CN101708164A - Rivastigmine slow-release microspheres and preparation method thereof - Google Patents
Rivastigmine slow-release microspheres and preparation method thereof Download PDFInfo
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Abstract
The invention discloses slow-release microspheres coated with rivastigmine tartrate/rivastigmine for PLGA/PLA injection and a preparation method thereof. The slow-release microspheres mainly comprise rivastigmine tartrate/rivastigmine and PLGA and PLA serving as biodegradable polymer medicinal materials, and can be prepared by adopting a W1/O/W2 composite emulsified solvent volatilization method, an O/W emulsified solvent volatilization method, an O1/O2 emulsion drying method and a spray drying method. The grain diameter of the microspheres is less than 100 microns. The slow-release microspheres have high medicament loading amount, have no obvious burst release effect, can be continuously released for one week, one mouth or three mouths, are used for treating senile diseases such as Alzheimer's disease, Parkinson disease and the like, and can prolong the acting time of the medicament, reduce the application times and greatly improve the administration compliance of patients.
Description
Technical field
The invention belongs to the pharmaceutical technology field, be specifically related to a kind of tartaric acid/rivastigmine-hydrogentartrate PLGA/PLA slow release microphere for injection and preparation method thereof.
Background technology
Alzheimer (Alzheimer ' s disease, AD) be senile dementia, be the senile central nervous system degenerative disease of a class, its definite cause of disease still imperfectly understands.Cholinergic nerve damage hypothesis is widely accepted at present, cognitive defect that it is generally acknowledged patients with Alzheimer disease is caused by the cholinergic nerve conduction function obstacle of cerebral cortex and forebrain substrate, and primary purpose of medication is to connect the cholinergic nerve conduction to improve symptom.Acetylcholinesteraseinhibitors inhibitors is by the activity of acetylcholine esterase inhibition, recovers the normal level of acetylcholine, improves the irritability of cholinergic neuron, from theoretical and clinically all proved effective.
Tartaric acid/rivastigmine-hydrogentartrate (trade name Exelon, Chinese Exelon is by Novartis Co.,Ltd's exploitation), its chemistry (S)-N by name, N-ethyl-methyl-carbamic acid-3-[1-(dimethylamino) ethyl] phenyl ester.Tartaric acid/rivastigmine-hydrogentartrate is the long-acting reversibility noncompetitive carbamate acetylcholinesteraseinhibitors inhibitors of a kind of selectively acting in brain, also is a kind of butyrylcholinesterase inhibitor, belongs to the third generation and improves the cholinergic nerve system function medicament.It is much better than than the effect of peripheral nervous system to central nervous system's effect, and clinical practice can not produce hepatotoxicity.In 2000 are used for the treatment of by drugs approved by FDA, severe Alzheimer's disease, be approved for again in 2006 treatment relevant with parkinson disease gently, moderate dementia.The clinical administration dosage form has capsule (every pastille 1.5,3,4.5 and 6mg), oral liquid and transdermal patch.Capsule and oral liquid took medicine twice on 1st, and transdermal patch once a day.These conventional formulations, except the frequent inconvenience treatment of administration, the drug level peak valley phenomenon also is a problem.Comparatively speaking, slow releasing preparation, but slow release one month even three months are particularly used from actual therapeutic, have more realistic meaning.
PLGA/PLA is a kind of good biocompatibility, biodegradable, safety good, physicochemical property is excellent pharmaceutical macromolecular material, and this material has been used for the device that slow releasing pharmaceutical carrier and other human bodies are implanted by drugs approved by FDA.PLGA/PLA is degraded to lactic acid and the hydroxyacetic acid that has in the human body earlier after entering human body, further is degraded to carbon dioxide again and water excretes, and is harmless.PLGA degradation rate in vivo can be regulated by the content and the ordering of hydroxyacetic acid in its molecule.
At present, do not find the research of relevant tartaric acid/rivastigmine-hydrogentartrate preparation as yet, so a kind of long-acting slow-release preparation that is used for the treatment of Senile disease such as Alzheimer and parkinson disease of exploitation has great clinical meaning and applied value.The technical problem to be solved in the present invention provides easy tartaric acid/rivastigmine-hydrogentartrate being wrapped in biodegradable poly lactic coglycolic acid (PLGA) or the polylactic acid (PLA) of a kind of preparation technology, be prepared into injection and can slowly continue to discharge 1 week, the method of one month even trimestral sustained-release micro-spheres, adopt the tartaric acid/rivastigmine-hydrogentartrate sustained release microsphere agents of this method preparation to have the drug loading height, the envelop rate height, there be not obviously prominent releasing, discharge characteristics such as lasting slow, in can being used for the treatment of, severe Alzheimer's disease and relevant with parkinson disease light, moderate dementia.
Summary of the invention
The invention discloses a kind of tartaric acid/rivastigmine-hydrogentartrate PLGA/PLA slow release microphere for injection, it is characterized in that by tartaric acid/rivastigmine-hydrogentartrate and molecular weight ranges 5,000～50, the biodegradable medicinal high polymer adjuvant between 000 is formed, and its parts by weight are:
Tartaric acid/rivastigmine-hydrogentartrate 0.28%～9.11%
High polymer adjuvant 90.89%～99.72%
Its preparation method can adopt W
1/ O/W
2Emulsion solvent evaporation method, O/W emulsion-solvent evaporation method, O
1/ O
2Emulsifying intra-liquid desiccation method and spray drying method for preparation, preferred O
1/ O
2The emulsifying intra-liquid desiccation method.
Tartaric acid of the present invention/rivastigmine-hydrogentartrate sustained-release micro-spheres, wherein active component is a Rivastigmine, and general English is called Rivastigmine, and the chinesization formal name used at school is (S)-N, N-ethyl-methyl-carbamic acid-3-[1-(dimethylamino) ethyl] phenyl ester, its structural formula is as shown below:
Can tartaric acid and liquor epinephrinae bitartratis ophthalmicus be arranged acid salifiable with it, form tartaric acid Rivastigmine and rivastigmine-hydrogentartrate biology respectively, degradable macromolecule pharmaceutic adjuvant PLGA/PLA, the molecular weight of PLGA is 5,000～50,000 dalton, wherein the ratio of lactic acid and hydroxyacetic acid is 90: 10 to 50: 50, the molecular weight of PLA is 6,000～100,000 dalton both can be a carboxyl terminal, also can be the alkyl end, the high polymer adjuvant of forming sustained-release micro-spheres be one or both and the two or more mixture in above-mentioned.
Tartaric acid of the present invention/rivastigmine-hydrogentartrate PLGA/PLA slow release microphere for injection comprises the following steps:
(1) PLGA/PLA has been dissolved in certain polar single or polynary organic solvent, has added tartaric acid/rivastigmine-hydrogentartrate, stirred and make it the clarifying decentralized photo of dissolving formation;
(2) continuous phase that decentralized photo and the oiliness inert media that contains certain density emulsifying agent are formed is mixed, and wherein the organic solvent in the decentralized photo does not dissolve each other mutually with the oiliness inert media of continuous phase, emulsifying a period of time under stirring fast;
(3) emulsifying is volatilized organic solvent after finishing gradually, separates out medicine carrying microballoons;
(4) filter the microsphere that collection obtains, use the oiliness inert media of non-polar solven flush away microsphere surface absorption successively, free drug with the absorption of intensive polar solvent flush away microsphere surface, normal freeze-drying promptly, wherein the organic solvent of decentralized photo is the single solvent of chloroform, dichloromethane, ethyl acetate, methyl acetate, dioxane, ether, acetone, oxolane, acetonitrile or blended by a certain percentage multicomponent solvent; The oiliness inert media of continuous phase is the mineral oil that liquid paraffin or simethicone etc. are formed, the polyhydric alcohol that vegetable oil that Oleum Camelliae, Oleum Arachidis hypogaeae semen or soybean oil are formed and glycerol are formed, and wherein the volume ratio of decentralized photo and continuous phase is 1: 40～1: 10.
Wherein the used emulsifying agent of step (2) is the nonionic surfactant of HLB value scope between 1.8～12.4, preferred sorbester p17 (Span80), and its concentration in continuous phase is 0.05%～2%.
The solvent that wherein is used for the oiliness inert media of flush away microsphere surface absorption in the step (4) is one or both of normal hexane, hexane, petroleum ether, and intensive polar solvent is one or both in water, methanol, the ethanol.
Four kinds of concrete preparation methoies of sustained release microsphere agents of the present invention are as follows:
1, W
1/ O/W
2Emulsionization-solvent evaporation method:
(1) an amount of tartaric acid/rivastigmine-hydrogentartrate and additives are dissolved in a certain amount of water water in forming.The concentration of its mesotartaric acid/rivastigmine-hydrogentartrate is 50-200 μ g/mL, and the kind of additives is gelatin, poloxamer 188, poloxamer 407, cetomacrogol 1000, polyethylene glycol 6000, cetomacrogol 1000 0, Macrogol 2000 0;
(2) get a certain amount of PLGA or PLA and be dissolved in organic solvent dichloromethane or the ethyl acetate, concentration is 10mg/mL-100mg/mL, forms oil phase;
(3) interior water is added to oil phase, ultrasonic emulsification forms colostrum;
(4) colostrum is dropped to rapidly in 0.1%～2% polyvinyl alcohol (PVA) aqueous solution, this solution also can also have 0～5% sodium chloride or 0～5% sucrose, and the abundant homogenize of magnetic agitation, mixing speed are 3,500～10,000 rev/min, continue stirring at low speed volatilization in 6 hours organic solvent under the room temperature, mixing speed is 300～600 rev/mins, promptly get sustained-release micro-spheres, washing is collected, and lyophilization promptly.
2, O/W emulsifying-solvent evaporation method
(1) an amount of tartaric acid/rivastigmine-hydrogentartrate and PLGA or PLA are dissolved in the mixed solvent of being made up of weakly polar organic solvent and strong polar organic solvent, wherein weakly polar organic solvent comprises dichloromethane, ethyl acetate, methyl acetate, and strong polar organic solvent comprises methanol, acetonitrile, propylene glycol, dimethyl sulfoxine.The concentration of organic facies mesotartaric acid/rivastigmine-hydrogentartrate is 50-200 μ g/mL, and the concentration of PLGA or PLA is 10mg/mL-100mg/mL;
(2) organic facies is added to contain in 0.1%～2% polyvinyl alcohol (PVA) aqueous solution, this solution also can also have 0～5% sodium chloride or 0～5% sucrose, and the abundant homogenize of magnetic agitation, mixing speed are 3,500～10,000 rev/min, continue stirring at low speed volatilization in 6 hours organic solvent under the room temperature, mixing speed is 300～600 rev/mins, promptly get sustained-release micro-spheres, washing is collected, and lyophilization promptly.
3, O
1/ O
2The emulsifying intra-liquid desiccation method
(1) PLGA or PLA are dissolved with in certain polar single or polynary organic solvent, add tartaric acid/rivastigmine-hydrogentartrate, stir and make it the clarifying decentralized photo of dissolving formation; Wherein the organic solvent of decentralized photo is the single solvent of chloroform, dichloromethane, ethyl acetate, methyl acetate, dioxane, ether, acetone, oxolane, acetonitrile or blended by a certain percentage multicomponent solvent; The concentration of PLGA or PLA is 10mg/mL～100mg/mL, and the concentration of tartaric acid/rivastigmine-hydrogentartrate is 1mg/mL～10mg/mL.
(2) continuous phase that decentralized photo and the oiliness inert media that contains certain density emulsifying agent are formed is mixed, and wherein the organic solvent in the decentralized photo does not dissolve each other mutually with the oiliness inert media of continuous phase, emulsifying a period of time under stirring fast.Wherein, the oiliness inert media of continuous phase is the mineral oil that liquid paraffin or simethicone etc. are formed; The polyhydric alcohol that vegetable oil that Oleum Camelliae, Oleum Arachidis hypogaeae semen or Semen sojae atricolor wet goods are formed and glycerol etc. are formed; Emulsifying agent is nonionic surfactant sorbester p17 (Span80), and its concentration in continuous phase is 0.05%-2%; The volume ratio of decentralized photo and continuous phase is 1: 40-1: 10; Mixing speed during emulsifying is 500-2,000 rev/min;
(3) emulsifying is volatilized the organic solvent stirring at low speed after finishing gradually, separates out medicine carrying microballoons.Wherein mixing speed is 300～600 rev/mins;
(4) filter the microsphere that collection obtains, use the oiliness inert media of non-polar solven normal hexane flush away microsphere surface absorption successively, the free drug of water flush away microsphere surface absorption, normal freeze-drying is promptly.
4, spray drying method
Tartaric acid/rivastigmine-hydrogentartrate and PLGA/PLA be dissolved in have certain polar organic solvent, stir, spray drying, promptly.Used organic solvent comprises one or both and the two or more mixed solvents in dichloromethane, ethyl acetate, glacial acetic acid, the methyl acetate.Wherein, the concentration of tartaric acid/rivastigmine-hydrogentartrate is 1-10mg/mL, and the concentration of PLGA or PLA is 10-100mg/mL.Inlet temperature is 50 ℃ during spray drying, 35 ℃ of outlet temperatures, flow velocity 30%, atomisation pressure 50%.
The Biodegradable high-molecular pharmaceutic adjuvant PLGA/PLA that the present invention is used, the molecular weight of PLGA is 5,000-50,000 dalton, wherein the ratio of lactic acid and hydroxyacetic acid is 90: 10 to 50: 50, the molecular weight of PLA is 6,000-100,000 dalton both can be a carboxyl terminal, also can be the alkyl end.The high polymer adjuvant of forming sustained-release micro-spheres is one or both and the two or more mixture in above-mentioned.
The sustained-release micro-spheres that the present invention is prepared, particle diameter are the 1-100 micron.
The sustained-release micro-spheres that the present invention is prepared, smooth surface rounding, no adhesion.
The sustained-release micro-spheres that the present invention is prepared, tartaric acid/rivastigmine-hydrogentartrate is distributed in the microsphere with molecule or amorphous state.
The sustained-release micro-spheres of the present invention's preparation, extracorporeal releasing experiment show can slowly continue to discharge a week or one month, and does not have and do not observe tangible burst effect.
The present invention has successfully prepared and has the drug loading height, the envelop rate height, do not have the obviously prominent slow release microphere for injection of releasing, discharge the parcel tartaric acid/rivastigmine-hydrogentartrate that continues characteristics such as slow, in can being used for the treatment of, severe Alzheimer's disease and light, the moderate dementia relevant with parkinson disease.
The specific embodiment
Embodiment 1:W
1/ O/W
2Emulsionization-solvent evaporation method prepares the tartaric acid rivastigmine slow-release microspheres
25mg tartaric acid Rivastigmine and 50mg poloxamer 188 are dissolved in the 0.2mL water, as interior water; With 100mg PLGA (RG502H, PLA: PGA=50: 50, Mw=20000) be dissolved in the 2.0mL ethyl acetate, form oil phase.Interior water is added to oil phase, the probe ultrasonic emulsification, 200 watts of operating frequencies were worked 1 second, intermittently 1 second, obtained W
1/ O colostrum.Colostrum is poured into rapidly in the 40mL 0.1%PVA aqueous solution of quick stirring and (regulated pH9.0 with glycine-sodium hydroxide, wherein contain 1% sodium chloride), mixing speed is 7,000 rev/min, emulsifying 2 minutes, the speed that continues under the room temperature with 500 rev/mins stirs 6 hours volatilization organic solvents, centrifugal collection solidified microsphere, it is inferior to give a baby a bath on the third day after its birth with distilled water, and lyophilization promptly gets microsphere.
Embodiment 2:O/W emulsifying-solvent evaporation method prepares the tartaric acid rivastigmine slow-release microspheres
With 25mg tartaric acid Rivastigmine and 100mg PLGA (RG502H, PLA: PGA=50: 50, Mw=20000) be dissolved in the mixed solvent of forming by 2mL ethyl acetate and 0.2mL propylene glycol, form oil phase.Oil phase is poured into rapidly in the 40mL 0.1%PVA aqueous solution of quick stirring and (regulated pH9.0 with glycine-sodium hydroxide, wherein contain 1% sodium chloride), mixing speed is 7,000 rev/min, emulsifying 2 minutes, the speed that continues under the room temperature with 500 rev/mins stirs 6 hours volatilization organic solvents, centrifugal collection solidified microsphere, it is inferior to give a baby a bath on the third day after its birth with distilled water, and lyophilization promptly gets microsphere.
Embodiment 3:O
1/ O
2Emulsifying-intra-liquid desiccation method prepares the tartaric acid rivastigmine slow-release microspheres
With 20mg tartaric acid Rivastigmine and 200mg PLGA (RG502H, PLA: PGA=50: 50, Mw=20000) be dissolved in the mixed solvent that 2mL is made up of dichloromethane and acetonitrile (volume ratio 3: 2), sonic oscillation makes its dissolving, oil phase in forming; Interior oil phase is injected the liquid paraffin that 40mL contains 0.2% sorbester p17, and 800 rev/mins of stirrings made its emulsifying in 15 minutes, continued 500 rev/mins under the room temperature and stirred 6 hours volatilization organic solvents, filter, use normal hexane and water washing microsphere successively, low amounts of water is redissolved, lyophilization promptly gets microsphere.
Embodiment 4:O
1/ O
2Emulsifying-intra-liquid desiccation method prepares the tartaric acid rivastigmine slow-release microspheres
With 20mg tartaric acid Rivastigmine, 50mg PLGA (RG752H PLA: PGA=75: 25, Mw=20000) and 150mgPLA (R202S, Mw=20000) be dissolved in the mixed solvent that 2mL is made up of dichloromethane and acetonitrile (volume ratio 3: 2), sonic oscillation makes its dissolving, oil phase in forming; Interior oil phase is injected the liquid paraffin that 40mL contains 0.2% sorbester p17, and 800 rev/mins of stirrings made its emulsifying in 15 minutes, continued 500 rev/mins under the room temperature and stirred 6 hours volatilization organic solvents, filter, use normal hexane and water washing microsphere successively, low amounts of water is redissolved, lyophilization promptly gets microsphere.
Embodiment 5: spray drying method for preparation tartaric acid rivastigmine slow-release microspheres
With 30mg tartaric acid Rivastigmine and 300mg PLGA (RG752H PLA: PGA=75: 25, Mw=20000) in dissolving and the 15mL glacial acetic acid, sonic oscillation makes its thorough dissolving, spray drying under the following conditions: 50 ℃ of inlet temperatures, 35 ℃ of outlet temperatures, flow velocity 30%, atomisation pressure 50% promptly gets microsphere.
Embodiment 6: the mensuration of tartaric acid rivastigmine slow-release microspheres drug loading
Precision takes by weighing a certain amount of microsphere (being less than 10mg), add the 0.5mL dichloromethane, sonic oscillation makes its thorough dissolving, then add 5mL 0.1M hydrochloric acid, vortex mixed is even, 4000 rev/mins centrifugal 10 minutes, go the supernatant to measure its mesotartaric acid Rivastigmine concentration with HPLC after filtering, calculate the drug loading of microsphere.
Embodiment 7: the external release experiment of tartaric acid rivastigmine slow-release microspheres
Precision takes by weighing a certain amount of microsphere (being less than 50mg), and adding 8mLpH7.4 phosphate buffer (containing 0.02% Tween 80 and 0.02% Hydrazoic acid,sodium salt) is release medium, in 37 ℃, and 50 rev/mins of joltings in constant temperature oscillator.Get supernatant 6mL respectively at 0.5,1,3,5,7,14,21,28 day, measure its mesotartaric acid Rivastigmine concentration with HPLC after filtering; Replenish with the fresh release medium of volume simultaneously.
Description of drawings
The scanning electron microscope picture of the tartaric acid rivastigmine slow-release microspheres of accompanying drawing 1 embodiment 3 preparations
The X ray diffracting spectrum of the tartaric acid rivastigmine slow-release microspheres of accompanying drawing 2 embodiment 3 preparations
Annotate: (1) is PLGA; (2) be tartaric acid Rivastigmine crude drug; (3) be the physical mixture of PLGA and tartaric acid Rivastigmine crude drug; (4) tartaric acid rivastigmine slow-release microspheres
The release in vitro curve of the tartaric acid rivastigmine slow-release microspheres of accompanying drawing 3 embodiment 3 preparations
The release in vitro curve of the tartaric acid rivastigmine slow-release microspheres of accompanying drawing 4 embodiment 4 preparations
Claims (10)
1. tartaric acid/rivastigmine-hydrogentartrate PLGA/PLA slow release microphere for injection, it is characterized in that by tartaric acid/rivastigmine-hydrogentartrate and molecular weight ranges 5,000～50, the biodegradable medicinal high polymer adjuvant between 000 is formed, and its parts by weight are:
Tartaric acid/rivastigmine-hydrogentartrate 0.28%～9.11%
High polymer adjuvant 90.89%～99.72%
2. sustained-release micro-spheres according to claim 1 is characterized in that adopting W
1/ O/W
2Emulsion solvent evaporation method, O/W emulsion-solvent evaporation method, O
1/ O
2Emulsifying intra-liquid desiccation method and spray drying method for preparation, preferred O
1/ O
2The emulsifying intra-liquid desiccation method.
3. sustained-release micro-spheres according to claim 1, it is characterized in that active component is a Rivastigmine, general English is called Rivastigmine, the chinesization formal name used at school is (S)-N, N-ethyl-methyl-carbamic acid-3-[1-(dimethylamino) ethyl] phenyl ester, can tartaric acid and liquor epinephrinae bitartratis ophthalmicus be arranged acid salifiable, form tartaric acid Rivastigmine and rivastigmine-hydrogentartrate respectively with it.
4. rivastigmine slow-release microspheres according to claim 1, it is characterized in that Biodegradable high-molecular pharmaceutic adjuvant PLGA/PLA, the molecular weight of PLGA is 5,000～50,000 dalton, wherein the ratio of lactic acid and hydroxyacetic acid is 90: 10 to 50: 50, and the molecular weight of PLA is 6,000～100,000 dalton, both can be carboxyl terminal, also can be the alkyl end, and the high polymer adjuvant of forming sustained-release micro-spheres is one or both and the two or more mixture in above-mentioned.
5. O according to claim 4
1/ O
2Emulsifying-intra-liquid desiccation method, this method comprises the following steps:
(1) PLGA/PLA has been dissolved in certain polar single or polynary organic solvent, has added tartaric acid/rivastigmine-hydrogentartrate, stirred and make it the clarifying decentralized photo of dissolving formation;
(2) continuous phase that decentralized photo and the oiliness inert media that contains certain density emulsifying agent are formed is mixed, and wherein the organic solvent in the decentralized photo does not dissolve each other mutually with the oiliness inert media of continuous phase, emulsifying a period of time under stirring fast;
(3) emulsifying is volatilized organic solvent after finishing gradually, separates out medicine carrying microballoons;
(4) filter the microsphere that collection obtains, with the oiliness inert media of non-polar solven flush away microsphere surface absorption, with the free drug of intensive polar solvent flush away microsphere surface absorption, normal freeze-drying promptly successively.
6. method according to claim 5, the organic solvent that it is characterized in that decentralized photo are the single solvent of chloroform, dichloromethane, ethyl acetate, methyl acetate, dioxane, ether, acetone, oxolane, acetonitrile or blended by a certain percentage multicomponent solvent; The oiliness inert media of continuous phase is the mineral oil that liquid paraffin or simethicone etc. are formed, the polyhydric alcohol that vegetable oil that Oleum Camelliae, Oleum Arachidis hypogaeae semen or soybean oil are formed and glycerol are formed, and wherein the volume ratio of decentralized photo and continuous phase is 1: 40～1: 10.
7. method according to claim 5, wherein the used emulsifying agent of step (2) is the nonionic surfactant of HLB value scope between 1.8～12.4, preferred sorbester p17 (Span80), its concentration in continuous phase is 0.05%～2%.
8. method according to claim 5, the solvent that it is characterized in that being used in the step (4) the oiliness inert media of flush away microsphere surface absorption is one or both of normal hexane, hexane, petroleum ether, and intensive polar solvent is one or both in water, methanol, the ethanol.
9. sustained-release micro-spheres according to claim 1 is characterized in that microspherulite diameter is 1～100 micron.
10. the slow release microphere for injection of the described tartaric acid/rivastigmine-hydrogentartrate of claim 1 is characterized in that being used for the treatment of Senile disease as Alzheimer and parkinson disease etc. as durative action preparation.
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