CN107049985A - A kind of long-acting slow-release preparation of antiparkinsonism drug and preparation method thereof - Google Patents
A kind of long-acting slow-release preparation of antiparkinsonism drug and preparation method thereof Download PDFInfo
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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Abstract
The invention discloses a kind of long-acting slow-release preparation for treating anti-parkinson drug and preparation method thereof, the long-acting slow-release preparation is microballoon, the microballoon includes Rasagiline or its pharmaceutically acceptable salt and biodegradable biocompatibility macromolecule polymer, and the microballoon includes the microballoon that average grain diameter is 0.5 5 μm of microballoon and average grain diameter is 20 150 μm.The present invention can substantially reduce the fluctuation of Rasagiline concentration in blood plasma by the proper combination in the pharmaceutical composition of the present invention using 2 kinds of different-grain diameter microballoons, and without obvious delay acquisition time.The present invention is in the case where drugloading rate is high simultaneously, no burst drug release phenomenon.
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of long-acting slow-release preparation of antiparkinsonism drug and its preparation side
Method.
Background technology
Rasagiline is second generation MAOI, the decomposition of energy blocking nerves neurotransmitter dopamine, with the first generation
MAOI, including selegiline, Si Jining, miaow tremble pyrrole, gold think equality compare, inhibitory action is stronger, to long-term
The patient for occurring failing using DOPA preparation drug effect also plays the role of improvement.In addition, the metabolite of Rasagiline is a kind of nothing
The non-amphetamine material of activity, Small side effects, it is often more important that, the medicine plays the role of certain remission, and has more card
It is demonstrated that this kind of medicine plays the role of certain neuroprotection.
Rasagiline clinically only has oral tablet at present.Oral tablet is although convenient to take, but patient Parkinson with
The development of the state of an illness, often with neurotrosis, failure of memory occurs, so as to cause to miss medicine, it is impossible to which rule takes medicine
Thing, causes the state of an illness further to deteriorate.Furthermore Parkinson's later stage patient usually has dysphagia, be not suitable for drug administration.In addition,
Oral administration has obvious blood concentration fluctuation, aggravates side effect, the last phenomenon of agent and on-off phenomenon occurs.
Patent CN 103494766 discloses a kind of rasagiline orally disintegrating compositions, although solve medicine swallow it is tired
Difficult the problem of, but can not solve to miss medicine, and the problems such as frequent medication.
Patent CN 1762495 discloses a kind of preparation technology for the long-acting slow-release preparation for treating Parkinson's, using organic
Solvent dissolves medicine and biodegradable medicinal high polymer adjuvant, and organic solvent is mutually injected into and uses medicinal soluble high score
To form microballoon in the continuous aqueous phase that son is prepared, organic solvent is then vapored away, sustained-release micro-spheres i.e. O/W techniques are filtrated to get；Or
Medicine and biodegradable medicinal high polymer adjuvant are dissolved with organic solvent, microballoon is then made using spray drying process；Or
Medicine and biodegradable medicinal high polymer adjuvant are fully dissolved and be configured to organic solution with organic dissolution agent, is sprayed
Into an organic non-solvents or water, microballoon i.e. O/O techniques or O/W techniques are made through extraction.Using O/W techniques, due to medicine
It is water-soluble active, does not have any safeguard measure, outer water phase can be directly exposed to and reduce envelop rate, accordingly, it is difficult to obtain
Take the microballoon with high content and high encapsulation rate.And using O/O techniques, it is necessary to use substantial amounts of organic solvent, and need to go
Except the whole organic solvents used, complex process.Being the need for high temperature using spray drying first makes supplementary material cause degraded, and
Organic solvent is spray-dried, it is necessary to explosion-proof, there is certain danger.
Patent CN 105769771 discloses a kind of preparation method of Exenatide release microsphere composition, first by raw material
Medicine is dissolved using intensive polar solvent, then dissolves polymer weak polar solvent, intensive polar solvent then is added into low pole
Suspension or uniform solution are formed in solvent, it is rear to add in quencher, obtain particulate.Wherein quencher is selected from silicone oil, liquid stone
Wax, mineral oil are, it is necessary to use substantial amounts of organic solvent, and need to remove the whole organic solvents used, complex process.
M.Fern á ndez et al. document《Controlled release of rasagiline mesylate
promotes neuroprotection in a rotenone-induced advanced model of Parkinson’s
disease》Disclosing one kind uses 50/50PLGA as slow-release material, prepares Rasagiline using O/W and W/O/W techniques and delays
The method for releasing microballoon.But it is shorter deenergized period that this method prepares microballoon, only two weeks, and the drugloading rate of medicine is relatively low, phase
With under dosage, the medicine total amount of injection is bigger than normal, is unfavorable for the compliance of patient.
Patent CN 103338752 discloses a kind of risperidone slow-release microsphere composition, and it discloses glued using two kinds of differences
The polymer of degree is reached with this to prepare microballoon and adjusts release purpose, eliminate the sustained release phase.But two kinds are used without viscous
The polymer of degree is dissolved in organic solvent and then prepares microballoon simultaneously, on the one hand can increase prescription complexity, different viscosities polymerization
Thing is possible to bring prescription consistency problem, and another aspect this method is applied can also cause the problem of product is prominent to be released in the present invention.
Patent CN 104010629 discloses a kind of Triptorelin microsphere drug composition, and it in microballoon by adding glucose or sweet
Reveal alcohol to adjust release, the initial release amount of medicine is improved, so that medicine works as early as possible.But use addition release regulator
Method on the one hand same increase prescription complexity, it is possible to bring prescription consistency problem, another aspect this method is applied
The present invention still can also cause the problem of product is prominent to be released.
The content of the invention
Goal of the invention：To solve problems of the prior art, the present invention provides a kind of Rasagiline long-acting slow-release group
Compound and preparation method thereof.Present invention improves clinically only have at present the Rasagiline medicine that is administered of oral form according to
From property, and it is short deenergized period to improve sustained release microsphere agents pharmaceutical composition disclosed in current document, the low shortcoming of drugloading rate,
And without the sustained release phase.
Rasagiline is prepared into longer sustained release deenergized period by the present inventor according to presently disclosed technical data, trial
Microballoon, according to those skilled in the art's common technology means, replaces 50/50 PLGA using 65/35-100/0 PLGA, finds
Really the deenergized period of microballoon can be extended, however, it was found that microballoon occurs in that the sustained release phase.
In the field, solving the common technology of microballoon sustained release phase has the mixed with polymers using different viscosities model to make
With, and the methods such as release regulator are added, but these methods one are to add prescription complexity, it is possible to bring prescription
Inscribed between compatibility, another is, using the problem of product is prominent to be released can be caused in the present invention.
Moreover the inventors have discovered that in the range of microballoon conventional particle size, with the reduction of microspherulite diameter, microballoon deenergized period
And the sustained release phase can shorten really, but change is not obvious.But the present inventor's creative discovery, will be micro-
Ball is prepared into nanometer to sub-micron rank, and microballoon release behavior but there occurs obvious change, first be no sustained release phase and
Released without prominent, second is substantially to shorten deenergized period.And the discovery nanometer of the present inventor's miracle is to the release of sub-micron rank microballoon
Phase and the sustained release phase of common particle diameter microballoon approach, or even identical in certain embodiments.
Therefore the present inventor expects the microballoon of two kinds of different-grain diameters being used in mixed way, and it is longer to be not only released the cycle
Product, and without the sustained release phase.
Other the present inventor's experiment is found, uses currently known technology, it is impossible to obtain the product of high drug load and envelop rate.
But according to technology disclosed by the invention, can but obtain high drug load and the microballoon of high encapsulation rate.
Specifically, to realize technical purpose of the invention, the technical scheme is that：
A kind of long-acting slow-release preparation for treating anti-parkinson drug, the long-acting slow-release preparation is microballoon, the microballoon bag
Containing Rasagiline or its pharmaceutically acceptable salt and biodegradable biocompatibility macromolecule, the microballoon includes average grain
The microballoon that footpath is 0.5-5 μm of microballoon and average grain diameter is 20-150 μm.
The average grain diameter is that 0.5-5 μm of microballoon accounts for the 10-50wt% of long-acting slow-release preparation, and average grain diameter is 20-150
μm microballoon account for 50-90wt%.
It is further preferred that the average grain diameter, which is 0.5-5 μm of microballoon, accounts for the 20-40wt% of long-acting slow-release preparation, put down
Equal particle diameter accounts for 60-80wt% for 20-150 μm of microballoon.
Preferably, a kind of long-acting slow-release preparation for treating anti-parkinson drug, the long-acting slow-release preparation is microballoon, described
Microballoon includes Rasagiline or its pharmaceutically acceptable salt and biodegradable biocompatibility macromolecule, and the microballoon is preferred
Including the microballoon that average grain diameter is 0.5-3 μm and the microballoon that average grain diameter is 40-100 μm.
The average grain diameter is that 0.5-3 μm of microballoon accounts for the 10-50wt% of long-acting slow-release preparation, and average grain diameter is 40-100
μm microballoon account for 50-90wt%.
It is further preferred that the average grain diameter, which is 0.5-3 μm of microballoon, accounts for the 20-40wt% of long-acting slow-release preparation, put down
Equal particle diameter accounts for 60-80wt% for 40-100 μm of microballoon.
Preferably, Rasagiline or its pharmaceutically acceptable salt account for the 10-50wt% of long-acting slow-release preparation.
Low content medicine can make always to be administered weight increase, high drug load may envelop rate decline, it is further preferred that
Rasagiline or its pharmaceutically acceptable salt account for the 20-40wt% of long-acting slow-release preparation.
It is preferably carried out in one kind in scheme, the biodegradable biocompatibility macromolecule is poly- (lactide-second friendship
Ester).
It is further preferred that in poly- (lactide coglycolide), the mol ratio of lactide and glycolide for 65: 35~
100∶0。
In clinical practice, the longer the better for pharmaceutical release time, but the longer time may single administration it is excessive, it is unfavorable
In patient's compliance, therefore in some cases, in poly- (lactide coglycolide), lactide and the preferred of glycolide rub
You are than being 70: 30~95: 5.
In clinical practice, the longer the better for pharmaceutical release time, but the longer time may single administration it is excessive, it is unfavorable
In patient's compliance, therefore in some cases, in poly- (lactide coglycolide), lactide and glycolide are more preferably
Mol ratio is 75: 25~85: 15.
It is preferably carried out in one kind in scheme, the range of viscosities of poly- (lactide coglycolide) is 0.2-0.8dl/g.
It is further preferred that the range of viscosities of poly- (lactide coglycolide) is 0.3-0.6dl/g.
It is preferably carried out in one kind in scheme, the molecular weight ranges 21kDa-89kDa of poly- (lactide coglycolide).
It is preferably carried out in one kind in scheme, the terminal groups of poly- (lactide coglycolide) are ester group or carboxyl.
It is further preferred that the terminal groups of poly- (lactide coglycolide) are carboxyl.
The deenergized period of long-acting slow-release preparation of the present invention was at 4~12 weeks.
Present invention further proposes a kind of preparation method for the long-acting slow-release preparation for treating anti-parkinson drug, including such as
Lower step：
A) biodegradable biocompatibility macromolecule is dissolved in first kind organic solvent, obtains uniform solution A；
B) Equations of The Second Kind that being dissolved in Rasagiline or its pharmaceutically acceptable salt can dissolve each other with first kind organic solvent has
Machine solvent, obtains uniform solution B；
C) the uniform solution B for obtaining step b) is added in the uniform solution A that step a) is obtained and is obtained homogeneous emulsion C；
D) the homogeneous emulsion C for obtaining step c) adds in the continuous aqueous phase prepared with medicinal water soluble polymer to be formed
Microballoon；Preferably, the medicinal soluble macromolecule is polyvinyl alcohol；The poly-vinyl alcohol solution concentration is 0.5-4%；It is described
Continuous aqueous phase temperature is 2-15 DEG C, preferably 4 DEG C.
E) organic solvent in removal step d) microballoons, is filtered, washing；
F) step e) thus obtained microspheres are freeze-dried, obtain sustained-release micro-spheres.
Preferably, first kind organic solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethyl
Any one in formamide or dimethyl acetamide.Equations of The Second Kind organic solvent be selected from ethanol, acetic acid, hydrochloric acid, dimethyl sulfoxide (DMSO),
Any one in dimethylformamide or dimethyl acetamide.
It is further preferred that first kind organic solvent is any one in dichloromethane, ethyl acetate, tetrahydrofuran
Kind.Equations of The Second Kind organic solvent is any in ethanol, acetic acid, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide
It is a kind of.
It is further preferred that first kind organic solvent is selected from dichloromethane.Equations of The Second Kind organic solvent is selected from ethanol, acetic acid
Any one.
The solution that step b) is obtained is when adding step a) using ultrasound, vortex, homogeneous or agitating mode.
Using super when the homogeneous emulsion C that step c) is obtained is added in the continuous aqueous phase prepared with medicinal water soluble polymer
Sound, vortex, homogeneous, high-pressure homogeneous or stirring mode.
Wherein ultrasonic power is in 200-400w, and vortex rotating speed is in 2000-4000rpm, and homogeneous speed is in 4000-
20000rpm, it is high-pressure homogeneous in 600-1500bar；Mixing speed is in 1000-3000rpm.
It is preferred that, the ratio of first kind organic solvent and Equations of The Second Kind organic solvent is 2: 1-20: 1.
It is further preferred that the ratio of first kind organic solvent and Equations of The Second Kind organic solvent is 2: 1-10: 1.
Beneficial effect：Compared with prior art, the pharmaceutical composition that microspheres form proposed by the present invention is present, with medicine
The property discharged for a long time, can discharge Rasagiline in the time more than one month.It is a feature of the present invention that by this hair
Using the proper combination of 2 kinds of different-grain diameter microballoons in bright pharmaceutical composition, Rasagiline concentration in blood plasma can be substantially reduced
Fluctuation, and without obvious delay acquisition time.Another feature of the invention is no burst drug release in the case where drugloading rate is high
Phenomenon.
Brief description of the drawings
Fig. 1 is the release characteristics of embodiment 1, embodiment 1-2, embodiment 1-4 and sustained-release micro-spheres obtained by embodiment 1-6, from
It can be seen from the figure that, in common particle size range, i.e., in 20-150 μm particle size range, although different-grain diameter scope microballoon release row
To be variant, but it is unobvious；
Fig. 2 is the sustained-release micro-spheres of embodiment 1 (being labeled as embodiment 1), the sustained-release micro-spheres of embodiment 2 (being labeled as embodiment 2), two
Part embodiment 1 and the In-vitro release curves of a mixture of embodiment 2 (being labeled as embodiment 1+2)；
Fig. 3 is the sustained-release micro-spheres of embodiment 3 (being labeled as embodiment 3), the sustained-release micro-spheres of embodiment 4 (being labeled as embodiment 4), three
Part embodiment 1 and the In-vitro release curves of a mixture of embodiment 4 (being labeled as embodiment 3+4)；
Fig. 4 is the sustained-release micro-spheres of embodiment 5 (being labeled as embodiment 5), the sustained-release micro-spheres of embodiment 6 (being labeled as embodiment 6), three
Part embodiment 5 and the In-vitro release curves of a mixture of embodiment 6 (being labeled as embodiment 5+6)；
Fig. 5 is the sustained-release micro-spheres of embodiment 7 (being labeled as embodiment 7), the sustained-release micro-spheres of embodiment 8 (being labeled as embodiment 8), two
Part embodiment 7 and the In-vitro release curves of a mixture of embodiment 8 (being labeled as embodiment 7+8).
Fig. 6 be the sustained-release micro-spheres of embodiment 9 (being labeled as embodiment 9), the sustained-release micro-spheres of embodiment 10 (being labeled as embodiment 10),
Five parts of embodiments 9 and the In-vitro release curves of a mixture of embodiment 10 (being labeled as embodiment 9+10).
Fig. 7 is the sustained-release micro-spheres of embodiment 11 (being labeled as embodiment 11), the sustained-release micro-spheres of embodiment 12 (are labeled as embodiment
12), the In-vitro release curves of three parts of embodiments 11 and two parts of mixtures of embodiment 12 (being labeled as embodiment 11+12).
Embodiment
Technical solution of the present invention is described in detail below, but protection scope of the present invention is not limited to the implementation
Example.
It is prepared by the sustained-release micro-spheres of embodiment 1..
By 8.00gPLGA (lactide/glycolides=65/35, is lactide/glycolides hereafter together, 0.65dl/g,
71kDa, ester group end group) 80.00g dichloromethane is dissolved in, obtain uniform solution A；2.00g Rasagilines are dissolved in 10.00g ethanol,
Obtain uniform solution B；Under 3000rpm vortex conditions, solution A addition solution B is obtained into homogeneous emulsion C.Uniform solution C is added
In 4 DEG C of 1.0% polyvinyl alcohol water solution, microballoon is prepared using 2000rpm mechanical agitator stirring.Then heat to 40
DEG C organic solvent is volatilized, filter microballoon afterwards, and using water for injection cleaning microballoon 7 times, be then freeze-dried, delayed
Release microballoon.
The preparation of the sustained-release micro-spheres of embodiment 2..
8.00g PLGA (65/35,0.65dl/g, 71kDa, ester group end group) are dissolved in 80.00g dichloromethane, obtain homogeneous
Solution A；2.00g Rasagilines are dissolved in 10.00g ethanol, uniform solution B is obtained；Under ultrasound condition, power 300w, by solution A
Add solution B and obtain homogeneous emulsion C.In the 1.0% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, 900bar's
It is high-pressure homogeneous under pressure to prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards and removes continuous aqueous phase,
And clean microballoon 7 times using water for injection, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 3..
7.00g PLGA (75/25,0.5dl/g, 57kDa, carboxyl end groups) are dissolved in 70.00g ethyl acetate, obtain homogeneous molten
Liquid A；3.00g Rasagilines are dissolved in 15.00g acetic acid, uniform solution B is obtained；Under 3000rpm vortex conditions, by solution A plus
Enter solution B and obtain homogeneous emulsion C.In the 0.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, 4000rpm is used
Homogenizer homogeneous prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use injection
Water cleaning microballoon 7 times, is then freeze-dried, obtains sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 4..
7.00g PLGA (75/25,0.5dl/g, 57kDa, carboxyl end groups) are dissolved in 70.00g ethyl acetate, obtain homogeneous molten
Liquid A；3.00g Rasagilines are dissolved in 15.00g acetic acid, uniform solution B is obtained；Under 4000rpm vortex conditions, by solution A plus
Enter solution B and obtain homogeneous emulsion C.In the 0.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, 1000bar's
It is high-pressure homogeneous under pressure to prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use injection
Microballoon is cleaned with water 7 times, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 5..
6.00g PLGA (85/15,0.4dl/g, 46kDa, carboxyl end groups) are dissolved in 60.00g dichloromethane, obtain homogeneous molten
Liquid A；4.00g Rasagilines are dissolved in 20.00g ethanol, uniform solution B is obtained；Under ultrasound condition, power 300w, by solution A plus
Enter solution B and obtain homogeneous emulsion C.In the 0.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, 1000rpm is used
Mechanical agitation prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use water for injection
Clean microballoon 7 times, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 6..
600g PLGA (85/15,0.45dl/g, 51kDa, carboxyl end groups) are dissolved in 60.00g dichloromethane, obtain homogeneous molten
Liquid A；4.00g Rasagilines are dissolved in 20.00g ethanol, uniform solution B is obtained；Under 4000rpm vortex conditions, by solution A plus
Enter solution B and obtain homogeneous emulsion C.In the 1.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, 1000bar's
It is high-pressure homogeneous under pressure to prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use injection
Microballoon is cleaned with water 7 times, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 7..
5.00g PLGA (100/0,0.65dl/g, 73kDa, ester group end group) are dissolved in 50.00g tetrahydrofurans, obtain homogeneous
Solution A；5.00g Rasagilines are dissolved in 25.00g dimethyl sulfoxide (DMSO)s, uniform solution B is obtained；Under ultrasound condition, power 400w,
Solution A addition solution B is obtained into homogeneous emulsion C.In the 0.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C, make
Microballoon is prepared with 1000rpm mechanical agitation.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and make
Microballoon is cleaned with water for injection 7 times, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 8..
5.00g PLGA (100/0,0.45dl/g, 53kDa, carboxyl end groups) are dissolved in 50.00g tetrahydrofurans, obtain homogeneous
Solution A；5.00g Rasagilines are dissolved in 25.00g dimethyl sulfoxide (DMSO)s, uniform solution B is obtained；Under 4000rpm vortex conditions,
Solution A addition solution B is obtained into homogeneous emulsion C.In the 1.5% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 4 DEG C,
It is high-pressure homogeneous under 1000bar pressure to prepare microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and
And clean microballoon 7 times using water for injection, then it is freeze-dried, obtains sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 9..
6.00g PLGA (75/25,0.6dl/g, 69kDa, ester group end group) are dissolved in 100.00g dimethyl sulfoxide (DMSO)s, obtained
One solution A；4.00g Rasagilines are dissolved in 10.00g dimethylformamides, uniform solution B is obtained；In 2000rpm mechanical agitation
Under the conditions of, solution A addition solution B is obtained into homogeneous emulsion C.By 10 DEG C of the continuous water of 3.0% polyvinyl alcohol of uniform solution C additions
Xiang Zhong, microballoon is prepared using 1500rpm mechanical agitation.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards,
And clean microballoon 7 times using water for injection, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 10..
6.00g PLGA (65/35,0.5dl/g, 58kDa, carboxyl end groups) are dissolved in 150.00g dimethylformamides, obtained
Uniform solution A；4.00g Rasagilines are dissolved in 8.00g acetic acid, uniform solution B is obtained；, will be molten under 4000rpm processing condition
Liquid A adds solution B and obtains homogeneous emulsion C.In the 3.0% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 10 DEG C,
Microballoon is prepared under the conditions of 10000rpm high speed homogenization.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and
And clean microballoon 7 times using water for injection, then it is freeze-dried, obtains sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 11..
6.50gPLGA (85/15,0.75dl/g, 81kDa, carboxyl end groups) is dissolved in 150.00g dichloromethane, obtains homogeneous
Solution A；3.50g Rasagilines are dissolved in 10.00g acetic acid, uniform solution B is obtained；Under 2000rpm vortex conditions, by solution A
Add solution B and obtain homogeneous emulsion C.In the 4.0% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 15 DEG C, use
The high-pressure homogeneous of 600bar prepares microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use note
Penetrate and microballoon is cleaned with water 7 times, be then freeze-dried, obtain sustained-release micro-spheres.
The preparation of the sustained-release micro-spheres of embodiment 12..
6.50gPLGA (100/0,0.3dl/g, 27kDa, ester group end group) is dissolved in 50.00g dichloromethane, obtains homogeneous molten
Liquid A；3.50g Rasagilines are dissolved in 10.00g acetic acid, uniform solution B is obtained；, will be molten under 2000rpm mechanical agitation
Liquid A adds solution B and obtains homogeneous emulsion C.In the 4.0% polyvinyl alcohol continuous aqueous phase that uniform solution C is added to 15 DEG C, use
The high-pressure homogeneous of 1500bar prepares microballoon.Then heating to 40 DEG C makes organic solvent volatilize, and microballoon is filtered afterwards, and use
Water for injection cleaning microballoon 7 times, is then freeze-dried, obtains sustained-release micro-spheres.
The measure of the microballoon technique rate of recovery of embodiment 13..
The sustained-release micro-spheres obtained after being freezed respectively in Example 1-12, weigh, and then calculate the technique rate of recovery, as a result such as
Shown in table 1.Wherein, the technique rate of recovery=lyophilized rear microspheres weight/inventory * 100%
Table 1
| Project | The technique rate of recovery/% |
| Embodiment 1 | 87.5 |
| Embodiment 2 | 86.7 |
| Embodiment 3 | 89.3 |
| Embodiment 4 | 83.2 |
| Embodiment 5 | 90.5 |
| Embodiment 6 | 84.2 |
| Embodiment 7 | 89.5 |
| Embodiment 8 | 83.9 |
| Embodiment 9 | 90.3 |
| Embodiment 10 | 87.6 |
| Embodiment 11 | 91.5 |
| Embodiment 12 | 87.7 |
The sustained-release micro-spheres particle size distribution measuring of embodiment 14..
Determined using laser particle analyzer and release microspherulite diameter distribution.Pump speed 40%, minute 90s, stand-by period
30s, PIDS are set to "ON", and it is 1 to determine number of times.During measure, take sustained-release micro-spheres appropriate, add the surface-active of 5-10 drops 1%
Agent solution, then adds 1ml water, mixes.Instrument is opened, is loaded into sample cell, until obscurity is 8-12%, record is surveyed
Determine result, parallel determination 3 times is averaged, as a result as shown in table 2.The microballoon quantity that wherein D10 represents less than the particle diameter is accounted for always
10%, D50 of amount represents that median diameter, the i.e. microballoon less than the particle diameter account for 50%, D90 of total amount and represent less than the micro- of the particle diameter
Ball quantity accounts for the 90% of total amount.
Table 2
| Project | D10/μm | D50/μm | D90/μm |
| Embodiment 1 | 38.64 | 70.21 | 113.88 |
| Embodiment 2 | 0.51 | 0.90 | 2.17 |
| Embodiment 3 | 29.53 | 74.07 | 118.68 |
| Embodiment 4 | 0.58 | 1.10 | 1.96 |
| Embodiment 5 | 35.34 | 81.05 | 138.05 |
| Embodiment 6 | 0.61 | 2.75 | 4.36 |
| Embodiment 7 | 27.46 | 60.57 | 112.89 |
| Embodiment 8 | 0.67 | 2.53 | 3.84 |
| Embodiment 9 | 23.17 | 40.31 | 60.08 |
| Embodiment 10 | 0.49 | 0.62 | 1.08 |
| Embodiment 11 | 65.89 | 108.4 | 145.79 |
| Embodiment 12 | 3.58 | 4.15 | 4.87 |
The Rasagiline assay of embodiment 15..
Take sustained-release micro-spheres accurately weighed, add acetonitrile dispersion microsphere, then add triithylamine-glacial acetic acid that pH value is 6.5
Cushioning liquid-acetonitrile (52: 48) flows phased soln and the quantitative test sample to about 100 μ g/ml.With method operation, reference substance is prepared.
Determined using HPLC, as a result as shown in table 3.Content is the percentage composition that medication amount accounts for microballoon weight.Content=medication amount/microballoon
Amount * 100
Table 3
The sustained-release micro-spheres release characteristics of embodiment 16..
The screening of sustained-release micro-spheres：Part sustained-release micro-spheres after Example 1 is lyophilized, respectively with 100,115,150,175,230,
325th, 500 eye mesh screens are sieved, and obtain different meshes microballoon, labeled as embodiment 1-1 to embodiment 1-6, as shown in table 4.For
Investigate in common particle size range, i.e., in 20-150 μ ms, the release behavior difference of different-grain diameter microballoon.Following table implication：Example
Such as embodiment 1-1 represents the microballoon of the 100-115 mesh obtained after section Example 1 is sieved.
Table 4
| Project | Mesh number |
| Embodiment 1-1 | 100-115 |
| Embodiment 1-2 | 115-150 |
| Embodiment 1-3 | 150-175 |
| Embodiment 1-4 | 175-230 |
| Embodiment 1-5 | 230-325 |
| Embodiment 1-6 | 325-500 |
Example 1 is prepared to embodiment 12 respectively sustained-release micro-spheres and the micro- of different-grain diameter is sieved into by embodiment 1
Ball is embodiment 1-2, embodiment 1-4, embodiment 1-6 progress release in vitro.
Method of testing：Accurately weighed microballoon (30mg), it is 7.4 PBS as dissolution medium to add 100ml pH value, in
Release experiment is carried out in 37 DEG C of shaking baths.Shaking speed 100rpm, at a fixed time, takes out sample and stands, then take
Clear liquid simultaneously crosses 0.45 μm of miillpore filter, while the fresh dissolution medium of supplement, content is determined using HPLC.It is parallel per batch microballoon
Three parts of progress.Data are discharged as shown in table 5 below, table 6 and Fig. 1 to Fig. 7.
Pass through embodiment 1-1, embodiment 1-4, embodiment 1-6 releasing results, in common particle size range, i.e. 20-
In 150 μm of particle size ranges, although different-grain diameter scope microballoon release behavior is variant, but unobvious.
By embodiment 1, embodiment 3, embodiment 5, embodiment 7, embodiment 9, the release behavior of embodiment 11, general
In logical particle size range, i.e., between 20-150 μm, microballoon acquisition time is longer, but occurs in that the sustained release phase；By embodiment 2, in fact
Example 4, embodiment 6, embodiment 8, embodiment 10, the release data of embodiment 12 are applied to understand, in the range of nanometer to sub-micron particle diameter,
That is between 0.5-5 microns, microballoon acquisition time is shorter, but is released without the sustained release phase and without prominent.
And by the way that nanometer to sub-micron particle diameter microballoon and common particle diameter microballoon are mixed according to certain ratio, such as embodiment
1 deenergized period was 30 days, and the sustained release phase is 10 days, and the deenergized period of embodiment 2 is 10 days, no sustained release phase.So may be used
So that embodiment 1 to be applied in combination with embodiment 2.Just the microballoon of embodiment 2 is responsible for the early stage release of composition of medicine, and embodiment 1 is micro-
Ball is responsible for later stage release.If the drug dose that whole deenergized period needs is 3 parts, embodiment 1 provides two parts, and embodiment 2 is carried
For portion.If the drug dose that specific whole deenergized period needs is 30mg, embodiment 1 needs to provide 20mg medicines, i.e.,
72.73mg microballoons (microspheres weight=required medication amount/content)；Embodiment 2 needs to provide 10mg medicines, i.e. 37.17mg microballoons；
Three parts of embodiments 3 are mixed with a embodiment 4 by that analogy implements (5.7 weeks or so deenergized period), three parts of embodiments 5 with a
Example 6 is mixed (8.6 weeks or so deenergized period), two parts of embodiments 7 mixes (12 weeks or so deenergized period), five with a embodiment 8
Part embodiment 9 mixes with a embodiment 8 and (6 weeks or so deenergized period), three parts of embodiments 11 mixes and (release with two parts of embodiments 12
Put the cycle 7 weeks or so), then carry out extracorporeal releasing experiment, you can be released the cycle 4-12 weeks, and release and delay is released without prominent
Put the pharmaceutical composition of phase.The premise of mixing is that nanometer can be released to the acquisition time of submicron microsphere with the delay of common particle diameter microballoon
Put the phase just overlapping.Embodiment 2/4/6/8/10/12 respectively the corresponding nanometer for being embodiment 1/3/5/7/9/11 to sub-micron
Particle diameter microballoon, both can reach that longer acquisition time has no the purpose of sustained release phase at mixing.
Table 5
Table 6
In summary, the study find that in the range of microballoon conventional particle size, with the reduction of microspherulite diameter, microballoon release is all
Phase and sustained release phase can shorten really, but change unobvious.Creative discovery, sub-micro is prepared into by microballoon in addition
Not, microballoon release behavior but there occurs obvious change to meter level, and first is no sustained release phase and is released without prominent, and second is release week
Phase substantially shortens.The acquisition time and the delay of common particle diameter microballoon for being surprised to find that the sub-micron rank microballoon of the present invention simultaneously are released
Put the phase identical.By the way that the microballoon of two kinds of different-grain diameters is used in mixed way, cycle longer product is not only released, and without delay
Acquisition time.And high drug load and the microballoon of high encapsulation rate can be obtained using the technical program, pass through the medicine group in the present invention
Using the proper combination of 2 kinds of different-grain diameter microballoons in compound, the fluctuation of Rasagiline concentration in blood plasma, and nothing can be substantially reduced
Obvious delay acquisition time.Meanwhile, the present invention is in the case where drugloading rate is high, and medicine is released without prominent.
Claims (11)
1. a kind of long-acting slow-release preparation for treating anti-parkinson drug, it is characterised in that the long-acting slow-release preparation is microballoon, institute
State microballoon and include Rasagiline or its pharmaceutically acceptable salt and biodegradable biocompatibility macromolecule polymer, it is described
Microballoon includes the microballoon that average grain diameter is 0.5-5 μm of microballoon and average grain diameter is 20-150 μm.
2. long-acting slow-release preparation according to claim 1, it is characterised in that the average grain diameter is 0.5-5 μm of microballoon
The 10-50wt% of long-acting slow-release preparation is accounted for, average grain diameter accounts for 50-90wt% for 20-150 μm of microballoon.
3. long-acting slow-release preparation according to claim 1, it is characterised in that Rasagiline or its pharmaceutically acceptable salt
Account for the 10-50wt% of long-acting slow-release preparation.
4. long-acting slow-release preparation according to claim 1, it is characterised in that the biodegradable biocompatibility high score
Sub- polymer is poly- (lactide coglycolide).
5. long-acting slow-release preparation according to claim 4, it is characterised in that in poly- (lactide coglycolide), third hands over
The mol ratio of ester and glycolide is 65: 35~100: 0.
6. long-acting slow-release preparation according to claim 4, it is characterised in that the viscosity of poly- (lactide coglycolide)
Scope is 0.2-0.8dl/g.
7. long-acting slow-release preparation according to claim 4, it is characterised in that the molecule of poly- (lactide coglycolide)
Measure scope 21kDa-89kDa.
8. long-acting slow-release preparation according to claim 1, it is characterised in that the deenergized period of the long-acting slow-release preparation exists
4~12 weeks.
9. a kind of preparation method for the long-acting slow-release preparation for treating anti-parkinson drug, it is characterised in that comprise the following steps：
A) biodegradable biocompatibility macromolecule is dissolved in first kind organic solvent, obtains uniform solution A；
B) Rasagiline or its pharmaceutically acceptable salt are dissolved in the Equations of The Second Kind that can be dissolved each other with first kind organic solvent organic molten
Agent, obtains uniform solution B；
C) the uniform solution B for obtaining step b) is added in the uniform solution A that step a) is obtained and is obtained homogeneous emulsion C；
D) the homogeneous emulsion C for obtaining step c) adds in the continuous aqueous phase solution prepared with medicinal water soluble polymer to be formed
Microballoon；
E) organic solvent in removal step d) microballoons, is filtered, washing；
F) step e) thus obtained microspheres are freeze-dried, obtain sustained-release micro-spheres.
10. preparation method according to claim 8, it is characterised in that first kind organic solvent is selected from dichloromethane, acetic acid
Any one in ethyl ester, tetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide；Equations of The Second Kind is organic molten
Any one of agent in ethanol, acetic acid, hydrochloric acid, dimethyl sulfoxide (DMSO), dimethylformamide or dimethyl acetamide.
11. the preparation method according to claim any one of 9-10, it is characterised in that first kind organic solvent and Equations of The Second Kind
The ratio of organic solvent is 2: 1-20: 1..
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018223895A1 (en) * | 2017-06-07 | 2018-12-13 | 广州帝奇医药技术有限公司 | Long-acting sustained-release preparation of drug against parkinson's disease and preparation method thereof |
| CN111389317A (en) * | 2020-04-28 | 2020-07-10 | 西北工业大学 | Preparation method of imidazole microcapsule based on mercapto-isocyanate click reaction and oil-in-oil interfacial polymerization |
| CN112190553A (en) * | 2020-11-05 | 2021-01-08 | 中国药科大学 | Rasagiline mesylate microsphere preparation and preparation method thereof |
| KR20210014289A (en) | 2019-07-30 | 2021-02-09 | (주)비씨월드제약 | Manufacturing method of sustained release rasagiline microsphere |
| CN112933051A (en) * | 2021-03-18 | 2021-06-11 | 青岛农业大学 | Preparation method of lung-targeted cefquinome sulfate PLGA microspheres |
| CN113242747A (en) * | 2018-10-12 | 2021-08-10 | 好利安科技有限公司 | Macrolide formulations, method for preparing them and use of said formulations in the treatment of diseases secondary to ocular parasites |
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| CN107049985B (en) * | 2017-06-07 | 2020-06-19 | 广州帝奇医药技术有限公司 | Long-acting sustained-release preparation of anti-Parkinson disease drug and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018223895A1 (en) * | 2017-06-07 | 2018-12-13 | 广州帝奇医药技术有限公司 | Long-acting sustained-release preparation of drug against parkinson's disease and preparation method thereof |
| CN113242747A (en) * | 2018-10-12 | 2021-08-10 | 好利安科技有限公司 | Macrolide formulations, method for preparing them and use of said formulations in the treatment of diseases secondary to ocular parasites |
| CN113242747B (en) * | 2018-10-12 | 2023-09-08 | 好利安科技有限公司 | Macrolide formulations, methods of preparation and use of said formulations in the treatment of diseases secondary to ocular parasites |
| KR20210014289A (en) | 2019-07-30 | 2021-02-09 | (주)비씨월드제약 | Manufacturing method of sustained release rasagiline microsphere |
| CN111389317A (en) * | 2020-04-28 | 2020-07-10 | 西北工业大学 | Preparation method of imidazole microcapsule based on mercapto-isocyanate click reaction and oil-in-oil interfacial polymerization |
| CN112190553A (en) * | 2020-11-05 | 2021-01-08 | 中国药科大学 | Rasagiline mesylate microsphere preparation and preparation method thereof |
| CN112933051A (en) * | 2021-03-18 | 2021-06-11 | 青岛农业大学 | Preparation method of lung-targeted cefquinome sulfate PLGA microspheres |
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