CN101606923A - Rasagiline transdermal patch that a kind of stable controlled release discharges and preparation method thereof - Google Patents
Rasagiline transdermal patch that a kind of stable controlled release discharges and preparation method thereof Download PDFInfo
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- CN101606923A CN101606923A CNA2008100698501A CN200810069850A CN101606923A CN 101606923 A CN101606923 A CN 101606923A CN A2008100698501 A CNA2008100698501 A CN A2008100698501A CN 200810069850 A CN200810069850 A CN 200810069850A CN 101606923 A CN101606923 A CN 101606923A
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
The present invention relates to the transdermal drug paster of a kind of rasagiline that is used for the treatment of or prevents nervous system disease (rasagiline) and pharmaceutically acceptable salt thereof, comprise rasagiline or pharmaceutically acceptable salt, at least a hydrophilic polymers substrate, the pH value of this paster is being not less than 3.5 to being not more than between 6.5.The stability that this paster tool is superior and control the characteristic of the transdermal release of rasagiline well.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to be used for the treatment of or prevent the rasagiline (rasagiline) of nervous system disease and the transdermal drug paster of pharmaceutically acceptable salt thereof, contain at least a hydrophilic polymers substrate, the pH value of this paster is not more than 7.0, especially is being not less than 3.0 to being not more than between 6.5.
Technical background
Rasagiline (rasagiline) is a kind of selectivity monoamine oxidase B inhibitors, is used for the treatment of central nervous system disease, as parkinson (PD), depression etc., goes on the market in Europe.The chemical structural formula of rasagiline is as follows.
Parkinson is that the dopaminergic nerve in the nerve centre is degenerated the result that the neurotransmitter dopamine burst size reduces.Because the deficiency of dopamine mediator burst size, cause patient's muscle control imbalance, initiation is trembled, muscular rigidity, feel nervous from head to foot, joint motion is dumb, even stand up all difficulty, be slow in action slow in one's movements, clumsy, activity is inharmonious, symptoms such as that severe patient is stood, walked is all very difficult, abnormal posture.
The main purpose of Drug therapy parkinson disease (PD) all is to improve directly or indirectly IC DOPAMINE CONTENT IN RABBIT.The main medicine of treatment Parkinson's disease has levodopa, dopamine-receptor stimulant, amantadine, anticholinergic agents, anticholinergic agents etc.In the later stage sixties, levodopa (L-dopa) begins to be applied in the parkinsonian treatment as the alternative medicine of neurotransmitter dopamine, remains main medicine so far.Owing to levodopa rapid decarboxylation outside brain is transformed into dopamine, cause a large amount of wastes of levodopa and the frequent generation of untoward reaction.Therefore, levodopa usually uses jointly with decarboxylase inhibitor, and the raising levodopa is by the ability of brain blood barrier.Treating parkinsonian another medicine classification is dopamine-receptor stimulant (dopamine agonist), comprises bromocriptine parlodel and pergolide mesylate.Promote the content of dopamine in brain by the enzyme that suppresses the decomposition dopamine.Dopamine agonist has the long half-life, can directly act on receptor, can reduce the administration number of times and the dosage of levodopa.
Rasagiline is irreversible selectivity monoamine oxidase-B (MAOB) inhibitor, and effectiveness (Arch Neurol, 2004 that rasagiline is treated early stage PD have been investigated in a double blind random clinical research; 61:561～566).The early stage PD patient of 404 examples is included in research in, and the patient accepts rasagiline (1mg/d or 2mg/d) treatment 1 year, or accepts 6 months rasagilines earlier and take 6 months placebo again.Main evaluation index changes for the score value of unified parkinson disease comprehensive grading scales (UPDRS).The result shows, 371 routine patients have finished clinical research, annual patient with the treatment of 2mg/d rasagiline hangs down 2.29 units than the back average UPDRS score value of accepting the patient of placebo treatment in 6 months, accepts low 1.82 units of average UPDRS score value of the patient of rasagiline treatment than annual 1mg/d.Researcher is summed up, and patient's the deterioration degree of accepting rasagiline (1mg/d or 2mg/d) treatment the whole year is low than placebo group.Although rasagiline is similar to other Antiparkinsonian medicine, the incidence rate of this product toxic and side effects (mainly comprise insomnia, feel sick and hallucination) is lower.
Because the rasagiline drug effect is very strong, and during oral administration, feed but can make the blood peak concentration of drug descend 60%, and it is handicapped to add the Parkinsonian, the oral administration difficulty is so make at least two days to rasagiline once or what be administered once is necessary via the skin dispenser longer time.Though rasagiline is selectivity monoamine oxidase-B (MAOB) inhibitor in addition, but when blood drug level is big, can suppress MAO-A, MAO-B simultaneously, produce so-called " cheese reaction ": when both having taken irreversible nonselective medicine, if the patient takes medicine or the food that contains tyramine or dopamine simultaneously, can cause hypertensive crisis.Because contain a large amount of tyramine compositions in the ripe cheese, so this reaction is called " cheese reaction ".Have report to show: when the oral rasagiline 10mg/ of patient days and and during the levodopa coupling, can be because of cardiovascular adverse effects such as hypertension and position hypertension therapy discontinued.These untoward reaction may be relevant with the non-selective inhibition of MAO-A, MAO-B.Rasagiline transdermal patch absorbs gentle, can avoid or reduce " cheese reaction ".In case and the patient also can tear paster off immediately because of " cheese reaction " do not feel well, and avoids producing more serious consequence.
Described a kind of system via skin treating in US2004013620, active component has wherein comprised rasagiline, it is characterized in that using the transdermal penetration promoter that has with the following formula structure:
It is desirable especially that this transdermal penetration promoter sees through effect to the percutaneous that promotes rasagiline, and what adopt is the spraying Transdermal absorption, administration inconvenience.It is convenient to seek a kind of medication, and the better patch of transdermal effect, for the patient provides more selection necessary.
A kind of rasagiline transdermal patche that is used for the treatment of or prevents nervous system disease has been described in CN101032474, the pH value of paster remains on alkaline range (greater than 7.0) among the embodiment, though can obtain the good transdermal osmotic effect, but discover under the thimble test condition, medicine stability is bad, may be unfavorable for long term storage, and adopt some that zest solvent such as chloroform are arranged.Therefore, seek a kind of both stablely, can keep good osmotic effect and better control drug release time again, and safety, the paster of cleaning is very necessary.
Summary of the invention
But the rasagiline transdermal patch that one of purpose of the present invention provides a kind of stable controlled release to discharge, comprise: the rasagiline of a effective dose and pharmaceutically acceptable salt thereof, at least a hydrophilic polymers substrate of b, the pH value of this paster of c be not more than 7.0.Preferred pH value is being not less than 3.0 to being not more than between 6.5.This paster can keep the stability and the good transdermal effect of active substance rasagiline, is fit to long-term storage, and less to the zest of skin.Be used for the treatment of or prevent nervous system disease, as parkinson medicine, senile dementia, depression etc.
Rasagiline transdermal patch of the present invention, rasagiline wherein comprises hydrochlorate, mesylate, esilate or sulfate at pharmaceutically acceptable salt, preferred salt hydrochlorate and mesylate, more preferably mesylate.
Rasagiline transdermal patch of the present invention, described hydrophilic polymer substrate, be selected from least a in the following material: polyvinylpyrrolidone and derivant thereof, Polyethylene Glycol and derivant thereof, ethylene-vinyl acetate copolymer and derivant thereof, cellulose and derivant thereof and carbopol and derivant thereof, preferred two kinds of materials wherein, more preferably polyvinylpyrrolidone and derivant thereof and Polyethylene Glycol and derivant thereof, cellulose and derivant thereof and carbopol and derivant thereof.
Above-mentioned rasagiline transdermal patch also further comprises at least a hydrophobic polymeric matrix, and said hydrophobic polymer substrate comprises polyacrylic resin and derivant or silicone and derivant thereof.
Rasagiline transdermal patch of the present invention, as required, can also further add one deck release-controlled film, its membrane material is selected from least a in the following material: polyethylene and derivant thereof, ethylene-vinyl acetate copolymer and derivant thereof, polyurethane and derivant thereof, polrvinyl chloride and derivant thereof, its moist steam permeability are 100 grams/square metre/day to 3000 grams/square metre/day.
Rasagiline transdermal patch of the present invention, as required, as when needs come the control drug release rate by the release area, adopt to add a skim, this film has a hole less than the paster area at least, the rate of control drug release recently of the size by control paster area and fenestra.
Rasagiline transdermal patch of the present invention also can comprise a kind of PH regulator or buffer in case of necessity, makes the pH value of paster remain on 3.0-6.5.The PH regulator is selected from least a material in the following acidic materials: adipic acid, caproic acid, propanoic acid, benzoic acid, phenylacetic acid, phthalic acid, formic acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulphuric acid, nitric acid, sulfonic acid, methanesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid and silicic acid, preferred hydrochloric acid and methanesulfonic acid, more preferably methanesulfonic acid; Described buffer is selected from least a in the following solution: formates buffer, acetate buffer, phosphate buffer, citrate buffer and phthalate buffer.
Rasagiline transdermal patch of the present invention, in order to improve transdermal effect, also comprise at least a transdermal enhancer, said transdermal enhancer is selected from least a in the following material: ethanol, propylene glycol, oleic acid, oleyl alcohol, linoleic acid, lauryl alcohol, lauric acid, isopropyl myristate and laurocapram.
Another purpose of the present invention also provides a kind of usefulness purposes that parkinson, Alzheimer, depression, hyperkinetic syndrome, restless legs syndrome, multiple sclerosis and withdrawal syndrome were treated or prevented to rasagiline transdermal patche of the present invention.
The percutaneous plaster that contains rasagiline and pharmaceutically acceptable salt thereof of the present invention, wherein rasagiline and the effective dose of pharmaceutically acceptable salt in hypothallus thereof are 0.01mg/cm
2～50mg/cm
2, effective dose is the free alkali in rasagiline.
Sha Jilan transdermal drug paster of the present invention is 1cm via the area of using of skin treating
2～50cm
2
Specifically describe
But the invention provides a kind of rasagiline transdermal patch of stable controlled release release, the rasagiline and the pharmaceutically acceptable salt thereof that comprise effective dose, at least a hydrophilic polymer substrate that contains rasagiline and pharmaceutically acceptable salt thereof, the pH value of this paster is not more than 7.0, preferably is being not less than 3.0 to being not more than between 6.5.The backing layer and the conventional back lining materials that also comprise this area routine simultaneously, and the protective layer that tears off before one deck use.Described inertia supporting layer (backing layer) can be selected diaphragm that film material, ethylene-vinyl acetate copolymer, Merlon such as paillon foil or polyethylene, polypropylene are composited or non-woven fabrics etc. for use.The diaphragm that protective layer (adherent layer) also can select for use film materials such as paillon foil or polyethylene, polypropylene, ethylene-vinyl acetate copolymer or Merlon to be composited also can be selected the smooth ground paper of handling through paraffin or methyl-silicone oil for use.The solvent that also comprises this area routine in this paster, the preferred water soluble solvent as methanol, ethanol, propanol, isopropyl alcohol, butanols, amylalcohol, propylene glycol, glycerol, can be selected wherein one or more, or select as required.Also can add transdermal enhancer in order to improve transdermal effect, as ethanol, propylene glycol, oleic acid, oleyl alcohol, linoleic acid, lauryl alcohol, lauric acid, isopropyl myristate and laurocapram etc., preferred laurocapram.
Rasagiline transdermal patch of the present invention, wherein, rasagiline or its pharmaceutically acceptable salt exist with at least a form in the following form in hypothallus: salt, ionic species, crystallite, amorphous dispersion, microemulsion parcel, submicron emulsion parcel, lipid parcel or micelle parcel.
The pharmaceutically acceptable salt of above-mentioned said rasagiline is hydrochlorate, mesylate, benzene sulfonate, tosilate or sulfate, preferred mesylate.
The inventor finds, under alkali condition, though rasagiline has release rate and transdermal effect preferably, but its stability is not ideal under the thimble test condition, be unfavorable for long-term storage, and under acid condition, be not more than at 7.0 o'clock as PH, especially but keep stable being not more than 6.5 o'clock rasagilines, therefore, the PH scope of control paster is just particularly important, can add PH regulator or buffer in case of necessity, as when active substance is the rasagiline free alkali, pH value just need add the PH regulator of acidic materials greater than 6.5, and perhaps active substance is a rasagiline mesilate, but also can be when the substrate that adopts is alkaline matter by adding PH regulator or buffer, perhaps other reason cause paster pH value greater than 6.5 o'clock, also should add the PH regulator, the pH value of paster is remained on is less than or equal to 6.5 scope.Described PH regulator comprises adipic acid, caproic acid, propanoic acid, benzoic acid, phenylacetic acid, phthalic acid, formic acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulphuric acid, nitric acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid and silicic acid, or tart polymer such as carbopol and derivant (as card pool nurse) thereof, preferred hydrochloric acid, methanesulfonic acid and p-methyl benzenesulfonic acid; Described buffer is selected from least a in the following solution: formates buffer, acetate buffer, phosphate buffer, citrate buffer and phthalate buffer.Find simultaneously under acid condition, as PH less than under 6.5 the situation, the salt of rasagiline such as rasagiline mesilate dissolubility in hydrophobic substrate is less, causes the drug loading of substrate low, influences release rate and transdermal effect, and the dissolubility of rasagiline mesilate in hydrophilic substrate is fine, the drug loading height, drug release is fast, and transdermal effect is good, therefore, selecting hydrophilic substrate is comparatively ideal scheme.
Rasagiline and the pharmaceutically acceptable salt percutaneous plaster thereof of containing of the present invention, wherein rasagiline or its pharmaceutically acceptable salt exist with at least a form in the following form in hypothallus: salt, ionic species, crystallite, amorphous dispersion, microemulsion parcel, submicron emulsion parcel, lipid parcel or micelle parcel.
More common being easy to get of transdermal penetration promoter that rasagiline transdermal patch of the present invention is more used than US2004013620.Compare with CN101032474, more stable, hold time longlyer, prepare easier, safety and environmental protection.
In one embodiment, rasagiline transdermal patch of the present invention, the salt of its rasagiline is preferably its mesylate, at least contain 2 kinds of hydrophilic polymer substrate, these hydrophilic matrixs comprise polyvinylpyrrolidone and derivant thereof, as polyvinylpyrrolidone K15, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K60, polyvinylpyrrolidone K90, crospolyvinylpyrrolidone, vinyl pyrrolidone-Hydroxypropyl methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymer etc.; Polyethylene Glycol and derivant thereof are as Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, cetomacrogol 1000, polyethylene glycol 1500, Macrogol 2000, Macrogol 3000, Macrogol 4000, polyethylene glycol 6000, Sorbitan ethoxylate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene-polyoxypropylene copolymer etc.; Ethylene-vinyl acetate copolymer and derivant thereof are as ethylene-vinyl acetate copolymer 14/5, ethylene-vinyl acetate copolymer 28/250, polyvinyl acetate, polyvinyl acetate phthalate etc.; Cellulose and derivant thereof are as methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Cellulose ethyl hydroxypropyl ether etc.; Carbopol and derivant thereof are as carbomer 910, Acritamer 940, carbomer 934, carbomer 910, carbomer 980, carbopol ester etc.Preferred compositions is polyvinylpyrrolidone and derivant and Polyethylene Glycol and derivant thereof, cellulose and derivant thereof and carbopol and derivant thereof, wherein, the hydrophilic gel that the mixture of polyvinylpyrrolidone and Polyethylene Glycol makes is better to the rasagiline permeability, polyvinylpyrrolidone: Polyethylene Glycol (W/W) is 1: 9 to 9: 1.Wherein polyvinylpyrrolidone is preferably the K90D type, and Polyethylene Glycol is preferably the PEG400 type.Polyvinylpyrrolidone K90D: PEG400 (W/W) is preferably 3: 2.Select two kinds of hydrophilic polymers substrate, can improve the viscosity of substrate, help paster and stick on the skin better.
In another embodiment, rasagiline transdermal patch of the present invention, except that containing hydrophilic polymer substrate, for release rate or the release time of controlling rasagiline, also can add at least a hydrophobic polymer, that is to say and adopt hydrophilic polymer and hydrophobic polymer composite substrate, this combination can be that hydrophilic polymer and hydrophobic polymer mix, and also can be to add the hydrophobic polymer hypothallus that one deck contains rasagiline and pharmaceutically acceptable salt thereof on the hydrophilic polymer hypothallus basis of (containing rasagiline and pharmaceutically acceptable salt thereof).Said hydrophobic polymer is selected from least a among the following material: polyacrylic resin and derivant thereof, silicone and derivant thereof.
In another embodiment, rasagiline transdermal patch of the present invention, for release rate or the release time of controlling rasagiline, can adopt in paster, to add one deck release-controlled film, especially when selected polymeric matrix is hydrophilic polymers, active substance may occurs and discharge too fast, release time is short, for the release time of prolong drug, control release rate well, can add one deck release-controlled film.Adopt release-controlled film to decide according to the viscous characteristics and the control drug release speed characteristic of the different high molecular polymers that hypothallus adopted.Available membrane material be characterized as its moist steam permeability 100 the gram/square metre/day to 3000 the gram/square metre/day between.Moist steam permeability (moisture vapour transmission rate, MVTR) be the index of material to the penetrating ability of water vapour, can be used for weighing the penetrating ability to rasagiline, the method that MVTR measures has documents such as GB/T 16928, ASTM E96, ASTM D1653, ISO 2528 for reference.Generally MVTR is big more, good more to the penetrating effect of rasagiline, but the moist steam permeability is not to be the bigger the better, because it is big to the controlled-release effect that does not to a certain degree just have rasagiline, specifically can select for use and comprise among the following material one or more: polyurethane, polylactic acid, polyethylene, polrvinyl chloride, ethylene-vinyl acetate copolymer, the characteristics of some films see the following form 1.Preferred release-controlled film has following 3 kinds: CoTrans9702, CoTrans9728, CoTrans9701 (being Minnesota Mining and Manufacturing Company produces), and preceding 2 kinds is polyethylene-polyvinyl acetate release-controlled film, CoTrans9701 is the polyurethane release-controlled film.
The characteristics of the used release-controlled film of table 1
| Model | Vinyl acetate content | Thickness | The moist steam permeability |
| ????CoTrans9702 | ????9％ | ????50.8μm | ????52.8g/m 2/24h |
| ????CoTrans9707 | ????4.5％ | ????50.8μm | ????15.7g/m 2/24h |
| ????CoTrans9720 | ????0％ | ????76.2μm | ????6.0g/m 2/24h |
| ????CoTrans9726 | ????2％ | ????50.8μm | ????10.2g/m 2/24h |
| ????CoTrans9728 | ????19％ | ????50.8μm | ????97.2g/m 2/24h |
| ????CoTrans9701 | Be polyurethane film | ????51.8μm | ????709g/m 2/24h |
In yet another embodiment, rasagiline transdermal patch of the present invention, for release rate or the release time of controlling rasagiline, also can adopt control release area to come controlled release to discharge, its embodiment is by add a skim on paster substrate, has a hole on this film at least less than the paster area, the active substance rasagiline discharges by this hole, the size in hole can decide according to the different drug release features of different polymeric matrixs, and preferred hole area and paster area ratio are 1: 3～8.Its membrane material of selecting for use is the polymer relatively low to the permeability of rasagiline, as polyethylene film CoTrans9720, polyethylene-polyvinyl acetate film CoTrans9726 etc.
In one embodiment, adopted release-controlled film and backing layer involution to contain the paster of semi-solid bank, the factor that influences drug release is the affinity of medicine and substrate and the release-controlled film permeability to medicine.
Rasagiline of the present invention and pharmaceutically acceptable salt percutaneous plaster thereof, the pH value of paster is measured with following method: the rasagiline mesilate cubage of pressing paster, get a certain amount of paster is configured to contain rasagiline mesilate 1mg/ml with pure water solution, for the ease of making rasagiline mesilate stripping fully from paster, can get final product with PH instrumentation amount earlier with a small amount of absolute ethyl alcohol and stirring, supersound extraction.Do not making between the paster, it is to get a certain amount of medicine carrying substrate is configured to contain rasagiline mesilate 1mg/ml with pure water solution that the pH value of medicine carrying substrate is measured, for the ease of making rasagiline mesilate stripping fully from substrate, can be earlier with a small amount of absolute ethyl alcohol and stirring, supersound extraction, the centrifuging and taking supernatant gets final product with PH instrumentation amount.Blank substrate pH value is measured and can be measured by the amount of medicine carrying substrate with reference to various countries' pharmacopeia or other standards.This invention finds that rasagiline is stable under pH value is not more than 6.5 situation, otherwise then very fast degraded sees Table 2.Be not more than 6.5 requirement in order to reach pH value, rasagiline mesilate in substrate preferably with salt or/and ionic form exist.
In the embodiment of CN101032474, rasagiline has added alkaline conditioners such as sodium hydroxide or triethanolamine in matrix system after, can exist with the form of free alkali to a great extent, thereby promote to absorb, but rasagiline has caused adverse influence to its stability with the form of free alkali under hot conditions.Even employing double-decker: one deck contains rasagiline salt, one deck contains alkaline conditioner and also can exert an influence to stability, and therefore, the size of pH value has bigger influence to the stability of active substance rasagiline, as following table 2:
Table 2, rasagiline mesilate drug content under different PH changes
As known from Table 2, when PH greater than 6.5 the time, no matter be at 60 ℃ or 40 ℃, rasagiline all has remarkable degraded after 10 days.Equal at 6.5 o'clock at pH value, rasagiline is significantly degraded after 60 ℃, 10 days; 40 ℃, the degraded of rasagiline can be accepted after 10 days.PH value obviously influences the existence form of rasagiline: the pH value of rasagiline free alkali in pure water is about 7.5 (with rasagiline 1mg/ml time measure); The pH value of rasagiline mesilate in pure water is about 5.0 (with rasagiline mesilate 1mg/ml time measure), and PKa is calculated as 7.5, so when pH value was 6.5, the amount of rasagiline free alkali accounted for 10% of total amount, Theoretical Calculation conforms to substantially with experiment.Under the constant situation of other conditions, pH value is low more, and rasagiline is stable more.When rasagiline exists with the form of free alkali, R-NH-C ≡ CH key easy fracture between the alkynyl of its secondary amine group and connection, thereby caused degraded, so with regard to stability, rasagiline is difficult to stable for extended periods of time in alkaline matrix environment, when especially being in the state of free alkali, unstability is more obvious.
Rasagiline paster of the present invention, rasagiline wherein can exist with the various ways except that free alkali.The different forms that exist can adopt the diverse ways preparation, as when rasagiline exists with the form of salt or ionic form, such as rasagiline mesilate, can be dissolved in earlier in the organic solvents such as ethanol, propylene glycol, glycerol, be mixed and made into paster with organic polymer substrate, short skin penetrating agent etc. then.When being crystallite or amorphous dispersive form such as rasagiline and pharmaceutical salts thereof, can adopt solvent method, rasagiline or its salt is dissolved in ethanol or the water and and polyvidone, polyvinyl alcohol mixing, obtain the amorphous dispersion thing of rasagiline in polyvidone or polyvinyl alcohol after volatilizing ethanol or water, be mixed and made into paster, the also replaceable carrier that is carbamide, polyethylene glycols, fiber-like etc. as dispersion of polyvidone or polyvinyl alcohol with organic polymer substrate, short skin penetrating agent etc. then.It should be noted that and resemble polyvidone, polyvinyl alcohol, methylcellulose in the fiber-like, the carrier that fusing points such as ethyl cellulose are higher, what adopt during preparation is solvent method, and resemble the Macrogol 4000 of carbamide and Polyethylene Glycol apoplexy due to endogenous wind, polyethylene glycol 6000, then be to adopt the fusion method preparation, as with rasagiline with through the Macrogol 4000 mix homogeneously of refinement, be heated to 40～60 ℃ and make its fusing, make it be converted into solid again by violent reduction temperature again, obtain the crystallite or the amorphous dispersing morphology of rasagiline, then with organic polymer substrate, short skin penetrating agent etc. is mixed and made into paster.Rasagiline exists with microemulsion, submicron emulsion form can use oils, as liquid Paraffin, vaseline, long-chain fat alcohols such as hexadecanol, octadecanol etc. are as inner phase, form microemulsion, the submicron emulsion of oil-in-water structure, rasagiline and pharmaceutically acceptable salt thereof are dissolved in the oil phase, be the supersaturation attitude, because thermodynamic (al) labile state, be easy to separate out and see through skin, this microemulsion, submicron emulsion can make with high-speed mixing method, the even method of high speed breast, microemulsion, submicron emulsion and the organic polymer substrate that makes, short skin penetrating agent etc. can be mixed and made into paster.The percutaneous plaster of preparation rasagiline liposome form, available class Ester, as lecithin, hydrolecithin, cholesterol etc., rasagiline is wrapped up, make liposome, method has membrane process, reverse phase evaporation, freeze-drying, PH-gradient method, high-speed mixing method, breast is spared method etc. at a high speed, and the liposome of the rasagiline that makes is made paster with organic polymer substrate, short skin penetrating agent etc. then.More than the method for the rasagiline of preparation microemulsion parcel, submicron emulsion parcel, lipid parcel all is that those of ordinary skills can realize according to existing corresponding conventional formulation technology of preparing.Which kind of no matter prepare with method, all can regulate pH value by adding the PH regulator, the pH value that guarantees paster is not more than 6.5, because paster is to pass through percutaneous drug delivery, if the too low meeting of pH value causes zest to skin, so the pH value of paster also should be not less than 3.0, therefore, the preferred pH value scope of the present invention is for being not less than 3.0 greater than 6.5.
The method of regulating PH mainly is by adding acidic materials and/or adding pH value at the buffer reagent below 6.5.Acidic materials comprise: adipic acid, caproic acid, propanoic acid, benzoic acid, phenylacetic acid, phthalic acid, formic acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulphuric acid, nitric acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid, silicic acid etc., also comprise the pH value that will record in advance less than 6.5 substrate with greater than 6.5 mixing mutually, make the pH value of mixture be not more than 6.5; Buffer reagent comprises formates buffer, acetate buffer, phosphate buffer, citrate buffer, phthalate buffer etc., and acidic materials of the above and buffering reagent all are that this area is commonly used, and its using method also is a routine techniques.After it should be noted that the pharmaceutically acceptable salt of rasagiline such as rasagiline mesilate, hydrochloric acid rasagiline etc. join in the above-mentioned macromolecular material, because the complexity of macromolecular material makes the pH value of whole system might be less than 6.5, also might be greater than 6.5, adding pH value regulator purpose is exactly to guarantee that the pH value of paster is below 6.5 under preparation and condition of storage.
Keratodermatitis is the major obstacle that percutaneous absorbs, therefore, and some soften cuticles and strengthen the transdermal effect that the material of the lipid flowability in the skin histology can the enhanced activity composition.In patent CN101032474, mentioned the factor that influences the rasagiline transdermal effect: whether it becomes free alkali＞short penetrating agent kind for the short penetrating agent＞principal agent of substrate＞whether contain in proper order.In the embodiment 1 to 5 of patent CN101032474, used the NaOH aqueous solution to regulate pH value to 7.5, but the salt that makes rasagiline and hyoscine thereof exist with the form of rasagiline free alkali, thereby promote to absorb; In embodiment 6, triethanolamine is regulated pH value to 8.5 as regulator.So no doubt can strengthen the transdermal penetration of rasagiline, but its instability can not be stood its practical application.Being not more than at pH value under 6.5 the situation, is the paster of substrate with non-hydrophilic high molecular materials such as polyacrylic acid, silicone, and the rasagiline permeability is low excessively.Do the rasagiline paster of medicine carrying glue-line with hydrophilic macromolecular material such as polyvinyl alcohol, polyvinylpyrrolidone, Polyethylene Glycol, ethylene-vinyl acetate copolymer, carbopol, cellulose derivative etc., can absorb skin and extraneous moisture, make it to form the saturated solution of rasagiline, promote the release of rasagiline, greatly improved the infiltration capacity of rasagiline simultaneously.Surprisingly the transdermal effect of the composite bed of doing with hydrophilic high molecular material substrate and non-hydrophilic high molecular material substrate is also fine.The compound paster transdermal effect that has added release-controlled film is pretty good, and medicine moves in the experiment in vivo, the slow release effect optimum.With the scheme that the control drug release area comes controlled release, also reached the controlled release releasing effect of transdermal effect and medicine substantially.
The preparation method of rasagiline transdermal patch of the present invention is illustrated in an embodiment.The percutaneous plaster that makes uses Forlan diffusion cell (Franz cell now, effectively receptor area is that 2.54 square centimeters, volume are 17 milliliters), with two the monthly age rat the abdominal part skin of shedding study its penetration, rasagiline transdermal patch of the present invention as can be seen can provide abundant amount to reach the purpose of general action via skin.
The rasagiline of stable and controllable of the present invention and the percutaneous plaster of pharmaceutically acceptable salt thereof can every 1-3 day administrations 1 time or longer time as 1 all administrations 1 time.
Description of drawings
The generalized section of the paster of Fig. 1, embodiment 1,2,3.
The generalized section of the paster of Fig. 2, embodiment 4.
The generalized section of the paster of Fig. 3 embodiment 5.
The generalized section of the paster of Fig. 4 embodiment 6.
The floor map of the paster of Fig. 5 embodiment 6.
The generalized section of the paster of Fig. 6 embodiment 7.
Fig. 7 embodiment 1 paster contains the rasagiline time-accumulation infiltration capacity graph of relation of the single-layer polypropylene acid esters substrate paster of rasagiline.
Fig. 8 embodiment 2 pasters contain the rasagiline time-accumulation infiltration capacity graph of relation of the monolayer silicon ketone group matter paster of rasagiline.
Fig. 9 embodiment 3 pasters contain the rasagiline time-accumulation infiltration capacity graph of relation of the monolayer polyethylene ketopyrrolidine-polyvinyl alcohol composite interstitial substance paster of rasagiline.
Figure 10 embodiment 4 pasters contain the rasagiline time that the adds release-controlled film polyvinylpyrrolidone-polyvinyl alcohol composite interstitial substance paster-accumulation infiltration capacity graph of relation of rasagiline.
Figure 11 embodiment 5 pasters contain the rasagiline time-accumulation infiltration capacity graph of relation of the composite bed paster of rasagiline.
The paster of Figure 12 embodiment 7, the depot that contains rasagiline mesilate are the rasagiline time-accumulation infiltration capacity graph of relation of the paster of substrate with methylcellulose-Acritamer 940.
The paster of Figure 13 embodiment 2, rasagiline is blood drug level-time graph in the rabbit body.
The paster of Figure 14 embodiment 3, rasagiline is blood drug level-time graph in the rabbit body
The paster of Figure 15 embodiment 4, rasagiline is blood drug level-time graph in the rabbit body
The paster of Figure 16 embodiment 5, rasagiline is blood drug level-time graph in the rabbit body
The paster of Figure 17 embodiment 6, rasagiline is blood drug level-time graph in the rabbit body
The specific embodiment mode
Following examples are used to further specify content of the present invention, but do not limit the scope of the invention.
Embodiment 1: contain the single-layer polypropylene acid esters substrate paster of rasagiline mesilate, with the moon oleic acid be short skin penetrating agent
Get 0.25 gram rasagiline mesilate and be dissolved in the 1 gram propylene glycol, it is joined in polyacrylic acid ester gum 20 grams (national of the United States's starch company, 387-2287 type).Add oleic acid 0.3 gram, after stirring, with automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, coating thickness is 0.6 millimeter.60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable, again that paster is die-cut or cut into last thin slice.Recording rasagiline content is 220ug/cm
2, measuring PH is 4.4.The paster generalized section that makes is seen Fig. 1.
With the paster for preparing use Forlan now diffusion cell (Franz cell) and two the monthly age rat the abdominal part skin of shedding study its penetration.With the content of high effective liquid chromatography for measuring rasagiline in different time points, calculate the accumulation infiltration capacity of rasagiline more in view of the above, the result sees the following form 3 respectively; Rasagiline time-accumulation infiltration capacity graph of relation is seen Fig. 7.
Table 3 contains oleic rasagiline paster time-accumulation infiltration capacity tables of data
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????0 | ?????0.0 |
| ????1 | ?????0.0 |
| ????2 | ?????0.0 |
| ????4 | ?????0.0 |
| ????6 | ?????1.1 |
| ????8 | ?????9.9 |
| ????12 | ?????20.2 |
| ????24 | ?????41.6 |
| ????48 | ?????74.5 |
Embodiment 2: contain the monolayer silicon ketone group matter paster of rasagiline, be short skin penetrating agent with laurocapram
Get 0.25 gram rasagiline free alkali and be dissolved in the 1 gram propylene glycol, then it is joined in silicone adhesive 20 grams (Minnesota Mining and Manufacturing Company, PSA7-4302 type).Add laurocapram 0.3 gram, after stirring, it is 7.7 that the glue that takes a morsel records pH value as sample (being used for stability study).By above-mentioned prescription, prepared, and add 0.15 gram methanesulfonic acid and stir, make glue, take a morsel glue as sample survey (being used for stability study) pH value be 4.0.With automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, coating thickness is 0.6 millimeter.60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable, again that paster is die-cut or cut into last thin slice.Recording rasagiline content is 220ug/cm
2The paster generalized section that makes is seen Fig. 1.
The paster for preparing is calculated the accumulation infiltration capacity of rasagiline by the method for embodiment one, and the result sees the following form 4 respectively.Rasagiline time-accumulation infiltration capacity graph of relation is seen Fig. 8.
Table 4 contains the rasagiline paster time-accumulation infiltration capacity tables of data of laurocapram
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????0 | ????0.0 |
| ????1 | ????0.0 |
| ????2 | ????0.0 |
| ????4 | ????0.0 |
| ????6 | ????9.2 |
| ????8 | ????14.3 |
| ????12 | ????23.1 |
| ????24 | ????44.7 |
| ????48 | ????76.2 |
Adopt the prepared pasters of non-hydrophilic pressure sensitive adhesive such as polyacrylic acid, silicone at the 48th hour as can be seen from table 3 and table 4, the accumulation infiltration capacity is all below 200 μ g, compare with the embodiment one of patent CN101032474, the accumulation infiltration capacity obviously reduces, and reason is that rasagiline has added methanesulfonic acid and become mesylate, drug loading less.In order to improve the accumulation infiltration capacity, adopting the hydrophilic pressure sensitive adhesive is that substrate is necessary.
Embodiment 3: contain the monolayer polyethylene ketopyrrolidine-Polyethylene Glycol composite interstitial substance paster of rasagiline, be short skin penetrating agent with laurocapram
(ISP Technologies INC) is sprinkled in the 120 gram dehydrated alcohol, stirs to make its swelling complete, and 16 gram PEG400s (Nanjing Weir chemical industry) are joined wherein, mixes, and makes blank glue to get 24 gram polyvinylpyrrolidone PVP-K90D.Get glue 15 grams that prepare, add rasagiline free alkali 1.0 grams, stir ultrasonic its dissolving that makes.Add laurocapram 0.3 gram, after stirring, recording pH value is 7.4.By above-mentioned prescription, prepared, and add methanesulfonic acid 0.6 gram, recording pH value is 4.7.With automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, coating thickness is 0.4 millimeter.60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable, again that paster is die-cut or cut into last thin slice.The paster generalized section that makes is seen Fig. 1.
The paster for preparing is calculated the accumulation infiltration capacity of rasagiline by the method for embodiment one, the results are shown in following table 5; Rasagiline time-accumulation infiltration capacity graph of relation is seen Fig. 9.
Table 5 contains the rasagiline paster time-accumulation infiltration capacity tables of data of laurocapram
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????0 | ????0.0 |
| ????1 | ????88.9 |
| ????2 | ????152.6 |
| ????4 | ????327.8 |
| ????6 | ????520.6 |
| ????8 | ????752.7 |
| ????12 | ????925.7 |
| ????24 | ????1822.4 |
| ????48 | ????3178.4 |
Adopt polyvinylpyrrolidone, the prepared paster of Polyethylene Glycol composite interstitial substance pressure sensitive adhesive at the 48th hour as can be seen, the accumulation infiltration capacity is more than 1500 μ g, compare with the embodiment one of patent CN101032474, the accumulation infiltration capacity is higher, and since rasagiline mesilate do not add alkali and become free state, so stability is better.
Embodiment 4: what contain rasagiline mesilate adds release-controlled film polyvinylpyrrolidone-Polyethylene Glycol composite interstitial substance paster, is short skin penetrating agent with laurocapram
Release for the controlled release rasagiline, on the basis of embodiment 3 (pH value is 4.7), added one deck release-controlled film, the preparation method of paster just in the end one goes on foot the compound release-controlled film of going up with embodiment 3, adds vinylpyrrolidone-Polyethylene Glycol composite interstitial substance medicine carrying self-adhesive layer then.The generalized section that makes paster is seen Fig. 2.The release-controlled film that adopts has following six kinds: CoTrans9702, CoTrans9707, CoTrans9726, CoTrans9728, CoTrans9720, CoTrans9701 (being Minnesota Mining and Manufacturing Company produces), preceding four kinds is polyethylene-polyvinyl acetate release-controlled film, and CoTrans9720 is that polyethylene release-controlled film, CoTrans9701 are the polyurethane release-controlled film.
With the paster for preparing use Forlan now diffusion cell (Franz cell) acceptable solution volume be 17ml, receptor area is 2.54cm
2, be followed successively by sample time: 2h, 4h, 6h, 8h, 16h, 24h, 48h, 72h, 96h, 120h, result see Table 6,7,8,9,10 and table 11 respectively, and rasagiline time-accumulation infiltration capacity graph of relation is seen Figure 10.For six kinds of prescriptions that add release-controlled film, it is positively related that their rate of release and its moist steam permeability are into, but do not have strict linear relationship (particularly vinyl acetate content has surpassed after 10%).These six kinds of release-controlled films, that the cumulative release effect is best is CoTrans9701, its moist steam permeability also is maximum.For this invention, the moist steam permeability is too little, that rasagiline discharges is too slow, burst size very little, but the moist steam permeability is not to be the bigger the better, because greatly to a certain degree just not had the controlled-release effect of rasagiline.
Table 6 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9702
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????2.4 |
| ????4 | ????9.0 |
| ????6 | ????6.9 |
| ????8 | ????7.0 |
| ????16 | ????15.9 |
| ????24 | ????14.4 |
| ????48 | ????22.2 |
| ????72 | ????27.8 |
| ????96 | ????47.0 |
| ????120 | ????92.00 |
Table 7 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9707
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????1.6 |
| ????4 | ????1.5 |
| ????6 | ????1.9 |
| ????8 | ????2.5 |
| ????16 | ????5.1 |
| ????24 | ????7.4 |
| ????48 | ????13.6 |
| ????72 | ????18.0 |
| ????96 | ????23.9 |
| ????120 | ????31.8 |
Table 8 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9720
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????0.4 |
| ????4 | ????0.6 |
| ????6 | ????0.8 |
| ????8 | ????1.0 |
| ????16 | ????2.1 |
| ????24 | ????3.0 |
| ????48 | ????6.9 |
| ????72 | ????10.3 |
| ????96 | ????15.8 |
| ????120 | ????17.7 |
Table 9 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9726
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????0.6 |
| ????4 | ????1.0 |
| ????6 | ????1.4 |
| ????8 | ????1.74 |
| ????16 | ????3.7 |
| ????24 | ????5.3 |
| ????48 | ????10.0 |
| ????72 | ????13.7 |
| ????96 | ????16.4 |
| ????120 | ????18.9 |
Table 10 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9728
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????2.9 |
| ????4 | ????4.9 |
| ????6 | ????6.5 |
| ????8 | ????8.0 |
| ????16 | ????15.6 |
| ????24 | ????21.2 |
| ????48 | ????29.4 |
| ????72 | ????29.1 |
| ????96 | ????29.9 |
| ????120 | ????30.4 |
Table 11 is the rasagiline paster time-accumulation infiltration capacity tables of data of release-controlled film with CoTrans9701
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????58.5 |
| ????4 | ????162.9 |
| ????6 | ????243.4 |
| ????8 | ????287.0 |
| ????12 | ????328.3 |
| ????24 | ????396.8 |
| ????36 | ????452.0 |
| ????48 | ????483.4 |
| ????60 | ????516.2 |
As can be seen, CoTrans9701 cumulative release amount maximum in the pharmacokinetics experiment, also can be seen and use CoTrans9701 can reach comparatively ideal controlled-release effect, and keep certain blood drug level in the rabbit body of mentioning in the back.Consider the release that can influence medicine, so the moist steam permeability can be chosen between 3000 grams/square metre/day at 100 grams/square metre/day by control controlled release area and drug loading.
Embodiment 5: contain the composite bed paster of rasagiline mesilate, be short skin penetrating agent with laurocapram
Ground floor: get 24 gram polyvinylpyrrolidone PVP-K90D (ISP Technologies, INC) be sprinkled in the 120 gram dehydrated alcohol, stirring makes its swelling complete, and 16 gram PEG400s (Nanjing Weir chemical industry) are joined wherein, mix, make blank glue.Get glue 15 grams that prepare, add rasagiline mesilate 1.0 grams, stir ultrasonic its dissolving that makes.Add laurocapram 0.3 gram, after stirring, surveying pH value is 6.6.By above-mentioned prescription, prepared, and add methanesulfonic acid 0.05 gram, recording pH value is 4.8, with automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, and coating thickness is 0.6 millimeter.60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable.
The second layer: get 0.25 gram rasagiline mesilate and be dissolved in the 1.0 gram propylene glycol, then it is joined in silicone adhesive 20 grams (Minnesota Mining and Manufacturing Company, PSA7-4302 type).Add a large amount laurocapram 0.4 gram, after stirring, with automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, coating thickness is 0.6 millimeter.60 ℃ of oven dry were transferred on the ground floor after 5 minutes, and are again that paster is die-cut or cut into last thin slice.
The paster generalized section that makes is seen Fig. 3.
The paster for preparing is calculated the accumulation infiltration capacity of rasagiline by the method for embodiment one, the results are shown in Table 12.Rasagiline time-accumulation infiltration capacity graph of relation is seen Figure 11.
Table 12 contains the composite bed paster time-accumulation infiltration capacity tables of data of rasagiline
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????0.0 |
| ????4 | ????9.4 |
| ????6 | ????57.3 |
| ????8 | ????103.2 |
| ????11 | ????155.8 |
| ????22 | ????243.9 |
| ????34 | ????293.2 |
| ????48 | ????308.9 |
| ????72 | ????495.8 |
Embodiment 6: contain the control release area paster of rasagiline mesilate, with the short skin penetrating agent of laurocapram
(ISP Techno logies INC) is sprinkled in the 120 gram dehydrated alcohol, stirs to make its swelling complete, and 16 gram PEG400s (Nanjing Weir chemical industry) are joined wherein, mixes, and makes blank glue to get 24 gram polyvinylpyrrolidone PVP-K90D.Get glue 15 grams that prepare, add rasagiline mesilate 1.0 grams, stir ultrasonic its dissolving that makes.Add laurocapram 0.3 gram, after stirring, recording pH value is 5.9.This embodiment compares with the pH value that embodiment 5 records before adding methanesulfonic acid, reduces to some extent, meets PH and is not more than 6.5 requirement, and this difference mainly is because the difference of polyvinylpyrrolidone, PEG400 macromolecular material is caused.With automatic coating machine (the triumphant company of the Shanghai iron of fine quality, TB-04 type) glue that mixes is coated on the siliconised paper, coating thickness is 0.6 millimeter.60 ℃ of oven dry were covered with supporting layer after 5 minutes, and are promptly transferable, pertusate CoTrans9720 thin film in the middle of again paster being covered with, and hole area and paster area ratio are 1: 5.The paster generalized section that makes sees that Fig. 4, plane graph see Fig. 5.Because used prescription, technology are consistent with embodiment 3, verify so directly do pharmacokinetics.
Embodiment 7: the depot that contains rasagiline mesilate is the paster of substrate with methylcellulose-Acritamer 940, is short skin penetrating agent with laurocapram
The first step: get 2 gram methylcellulose and be sprinkled in the 100 gram cold water that contain ethanol 30% (W/V), stirring makes its swelling complete, and recording pH value is 8.0,1 gram Acritamer 940 is joined wherein, mix, leave standstill then and make its swelling complete, recording pH value is 5.5, makes blank glue.Get glue 15 grams that prepare, add rasagiline mesilate 1.0 grams, stir ultrasonic its dissolving that makes.Add laurocapram 0.3 gram, after stirring, make pastille glue.Surveying pH value is 5.0.
Second one: get CoTrans9720 film and CoTrans97201 film, the pouch of the 2cm*2cm of the synthetic openings at one side of heat-sealing adds as 0.25 gram pastille glue in bag, with the opening edge heat sealing, makes paster.
The paster generalized section that makes is seen Fig. 6.
The paster for preparing is calculated the accumulation infiltration capacity of rasagiline by the method for embodiment one, the results are shown in Table 13.Rasagiline time-accumulation infiltration capacity graph of relation is seen Figure 12.
Table 13 contain rasagiline mesilate the depot paster time-accumulation infiltration capacity tables of data
| Time (h) | Accumulation infiltration capacity (μ g) |
| ????2 | ????0 |
| ????4 | ????9.1 |
| ????6 | ????51.3 |
| ????8 | ????92 |
| ????11 | ????136.4 |
| ????22 | ????219.7 |
| ????34 | ????275.5 |
| ????48 | ????314.4 |
| ????72 | ????383.2 |
Therefore, according to paster of the present invention, use the paster of different substrate and about 4～10 square centimeters of sizes of technology to reach 1～3 day required therapeutic dose through the skin absorption, and can control the infiltration rate of rasagiline by the mode of preparation multiple-layered patches, because this dosing paster material source is extensive, be easy to get, and be easy to make, and can transmit rasagiline to skin absorbs via whole stromal surface, with respect to US2004013620 and described in system have preparation method simple, raw material sources extensively are easy to get, release is milder, drug release time is longer, wait advantage more fully via the skin absorbs amount.Compare with CN101032474, drug release time is longer, more stable, more environmental protection of preparation process, safety.
More than among seven embodiment, embodiment 1,2,3,5,6,7 has all related to the influence (embodiment 4 on the basis of embodiment 3 added release-controlled film) of pH value to rasagiline stability, the inventor has investigated under the different PH condition, rasagiline is in 40 ℃ of placement variations after 10 days, result such as following table 14.Data show, when pH value less than 6.5 the time, it is stable that the rasagiline in the paster keeps, and helps long-term all depositing, and PH is greater than 6.5 o'clock, the rasagiline instability in the paster is unfavorable for long-term storage.
More than seven embodiment, choose wherein 5 and carry out the body giving drugs into nose for dynamics research:
Reference examples: rasagiline mesilate sheet, dosage are 1.0mg/.
Embodiment 2: contain the monolayer silicon ketone group matter paster of rasagiline, be short skin penetrating agent with laurocapram, dosage is 0.503mg/.
Embodiment 3: contain the monolayer polyethylene ketopyrrolidine-polyvinyl alcohol composite interstitial substance paster of rasagiline, be short skin penetrating agent with laurocapram, dosage 3.3mg/ only.
Embodiment 4: contain the polyvinylpyrrolidone that the adds the Cotrans9701 release-controlled film-polyvinyl alcohol composite interstitial substance paster of rasagiline, be short skin penetrating agent with laurocapram, dosage is 13.2mg/.
Embodiment 5: contain the composite bed paster of rasagiline mesilate, be short skin penetrating agent with laurocapram, dosage is 8mg/.
Embodiment 6: contain the control release area paster of rasagiline mesilate, with the short skin penetrating agent of laurocapram, dosage is 8.4mg/.
Experimental subject is New Zealand's large ear rabbit, and body weight 1.5kg～2kg adopts high performance liquid chromatogram-GC-MS (U.S. Agilent company, Agilent1200,6410 Triple Quad LC/MS) to monitor the blood drug level of different time.
That measures the results are shown in following table 15, and blood drug level-time plot is seen Figure 13 in the body.
According to table 5, table 12-13, the data of table 14 and table 15, transdermal of the present invention pastes and has not only kept the good transdermal effect, has overcome unsettled shortcoming, and blood drug level is also very desirable, and controlled-release effect is obvious, is better than oral formulations.
Among table 14 embodiment, pH value is to the influence of rasagiline stability
Table 15 drug disposition dynamic metabolism is measured
Claims (13)
1. but the rasagiline transdermal patch of a stable controlled release release comprises: the rasagiline of a effective dose and pharmaceutically acceptable salt thereof, and at least a hydrophilic polymer substrate of b, the pH value of this paster of c is not more than 7.0.
2. rasagiline transdermal patch according to claim 1, said pH value are not more than between 6.5 being not less than 3.0.
3. rasagiline transdermal patch according to claim 1, rasagiline wherein comprises hydrochlorate, mesylate, tosilate, benzene sulfonate or sulfate at pharmaceutically acceptable salt.
4. rasagiline transdermal patch according to claim 1, described hydrophilic polymer substrate is selected from a kind of in the following material or two or more: polyvinylpyrrolidone and derivant thereof, Polyethylene Glycol and derivant thereof, ethylene-vinyl acetate copolymer and derivant thereof, cellulose and derivant thereof and carbopol and derivant thereof.
5. according to the arbitrary described rasagiline transdermal patch of claim 1 to 4, also can further comprise at least a hydrophobic polymeric matrix, said hydrophobic polymer substrate comprises polyacrylic resin and derivant or silicone and derivant thereof.
6. according to the arbitrary described rasagiline transdermal patch of claim 1 to 4, further comprise one deck release-controlled film, the moist steam permeability that it is characterized in that membrane material be 100 the gram/square metre/day to 3000 the gram/square metre/day.
7. rasagiline transdermal patch according to claim 5, said membrane material are selected from least a in the following material: polyethylene and derivant thereof, ethylene-vinyl acetate copolymer and derivant thereof, polyurethane and derivant thereof, polrvinyl chloride and derivant thereof.
8. according to the arbitrary described rasagiline transdermal patch of claim 1 to 4, also can further comprise a skim, this film has a hole less than the paster area at least.
9. rasagiline transdermal patch according to claim 1 also can comprise a kind of PH regulator or buffer in case of necessity.
10. rasagiline transdermal patch according to claim 7, said PH regulator is selected from least a material in the following acidic materials: adipic acid, caproic acid, propanoic acid, benzoic acid, phenylacetic acid, phthalic acid, formic acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulphuric acid, nitric acid, sulfonic acid, methanesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid, silicic acid, p-methyl benzenesulfonic acid and benzenesulfonic acid, preferred hydrochloric acid, methanesulfonic acid and p-methyl benzenesulfonic acid.
11. rasagiline transdermal patch according to claim 7, wherein, described buffer is selected from least a in the following solution: formates buffer, acetate buffer, phosphate buffer, citrate buffer and phthalate buffer.
12. rasagiline transdermal patch according to claim 1 also comprises at least a transdermal enhancer.
13. rasagiline transdermal patch according to claim 1, said transdermal enhancer are selected from least a in the following material: ethanol, propylene glycol, oleic acid, oleyl alcohol, linoleic acid, lauryl alcohol, lauric acid, isopropyl myristate and laurocapram.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN2008100698501A CN101606923B (en) | 2008-06-20 | 2008-06-20 | Stable controlled-release rasagiline transdermal patch and preparation method thereof |
| PCT/CN2009/072352 WO2009152777A1 (en) | 2008-06-20 | 2009-06-19 | A stable and release-controlled rasagiline transdermal patch and method of preparation thereof |
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| CN2008100698501A CN101606923B (en) | 2008-06-20 | 2008-06-20 | Stable controlled-release rasagiline transdermal patch and preparation method thereof |
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| CN101606923B CN101606923B (en) | 2013-01-09 |
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| CN2008100698501A Active CN101606923B (en) | 2008-06-20 | 2008-06-20 | Stable controlled-release rasagiline transdermal patch and preparation method thereof |
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| WO (1) | WO2009152777A1 (en) |
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| WO2011050728A1 (en) | 2009-10-29 | 2011-05-05 | 重庆医药工业研究院有限责任公司 | Stable composition of rasagiline |
| CN102475692A (en) * | 2010-11-29 | 2012-05-30 | 重庆医药工业研究院有限责任公司 | Transdermal patch preventing rasagiline from volatilizing |
| CN103315983A (en) * | 2012-12-20 | 2013-09-25 | 上海中西制药有限公司 | Rasagiline preparation and preparation method thereof |
| CN104510628A (en) * | 2013-09-27 | 2015-04-15 | 金红叶纸业集团有限公司 | Household paper |
| CN116077419A (en) * | 2023-02-24 | 2023-05-09 | 丽珠集团新北江制药股份有限公司 | Selaginella hydrochloride Ji Lantou skin absorbent for dogs and preparation method thereof |
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| US7150881B2 (en) * | 1997-06-26 | 2006-12-19 | Mylan Technologies, Inc. | Adhesive mixture for transdermal delivery of highly plasticizing drugs |
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| AU2007334428B2 (en) * | 2006-12-14 | 2014-05-29 | Teva Pharmaceutical Industries, Ltd. | Crystalline solid rasagiline base |
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2008
- 2008-06-20 CN CN2008100698501A patent/CN101606923B/en active Active
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- 2009-06-19 WO PCT/CN2009/072352 patent/WO2009152777A1/en active Application Filing
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| WO2011050728A1 (en) | 2009-10-29 | 2011-05-05 | 重庆医药工业研究院有限责任公司 | Stable composition of rasagiline |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2009152777A1 (en) | 2009-12-23 |
| CN101606923B (en) | 2013-01-09 |
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