to cause particle diameter distribution to be difficult to control, so as to have impact on medicine
Dissolution rate.
Comparative example 4
Embodiment 3 is repeated, difference is, the auxiliary material that polyvinylpyrrolidone and deionized water are made into 12mg/mL is water-soluble
Liquid 200mL, other conditions are constant, and obtained sirolimus Nano medication combination powder average grain diameter is 410nm or so.Dissolution speed
Spending test result is：5min drug dissolution is only 44%.
Comparative example 5
Embodiment 1 is repeated, difference is, temperature of reaction system is changed into 60 DEG C, and remaining condition is constant, obtained Xi Luomo
It is 500nm or so to take charge of Nano medication combination powder average grain diameter.Dissolution rate test result is：5min drug dissolution is only
75%.
Comparative example 6
Embodiment 1 is repeated, difference is, temperature of reaction system is changed into -5 DEG C, and remaining condition is constant, obtained Xi Luomo
It is 220nm or so, particle diameter distribution ± 150nm to take charge of Nano medication combination powder average grain diameter.Dissolution rate test result is：5min
Drug dissolution be only 59%.Although the pharmaceutical composition average grain diameter of this comparative example meets the requirements, temperature of reaction system
It is too small to cause the whard to control of particle diameter distribution, so as to have impact on drug dissolution.
Comparative example 7
Embodiment 1 is repeated, difference is, in step S2, the sirolimus drug solution adds hypergravity rotation filling
The speed of bed is 0.5mL/min；The speed that the auxiliary material aqueous solution adds high gravity rotating packed bed is 15mL/min, obtained western sieve
Department's Nano medication combination powder average grain diameter is not 270nm or so, particle diameter distribution ± 130nm.Dissolution rate test result is：
5min drug dissolution is only 67%.Although the pharmaceutical composition average grain diameter of this comparative example meets the requirements, drug solution
The speed of addition high gravity rotating packed bed is too small to cause the whard to control of particle diameter distribution, so as to have impact on drug dissolution.
Comparative example 8
Embodiment 1 is repeated, difference is, in step S2, the sirolimus drug solution adds hypergravity rotation filling
The speed of bed is 12mL/min；The speed that the auxiliary material aqueous solution adds high gravity rotating packed bed is 350mL/min, obtained western sieve
Department's Nano medication combination powder average grain diameter is not 300nm or so, particle diameter distribution ± 150nm.Dissolution rate test result is：
5min drug dissolution is only 59%.Although the pharmaceutical composition average grain diameter of this comparative example meets the requirements, drug solution
The speed of addition high gravity rotating packed bed is too small to cause the whard to control of particle diameter distribution, so as to have impact on drug dissolution.
Comparative example 9
Embodiment 1 is repeated, difference is, nano suspending liquid drying mode is changed to freeze-drying, -74 DEG C of cryogenic temperature --
20 DEG C, remaining condition is constant, and obtained sirolimus Nano medication combination powder average grain diameter is 600nm or so.Dissolution rate
Test result is：5min drug dissolution is only 45%.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair
The restriction of embodiments of the present invention.For those of ordinary skill in the field, may be used also on the basis of the above description
To make other changes in different forms.Here all embodiments can not be exhaustive.It is every to belong to this hair
Row of the obvious changes or variations that bright technical scheme is extended out still in protection scope of the present invention.
Claims (10)
1. a kind of sirolimus Nano medication composition, it is characterised in that include the raw material of following percentage by weight：
Sirolimus 10%-30wt%, auxiliary material 10%-50wt%, protective agent 20%-80%.
2. sirolimus Nano medication composition according to claim 1, it is characterised in that：The auxiliary material is selected from poly- second two
Alcohol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl methyl cellulose, mannitol, ten
One or more in sodium dialkyl sulfate, neopelex, sodium alginate, lactose.
3. sirolimus Nano medication composition according to claim 1, it is characterised in that：The protective agent be selected from lactose,
One or more in mannitol, xylitol, sucrose, trehalose, dextran, PVP.
4. the preparation method of sirolimus Nano medication composition as claimed in claim 1, it is characterised in that including following step
Suddenly：
S01, respectively preparation sirolimus drug solution and the auxiliary material aqueous solution；
S02, sirolimus drug solution and the auxiliary material aqueous solution that step S01 preparations are obtained are passed through high gravity rotating packed bed and entered
Row mixing, control system temperature is 0-40 DEG C, obtains sirolimus nano suspending liquid；
Spray drying protective agent is added in S03, the nano suspending liquid prepared to step S02, spray drying processing is carried out afterwards, obtains powdered
Nano medication composition.
5. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：Preferably, institute
It is 0-40 DEG C to state system temperature in high gravity rotating packed bed；It is highly preferred that system temperature in the high gravity rotating packed bed
For 10-25 DEG C.
6. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：Preferably, walk
In rapid S01, the solvent in the sirolimus drug solution is selected from methanol, absolute ethyl alcohol, dimethyl sulfoxide (DMSO), isopropanol, diformazan
One or more in base formamide and acetone.
7. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：Preferably, institute
Stating auxiliary material includes surfactant and cosurfactant；The surfactant is selected from polyethylene glycol, poloxamer, polyethylene
One or more in pyrrolidones, polyethylene oxide, polyacrylamide and hydroxypropyl methyl cellulose；It is described to help surface to live
One or more of the property agent in mannitol, lauryl sodium sulfate, neopelex, sodium alginate and lactose.
8. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：In step S01,
The concentration of the sirolimus drug solution is 5g/L-150g/L；The concentration of the auxiliary material aqueous solution is 0.5g/L-10g/L；More
Preferably, the concentration of the sirolimus solution is 10g/L-100g/L；The concentration of the auxiliary material aqueous solution is 0.5g/L-
5.5g/L；
Preferably, in step S01, the volume ratio of the sirolimus drug solution and the auxiliary material aqueous solution is 1:1-1:20.
9. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：Preferably, walk
In rapid S02, the mass ratio of the sirolimus in the sirolimus drug solution and the auxiliary material in the auxiliary material aqueous solution is 1:0.05-
1:10；It is highly preferred that foregoing mass ratio is 1:0.05-1:3；Most preferably, foregoing mass ratio is 1:0.5-1:1；
Preferably, in step S02, the speed that the sirolimus drug solution adds high gravity rotating packed bed is 1mL/min-
10mL/min；The speed that the auxiliary material aqueous solution adds high gravity rotating packed bed is 20mL/min-300mL/min；
Preferably, in step S02, the high gravity rotating packed bed rotating speed is 500rpm~2840rpm.
10. the preparation method of sirolimus Nano medication composition according to claim 4, it is characterised in that：Preferably, walk
In rapid S03, the spray drying protective agent is coughed up selected from lactose, mannitol, xylitol, sucrose, trehalose, dextran and polyethylene ratio
One or more in alkanone；The protectant addition of spray drying is 1-3 with the weight ratio for forming sirolimus drug:1；Spray
The condition of mist drying process is 100-160 DEG C of inlet temperature, 60-90 DEG C of outlet temperature, charging rate 2-20mL/min, gas velocity
Spend 500-800L/min compressed air pressures 0.5-0.7Mpa.
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