WO2009152777A1

WO2009152777A1 - A stable and release-controlled rasagiline transdermal patch and method of preparation thereof

Info

Publication number: WO2009152777A1
Application number: PCT/CN2009/072352
Authority: WO
Inventors: 林佳亮; 李群; 李宏忠; 张涛; 邓杰; 樊斌
Original assignee: 重庆医药工业研究院有限责任公司
Priority date: 2008-06-20
Filing date: 2009-06-19
Publication date: 2009-12-23
Also published as: CN101606923B; CN101606923A

Abstract

A transdermal patch of rasagiline or pharmaceutically acceptable salts thereof for treating or preventing nervous system diseases. Particularly, a stable and release-controlled transdermal patch of rasagiline is provided, wherein the patch contains rasagiline or pharmaceutically acceptable salts thereof and at least one hydrophilic polymer matrix, moreover, the pH value of the patch is less than 7.0. The patch has predominant stability and can well control the transdermal release characteristics of rasageline.

Description

One by one

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a rasagiline transdermal patch for treating or preventing a nervous system disease. More particularly, the present invention relates to a stable drug release controlled rasagiline transdermal patch. BACKGROUND OF THE INVENTION Rasagiline is a selective monoamine oxidase B inhibitor for the treatment of central nervous system diseases such as Parkinson's disease (PD), depression, etc., which has been marketed in Europe. The chemical structure of rasagiline is as follows.

Parkinson's disease is a result of degeneration of dopaminergic nerves in the nerve center and a decrease in the release of neurotransmitter dopamine. Due to insufficient release of dopamine transmitters, the patient's muscle control is dysfunctional, causing tremors, muscle stiffness, tightness of the body, inflexible joint activities, difficulty in turning over, slow movements, slow movements, clumsiness, inconsistent activities, severe cases Symptoms such as standing, walking, and abnormal posture. The main purpose of drug treatment for Parkinson's disease (PD) is to directly or indirectly increase the dopamine content in the brain. The main drugs for treating Parkinson's disease include levodopa, dopamine receptor agonists, amantadine, anticholinergic drugs, and anticholinergic drugs. In the late 1960s, levodopa (L-dopa) was used as an alternative to the neurotransmitter dopamine. - - It has been used in the treatment of Parkinson's disease and is still the main treatment. Due to the rapid decarboxylation of levodopa outside the brain and conversion to dopamine, a large amount of waste and adverse reactions of levodopa occur frequently. Therefore, levodopa is often used in combination with decarboxylase inhibitors to increase the ability of levodopa to pass the cerebral blood barrier. Another drug class for treating Parkinson's disease is the dopamine agonist, which includes ergobromide and pergolide sulfonate. Increases the amount of dopamine in the brain by inhibiting enzymes that break down dopamine. Dopamine agonists have a longer half-life and can act directly on the receptor, reducing the number and dose of levodopa. Rasagiline is an irreversible selective monoamine oxidase B (MAOB) inhibitor, a double-blind randomized clinical study examining the effectiveness of rasagiline in the treatment of early PD (Arch Neurol, 2004; 61:561–566). The study included 404 patients with early PD who were treated with rasagiline (1 mg/d or 2 mg/d) for 1 year, or 6 months for rasagiline followed by 6 months for placebo. The primary outcome measure was the change in the score for the Unified Parkinson's Disease Comprehensive Rating Scale (UPDRS). The results showed that 371 patients completed the clinical study, and the average UPDRS score for patients treated with 2 m _g /d rasagiline throughout the year was 2.29 units lower than that of patients receiving placebo after 6 months. Patients with lmg/d receiving rasagiline treatment had an average UPDRS score of 1.82 units. The investigators concluded that patients who received rasagiline (lm _g /d or 2 m _g /d) throughout the year had a lower degree of functional decline than the placebo group. Although rasagiline is similar to other anti-shock palsy drugs, the incidence of toxic side effects (mainly including insomnia, nausea, and hallucinations) is lower. Although rasagiline is very potent, when it is administered orally, eating peaks will reduce the peak concentration of blood by 60%. In addition, patients with Parkinson's disease have inconvenient action and oral administration is difficult, so rasagiline Applying through the skin by administering it once or twice a day or longer - - A dose is necessary. In addition, rasagiline is a selective monoamine oxidase B (MAOB) inhibitor, but at the time of high plasma concentration, it will inhibit MAO-A, MAO-B, and produce a so-called "cheese reaction": taking irreversible non-selection In the case of a sexual drug, if the patient takes a drug or food containing tyramine or dopamine at the same time, it may cause a hypertensive crisis. Because cooked cheese contains a lot of tyramine, this reaction is called "cheese reaction." It has been reported that when patients take rasagiline 10 mg / day orally with levodopa, treatment will be interrupted due to cardiovascular adverse reactions such as hypertension and postural hypertension. These adverse effects may be associated with non-selective inhibition of MAO-A, MAO-B. The rasagiline transdermal patch absorbs mildness and avoids or reduces the "cheese reaction." And once the patient feels unwell due to the "cheese reaction," the patch can be removed immediately to avoid more serious consequences. A system for the treatment via the skin has been described in US2004013620, wherein the active ingredient comprises rasagiline, which is characterized by the use of a transdermal penetration enhancer having the structure:

The transdermal permeation enhancer is not particularly effective for promoting transdermal permeation of rasagiline, and spray transdermal absorption is employed, which is inconvenient to administer. A rasagiline transdermal patch for the treatment or prevention of neurological disorders has been described in CN101032474A, in which the pH of the patch remains in the alkaline range (greater than 7.0), although good results are obtained. Transdermal penetration effect, but the study found that under high temperature stability test conditions, the drug stability is not good, may be detrimental to long-term storage, and One of the irritating solvents such as chloroform was used. Therefore, it is extremely necessary to seek a transdermal patch of rasagiline that is stable, maintains good penetration and better controls drug release time, and is convenient, safe and clean. SUMMARY OF THE INVENTION The inventors of the present invention found that for rasagiline transdermal patches, rasagiline has good release rate and transdermal effect under alkaline conditions, but under high temperature stability test conditions Its stability is not ideal, which is not conducive to long-term storage. The inventors have further unexpectedly found that rasagiline in the rasagiline transdermal patch remains stable under acidic conditions such as a pH of not more than 7.0, especially at not more than 6.5, and is effective for a long period of time. The inventors of the present invention have also found that under acidic conditions, such as a pH of not more than 7.0, especially a pH of not more than 6.5, the solubility of rasagiline salts such as rasagiline bismuth sulfonate in a hydrophobic matrix is higher. Small, resulting in low drug loading of the matrix, affecting the release rate and transdermal effect, and the solubility in the hydrophilic matrix is very good, the drug loading is high, the drug is released quickly, and the transdermal effect is good. Accordingly, in one aspect, the present invention provides a stable drug release controllable rasagiline transdermal patch, wherein the patch comprises a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof And at least one hydrophilic polymer matrix, and the patch has a pH of no greater than 7.0. In one embodiment, the pH of the patch is preferably not less than 3.0 to not more than

Between 6.5. In one embodiment, the pharmaceutically acceptable salt of rasagiline comprises Rasha The hydrochloride, sulfonate, ethanesulfonate or sulfate of geland is preferably a hydrochloride salt of rasagiline and an oxime sulfonate, more preferably rasagiline sulfonate. In one embodiment, the hydrophilic polymer matrix is selected from at least one of the following: polyvinylpyrrolidone and its derivatives, polyethylene glycol and its derivatives, ethylene-vinyl acetate copolymer and derivatives thereof And cellulose and its derivatives and carboxyvinyl (also known as polyacrylic acid) and derivatives thereof, preferably a combination of any two of them, more preferably polyvinylpyrrolidone and its derivatives and polyethylene glycol and its derivatives Combination of materials and combinations of cellulose and its derivatives with carboxyvinyl and its derivatives. In one embodiment, the rasagiline transdermal patch further comprises at least one hydrophobic polymeric matrix comprising a polyacrylic resin and derivatives thereof or silicone and derivatives thereof Things. In one embodiment, the rasagiline transdermal patch may further comprise a controlled release film, the material of the controlled release film being selected from the group consisting of polyethylene and its derivatives, ethylene-vinyl acetate copolymer and At least one of a derivative, a polyurethane and a derivative thereof, polyvinyl chloride and a derivative thereof, and having a wet vapor permeability of from 100 g/m 2 /day to 3,000 g/m 2 /day. In one embodiment, the above-described rasagiline transdermal patch further comprises a membrane having at least one pore smaller than the patch area when the drug release rate is controlled by the release area, thereby controlling the patch area and the membrane The ratio of the size of the holes controls the drug release rate. For example, the area of the hole: The patch area is 1:2~10. In one embodiment, the pore area of the rasagiline transdermal patch: patch area In one embodiment, the film is selected from the group consisting of a polyethylene film, an ethylene-vinyl acetate copolymer film, characterized by a wet vapor permeability of less than 100 grams per square meter per day. In one embodiment, the above-described rasagiline transdermal patch may further comprise a pH adjusting agent or buffer, if necessary, to maintain the pH of the patch at 3.0-6.5. The pH adjusting agent is selected from at least one of the following acidic substances: adipic acid, caproic acid, propionic acid, benzoic acid, phenylacetic acid, phthalic acid, citric acid, hypophosphorous acid, phosphoric acid, dihydrogen phosphate Sodium, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, sulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid and silicic acid, preferably hydrochloric acid and An oxime sulfonic acid, more preferably oxime sulfonic acid; the buffer is selected from at least one of the following solutions: citrate buffer, acetate buffer, phosphate buffer, citrate Buffer and phthalate buffer. In one embodiment, in order to enhance the transdermal effect, the above rasagiline transdermal patch further comprises at least one transdermal enhancer, said transdermal enhancer being selected from at least one of the following: ethanol, Propylene glycol, oleic acid, oleyl alcohol, linoleic acid, lauryl alcohol, lauric acid, isopropyl myristate and lauryl ketone. In one embodiment, the therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof in the rasagiline transdermal patch in the stromal layer is from 0.01 mg/cm ² to 50 mg/cm ² , therapeutically effective The amount is based on the free base of rasagiline. In another aspect, the present invention provides a method of preparing the rasagiline transdermal patch of any of the above embodiments, comprising:

Providing the at least one hydrophilic polymer matrix;

- administering a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof to said substrate Mix

- adjusting the pH of the substrate to not more than 7.0. In one embodiment, the pH of the substrate is adjusted to no greater than 7.0 by the addition of a pH adjusting agent or buffer to the matrix. In one embodiment, the pH adjusting agent is selected from at least one of the following acidic substances: adipic acid, caproic acid, propionic acid, benzoic acid, phenylacetic acid, phthalic acid, citric acid, hypophosphorous acid , phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, sulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid and Silicic acid, preferably hydrochloric acid and hydrazine sulfonic acid, more preferably hydrazine sulfonic acid; the buffer is selected from at least one of the following solutions: citrate buffer, acetate buffer, phosphate buffer Liquid, citrate buffer and phthalate buffer. In another aspect, the present invention provides a method for treating or preventing Parkinson's disease, Alzheimer's disease, depression, pediatric hyperactivity disorder, restless legs by using the above-mentioned rasagiline transdermal patch. Use or method of sign, multiple sclerosis and withdrawal syndrome. In one embodiment, the above-described rasagiline transdermal patch has an application area of from ¹ cm ² to 50 cm ² via skin treatment. Accordingly, the present invention provides a stable, controlled release rasagiline transdermal patch comprising a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof and at least one rasagiline Or a hydrophilic polymer matrix of a pharmaceutically acceptable salt thereof, wherein the patch has a pH of not more than 7.0, preferably not less than 3.0 to not more than 6.5. The patch may also include conventional backing layers and conventional backing materials in the art, as well as a protective layer that can be peeled off prior to use. The back layer (such as the inert support layer) may be foil or poly A film made of a film of ethylene or polypropylene, a film of ethylene-vinyl acetate copolymer or polycarbonate, or a nonwoven fabric. The protective layer (for example, the release layer) may be a film formed by laminating a foil or a film of polyethylene, polypropylene, ethylene-vinyl acetate copolymer or polycarbonate, or may be selected from paraffin or silicone-based silicone oil. Treated smooth thick paper. The patch also includes a solvent conventional in the art, preferably a water-soluble solvent such as decyl alcohol, ethanol, propanol, isopropanol, butanol, pentanol, propylene glycol, glycerin, one or more of which may be selected. , or choose as needed. In order to enhance the transdermal effect, a transdermal enhancer such as ethanol, propylene glycol, oleic acid, oleyl alcohol, linoleic acid, lauryl alcohol, lauric acid, isopropyl myristate and lauryl ketone may be added, preferably laurel nitrogen. Anthrone. In one embodiment, in the above rasagiline transdermal patch, rasagiline or a pharmaceutically acceptable salt thereof is present in the matrix in at least one of the following forms: salt, ionic form, microcrystalline , amorphous dispersion, microemulsion wrap, submicron milk wrap, lipid wrap or micelle wrap. In one embodiment, the above pharmaceutically acceptable salt of rasagiline is a hydrochloride, an oxime sulfonate, a besylate, a p-toluenesulfonate or a sulfate, preferably an oxime sulfonate. In order to control the pH of the patch to be no more than 7.0, especially not more than 6.5, if necessary, the above-mentioned rasagiline transdermal patch may be added with a pH adjuster or a buffer. For example, when the active substance is rasagiline free base, it may be necessary to add a pH adjusting agent for the acidic substance to adjust the pH to not more than 7.0, especially not more than 6.5. Further, for example, when the active material is rasagiline sulfonate, but the substrate used is a basic substance, it is also possible to add a pH adjuster or a buffer. Generally, once the patch is alkaline, a pH adjusting agent may be added to maintain the pH of the patch in a range of less than or equal to 7.0, especially not more than 6.5. — — Wai. The pH adjusting agent includes adipic acid, caproic acid, propionic acid, benzoic acid, phenylacetic acid, phthalic acid, citric acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid. , acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid and silicic acid, or acidic a polymer such as carboxyvinyl chloride and its derivatives (such as carbomer), preferably hydrochloric acid, hydrazine sulfonic acid and p-toluene sulfonic acid; the buffer is selected from at least one of the following solutions: citrate Buffer, acetate buffer, phosphate buffer, citrate buffer and phthalate buffer. In a specific embodiment, the rasagiline transdermal patch comprises oxalate sulfonate of rasagiline. In another specific embodiment, the rasagiline transdermal patch comprises a hydrophilic matrix selected from the group consisting of polyvinylpyrrolidone and derivatives thereof, such as polyvinylpyrrolidone K15, polyvinylpyrrolidone 25, polyethylene Pyrrolidone 30, polyvinylpyrrolidone 60, polyvinylpyrrolidone 90, crosslinked polyvinylpyrrolidone, vinylpyrrolidone-hydroxypropyl methacrylate copolymer, vinylpyrrolidone-vinyl acetate copolymer, etc.; polyethylene glycol and its derivatives , such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, Polyethylene glycol 4000, polyethylene glycol 6000, polyoxyethylene sorbitan ester, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene-polyoxypropylene copolymer, etc.; ethylene-vinyl acetate copolymerization And derivatives thereof, such as ethylene-vinyl acetate copolymer 14/5, ethylene-vinyl acetate copolymer 28/250, polyvinyl acetate, polyvinyl acetate phthalate, etc.; cellulose and its derivatives Yue as methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium Yue group, hydroxyethyl cellulose, hydroxyethyl cellulose Yue, hydroxypropyl cellulose, hydroxypropyl - - mercapto cellulose, hydroxypropyl ethyl cellulose, etc.; carboxyvinyl and its derivatives, such as carbomer

910, carbomer 940, carbomer 934, carbomer 910, carbomer 980, carbopol ester, and the like. In another specific embodiment, the rasagiline transdermal patch comprises a combination of at least two of the above hydrophilic polymer matrices, preferably polyvinylpyrrolidone and its derivatives and polyethylene glycol and derivatives thereof Combination, a combination of cellulose and its derivatives with carboxyvinyl and its derivatives. In some cases, the hydrophilic gel prepared from the mixture of polyvinylpyrrolidone and polyethylene glycol has better permeability to rasagiline, wherein polyvinylpyrrolidone: polyethylene glycol (WAV) can be 1:9 to 9: 1. For example, polyvinylpyrrolidone may preferably be of the K90D type, and polyethylene glycol may preferably be of the polyethylene glycol type 400, wherein the polyvinylpyrrolidone K90D: polyethylene glycol 400 (W/W) may preferably be 3:2. The choice of two hydrophilic polymer matrices increases the viscosity of the matrix and facilitates better adhesion of the patch to the skin. In another embodiment, in order to control the release rate or release time of rasagiline, the above rasagiline transdermal patch may contain at least one hydrophobic polymer in addition to the hydrophilic polymer matrix. That is, a combination matrix of a hydrophilic polymer and a hydrophobic polymer is used. The combination matrix may be a matrix formed by mixing a hydrophilic polymer and a hydrophobic polymer, or may be a hydrophilic polymer matrix layer containing rasagiline or a pharmaceutically acceptable salt thereof. A layer of a hydrophobic polymer matrix layer comprising rasagiline or a pharmaceutically acceptable salt thereof is added. The hydrophobic polymer may be selected from at least one of the following: polyacrylic resins and derivatives thereof, silicones and derivatives thereof. In another embodiment, the above rasagiline transdermal patch further comprises a controlled release film. when - - When the selected polymer matrix is a hydrophilic polymer, there may be a phenomenon that the active substance is released too fast and the release time is short. Therefore, in order to prolong the release time of the drug and control the release rate, a controlled release can be added. membrane. Whether or not the controlled release film is used can be determined according to the viscosity characteristics of the polymer used in the matrix layer and the characteristics of controlling the release rate of the drug. In another embodiment, the membrane material selectable for the controlled release membrane is characterized by a wet steam permeability of between 100 grams per square meter per day to 3000 grams per square meter per day. The moisture vapour transmission rate (MVTR) is a measure of the permeability of a material to water vapor and can be used to measure the permeability of rasagiline. For the method of measuring MVTR, GB/T 16928, ASTM E96, ASTM D1653. ISO 2528 and other documents are available for reference. Under normal circumstances, the larger the MVTR, the better the effect of rasagiline permeability, but the wet steam permeability is not as large as possible, because the controlled release effect of rasagiline is not obtained to a certain extent. The controlled release film may specifically comprise one or more of the following materials: polyurethane, polylactic acid, polyethylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, and some of the films are characterized by the following Table 1. The preferred controlled release membranes may be the following three types: CoTrans9702, CoTrans9728, CoTrans9701 (all produced by 3M Company of the United States), wherein the first two are polyethylene-polyvinyl acetate controlled release membranes, and CoTrans9701 is a polyurethane controlled release membrane. Table 1. Characteristics of Controlled Release Membranes Model Type Vinyl Acetate Content Thickness Wet Steam Permeability

CoTrans9702 9% 50.8μιη 52.8g/m ² /24h

CoTrans9707 4.5% 50.8μιη 15.7 g/m ² /24h

CoTrans9720 0% 76.2μιη 6.0 g/m ² /24h

CoTrans9726 2% 50.8μιη 10.2 g/m ² /24h - -

In yet another embodiment, to control the release rate or release time of rasagiline, the rasagiline transdermal patch of the present invention can also be controlled release release by controlling the release area. Embodiments are such that the active substance rasagiline is released through the pore by adding a membrane having at least one pore smaller than the patch area to the patch substrate. The size of the pores may be determined according to the release characteristics of the polymer matrix, and the ratio of the pore area to the patch area is preferably 1:3 to 8. The membrane material of the membrane is a polymer having relatively low permeability to rasagiline, such as polyethylene film CoTrans9720, polyethylene-polyvinyl acetate film CoTrans9726, and the like. In one embodiment, a controlled release film and a back layer are used to seal a patch containing a semi-solid reservoir. The factors affecting drug release are the affinity of the drug and matrix and the permeability of the controlled release film to the drug. For transdermal patches of the above rasagiline or a pharmaceutically acceptable salt thereof, the pH of the patch can be determined according to the following method: Calculated according to the content of rasagiline or its pharmaceutically acceptable salt of the patch Take a certain amount of patch with pure water to prepare a solution containing rasagiline or its pharmaceutically acceptable salt 1mg/ml, which can be measured with a pH meter, in order to facilitate the rasagiline or its drug The accepted salt is completely dissolved from the patch and can be stirred with a small amount of absolute ethanol, ultrasonically extracted, and then measured with a pH meter. The pH of the drug-loaded substrate which is not prepared into a patch can be determined by the following method: A certain amount of the drug-loading substrate is configured with pure water to prepare a solution containing rasagiline or a pharmaceutically acceptable salt thereof at 1 mg/ml. It can be measured with a pH meter. In order to facilitate the complete dissolution of rasagiline or its pharmaceutically acceptable salt from the matrix, it can be stirred with a small amount of absolute ethanol, ultrasonically extracted, centrifuged to remove the supernatant, and then used for PH. Meter measurement. — The pH of the blank matrix can be determined by reference to national pharmacopoeia or other standards, or by the amount of drug-loaded matrix. The inventors of the present invention have found that rasagiline is stable at a pH of not more than 7.0, especially not more than 6.5, and on the contrary, it degrades rapidly, as shown in Table 2. In order to achieve a pH of not more than 7.0, especially not more than 6.5, rasagiline or a pharmaceutically acceptable salt thereof, such as rasagiline sulfonate, is preferably in the form of a salt or/and an ion in the matrix. presence. In the embodiment of CN101032474A, rasagiline is added to the matrix system with an alkali regulator such as sodium hydroxide or triethanolamine, and is largely present in the form of a free base to promote absorption. However, the inventors of the present invention have found that when rasagiline is present in the form of a free base, high temperatures may adversely affect its stability. The inventors of the present invention have also found that even with a two-layer structure in which one layer contains rasagiline salt and the other layer contains a basic regulator, high temperature has an effect on the stability of rasagiline. The content of the main drug rasagiline and related substances (impurities) was determined by high performance liquid chromatography (HPLC). The HPLC color column was subjected to C18 column and Daicel AD column. The results are shown in Table 2 below. The results from Table 2 show that the pH value has a large influence on the stability of the active substance rasagiline. Table 2. Changes in the content of the main drug (rasagiline) at different pH values

Sustained acid rasagi

60°C 10 days 40°C 10 days Blue concentration is lmg/ml Experimental object \^

Rasagiline free base is contained in the main drug content of 7.0 ~ 8.0 main drug - -

It can be seen from Table 2 that when the pH is greater than 6.5, especially greater than 7.0, rasagiline has significant degradation after 10 days, whether at 60 °C or 40 °C. At a pH of 6.5, rasagiline significantly degraded after 10 days at 60 ° C; degradation of rasagiline after 10 days at 40 ° C was acceptable. Without being bound by any existing theory, the above experimental results may be solved as follows. - - Released. The pH of the medium significantly affects the form of rasagiline: the pH of rasagiline free base in pure water is about 7.5 (measured as rasagiline at 1 mg/ml); The pH in pure water was about 5.0 (measured at 1 mg/ml of rasagiline sulfonate), and the PKa was calculated to be 7.5. When the pH is 6.5, the amount of rasagiline free base accounts for 10% of the total, and the calculated value is basically consistent with the experimental value. Therefore, the lower the pH, the more stable the rasagiline is, under other conditions. When rasagiline is present in the form of free ruthenium, the R-NH-C≡CH bond between the secondary amine group and the attached alkynyl group is easily broken, thereby causing degradation. Therefore, in terms of stability, rasagiline is difficult to maintain stability in the alkaline matrix environment for a long time, especially in the state of free alkali, the instability is more obvious. For the above rasagiline patch, rasagiline may exist in various forms other than the free base. For different forms of rasagiline, the patch can be prepared in different ways. For example, when rasagiline is present in the form of a salt or an ionic form, such as rasagiline bismuth sulfonate, it can be first dissolved in an organic solvent such as ethanol, propylene glycol or glycerin, and then with an organic polymer matrix, The skin penetration enhancer or the like is mixed to form a patch. For example, when rasagiline or a pharmaceutically acceptable salt thereof is in the form of microcrystalline or amorphous dispersion, rasagiline or a salt thereof can be dissolved in ethanol or water by a solvent method, and povidone and polyvinyl alcohol can be used. After mixing, volatilizing dry ethanol or water to obtain an amorphous dispersion of rasagiline in povidone or polyvinyl alcohol, and then mixing with an organic polymer matrix, a skin penetration enhancer or the like to form a patch, wherein the patch is formed. The ketone or polyvinyl alcohol may also be replaced by a carrier of urea, polyethylene glycol, fiber or the like as a dispersion. It is worth noting that for povidone, polyvinyl alcohol, ketone cellulose, ethyl cellulose, etc., which have higher melting points, the method used in the preparation may be a solvent method, and for urea and polyethylene. In the case of a diol having a lower melting point such as polyethylene glycol 4000 or polyethylene glycol 6000, a patch may be prepared by a melt method. For example, rasagiline and refined polyethylene glycol 4000 are uniformly mixed and heated to 40 ~ 60 ° C to melt. - - Re-converting to a solid by drastically lowering the temperature to obtain a crystallite or amorphous dispersion form of rasagiline, and then mixing with an organic polymer matrix, a skin penetration enhancer or the like to prepare a patch. When rasagiline is present in the form of microemulsions or submicron emulsions, oils such as liquid paraffin, petrolatum, long-chain fatty alcohols such as cetyl alcohol, stearyl alcohol, etc. may be used as internal phases to form a water pack. An oil-structured microemulsion, a submicron emulsion in which rasagiline or a pharmaceutically acceptable salt thereof is dissolved in an oil phase and is in a supersaturated state, which is easily precipitated and penetrates the skin due to a thermodynamically unstable state. The microemulsion and submicron emulsion can be obtained by a high-speed stirring method and a high-speed emulsion homogenization method. The prepared microemulsion, submicron emulsion, organic polymer matrix, skin penetration enhancer, and the like can be mixed to form a patch. For example, in the preparation of a transdermal patch in the form of rasagiline liposomes, rasagiline can be encapsulated into liposomes using an ester-like substance such as lecithin, hydrogenated lecithin, cholesterol, etc. to prepare a lipid. The method may be a thin film method, a reverse phase evaporation method, a freeze drying method, a PH-gradient method, a high-speed stirring method, a high-speed emulsion homogenization method, etc., and the rasagiline liposome and the organic polymer matrix are obtained. A penetrant or the like is used to form a patch. The above methods for preparing microemulsion wrap, submicron milk wrap, and lipid-encapsulated rasagiline are now available. Regardless of the method of preparation, the pH can be adjusted by adding a pH adjusting agent to ensure that the pH of the patch is not more than 7.0, especially not more than 6.5. Since the patch is administered through the skin, the pH value is too low to cause irritation to the skin, so the pH of the patch should also be not less than 3.0. Therefore, a preferred pH range is from not less than 3.0 to not more than 7.0, especially not more than 6.5. - - The method of adjusting the pH is mainly by adding an acidic substance and/or adding a buffering agent having a pH of 7.0 or less, especially 6.5 or less. The acidic substance includes: adipic acid, caproic acid, propionic acid, benzoic acid, phenylacetic acid, phthalic acid, citric acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, Acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid, silicic acid and the like. The method of adjusting the pH may also be a method of mixing a matrix having a pH value of less than 6.5 and a matrix having a pH of more than 6.5, such that the pH of the mixed matrix is not more than 6.5. The buffering reagent includes a citrate buffer, an acetate buffer, a phosphate buffer, a citrate buffer, an phthalate buffer, and the like. The acidic substances and buffering agents described above are all commonly used in the art, and the method of use thereof is also a conventional technique. It should be noted that after the pharmaceutically acceptable salts of rasagiline, such as rasagiline sulfonate, rasagiline hydrochloride, etc., are added to the above matrix, the pH of the whole system may be less than, for example, 6.5, and it is also possible More than 6.5. The purpose of adding a pH adjusting agent is to ensure that the pH of the patch is below 7.0, especially below 6.5, under the conditions of preparation and storage. The stratum corneum of the skin is usually the main obstacle to percutaneous absorption. Therefore, some substances which soften the stratum corneum and enhance the fluidity of lipids in the skin tissue can enhance the transdermal effect of the active ingredient. In Chinese patent CN101032474A, factors affecting the transdermal effect of rasagiline have been mentioned: the order is whether the matrix contains a penetration enhancer > whether the main drug is a free base > a penetration enhancer species. In Examples 1 to 5 of the patent CN101032474A, an aqueous NaOH solution was used to adjust the pH to 7.5, so that rasagiline or a pharmaceutically acceptable salt thereof was present in the form of rasagiline free base to promote absorption; In Example 6, triethanolamine was used as a regulator to adjust the pH to 8.5. This will certainly enhance the transdermal permeability of rasagiline, but it may also lead to instability of rasagiline and thus affect its practical application. - - When the pH is not more than 7.0, especially not more than 6.5, the rasagiline permeability is too low with a patch based on a non-hydrophilic polymer material such as polyacrylic acid or silicone. A rasagiline paste carrying a hydrophilic polymer material such as polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, ethylene-vinyl acetate copolymer, carboxyvinyl cellulose, cellulose derivative, etc. The film absorbs the moisture of the skin and the outside world, forming a saturated solution of rasagiline, which promotes the release of rasagiline and greatly increases the penetration of rasagiline. Surprisingly, the composite patch made of a hydrophilic polymer matrix and a non-hydrophilic polymer matrix has a good transdermal effect. The transdermal effect of the composite patch with controlled release membrane is also good, and the sustained release effect is good in the in vivo drug experiment. The controlled release of the drug to control the release area has also basically achieved the transdermal effect and the controlled release of the drug. The preparation method of the above rasagiline transdermal patch is illustrated by way of example in the examples. It will be appreciated that those skilled in the art, after reading this disclosure, are free to adapt the variations of these exemplary methods of preparation in the prior art. The prepared transdermal patch was subjected to a Franz cell (effectively accepted area of 2.54 cm 2 and a volume of 17 ml) to study the penetration of the skin of a two-month-old rat's abdomen. It can be seen that the above-mentioned rasagiline transdermal patch can provide a sufficient amount of rasagiline through the skin to achieve the purpose of causing systemic action. The above-mentioned stable and controllable transdermal patch of rasagiline or a pharmaceutically acceptable salt thereof can be administered once every 1-3 days or more once as once every week. The above-mentioned rasagiline transdermal patch maintains the stability of the active substance rasagiline and a good and controllable transdermal release effect, is suitable for long-term storage, and is less irritating to the skin. The - - Patches can be used to treat or prevent neurological diseases such as Parkinson's disease, Alzheimer's disease, depression, etc. The above rasagiline transdermal patch is more commonly available than the formulation obtained with a specific transdermal penetration enhancer in US2004013620. The above-mentioned rasagiline transdermal patch is more stable and longer lasting than the CN101032474A patch, making preparation easier, safer and more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic cross-sectional view of a patch of Examples 1, 2, and 3. 2 is a schematic cross-sectional view of the patch of Embodiment 4. Fig. 3 is a schematic cross-sectional view showing the patch of the fifth embodiment. 4 is a schematic cross-sectional view of the patch of Example 6. Fig. 5 is a plan view showing the patch of the embodiment 6. Fig. 6 is a schematic cross-sectional view showing the patch of the seventh embodiment. Figure 7. Schematic of the rasagiline time-cumulative permeation amount of the patch of Example 1 and the rasagiline-containing single-layer polyacrylate matrix patch. Figure 8. The patch of Example 2, the rasagiline time-cumulative permeation amount curve of a single layer silicone matrix patch containing rasagiline. Figure 9. The patch of Example 3, the rasagiline time-cumulative permeation curve of a single layer polyvinylpyrrolidone-polyvinyl alcohol composite matrix patch containing rasagiline. Figure 10. The patch of Example 4, the rasagiline time-cumulative permeation curve of the rasagiline-containing modified release film polyvinylpyrrolidone-polyvinyl alcohol composite matrix patch - - Figure. Figure 11. The patch of Example 5, the rasagiline time-cumulative permeation amount curve of the rasagiline-containing composite layer patch. Fig. 12 is a graph showing the relationship between the time and the cumulative permeation amount of the rasagiline time of the patch containing the thiol cellulose-carbomer 940 as a substrate containing the rasakiline sulfonate. . Figure 13. The patch of Example 2, the blood concentration-time curve of rasagiline in rabbits. Figure 14, the patch of Example 3, the blood concentration-time curve of rasagiline in rabbits Figure 15, the patch of Example 4, the blood concentration-time curve of rasagiline in rabbits Figure 16, implementation The patch of Example 5, the blood concentration-time curve of rasagiline in rabbits, the patch of Example 6, the blood concentration-time curve of rasagiline in rabbits, the specific embodiment is as follows The content of the invention is further described, but does not limit the scope of the invention. Example 1: A single-layer polyacrylate matrix patch containing rasagiline bismuth sulfonate, 0.25 g of rasagiline bismuth sulfonate dissolved in 1 g of propylene glycol with oleic acid as a penetration enhancer, and added To 20 grams of polyacrylate rubber (American National Starch Corporation, Type 387-2287). 0.3 g of oleic acid was added, and after stirring uniformly, the mixed glue was applied on a siliconized paper by an automatic coater (Shanghai Yukai Co., Ltd., type TB-04) to a coating thickness of 0.6 mm. Drying at 60 ° C 5 - After a minute, cover the support layer and transfer, then cut or cut the patch into the final sheet. The rasagiline content was determined to be 22 (^g/cm ² , and the pH was determined to be 4.4. The profile of the prepared patch is shown in Fig. 1. The prepared patch was a Franz cell and two The permeation of the skin of the aged rats was studied by fading the skin. The content of rasagiline at different time points was determined by high performance liquid chromatography, and the cumulative permeation amount of rasagiline was calculated according to the results. Table 3. The rasagiline time-cumulative permeation curve is shown in Figure 7. Table 3 rasagiline patch time-cumulative permeation data table with oleic acid

Example 2: A single-layer silicone matrix patch containing rasagiline, 0.25 g of rasagiline free base was dissolved in 1 g of propylene glycol using lauryl ketone as a penetration enhancer, and then added. - - To 20 grams of silicone glue (3M Company, PSA7-4302 type). 0.3 g of lauropyridone was added, and after stirring uniformly, a small amount of glue was used as a sample (for stability study), and the pH was measured to be 7.7. Prepared according to the above prescription and process, and added 0.15 g of sulfonic acid and stirred to obtain a glue solution. A small amount of glue was taken as a sample (for stability study) to obtain a pH of 4.0. The mixed glue was applied to siliconized paper by an automatic coater (Shanghai Yukai Co., Ltd., Model TB-04) to a coating thickness of 0.6 mm. After drying at 60 ° C for 5 minutes, the support layer is covered and transferred, and the patch is die cut or cut into the final sheet. The rasagiline content was measured to be 220 ug/cm ² . A schematic view of the prepared patch is shown in Fig. 1. The prepared patch was subjected to the method of Example 1 to calculate the cumulative permeation amount of rasagiline. The results are shown in Table 4 below. The rasagiline time-cumulative permeation curve is shown in Figure 8. Table 4: rasagiline patch time-cumulative permeation data table with cumulative abortion

( h ) ( μ §)

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 - - It can be seen from Tables 3 and 4 that the patch made of non-hydrophilic pressure sensitive adhesive such as polyacrylic acid or silicone has a cumulative penetration of less than 200 g at the 48th hour, and the implementation of the patent CN101032474A In comparison with Example 1, the cumulative amount of permeation was significantly reduced because rasagiline was added with sulfonic acid sulfonate and the drug loading was small. In order to increase the cumulative amount of permeation, it is necessary to use a hydrophilic pressure sensitive adhesive as a matrix. Example 3: A single layer polyvinylpyrrolidone-polyethylene glycol composite matrix patch containing rasagiline, 24 g of polyvinylpyrrolidone PVP-K90D (ISP Technologies, INC) with a pentazone as a penetration enhancer Sprinkle into 120 g of absolute ethanol, stir to completely swell, add 16 g of polyethylene glycol 400 (Nanjing Weil Chemical) to it, stir and mix well to obtain a blank glue. 15 g of the prepared glue was taken, 1.0 g of rasagiline free base was added, and the mixture was stirred and dissolved to dissolve. 0.3 g of lauropyridone was added, and after stirring well, the pH was measured to be 7.4. Prepared according to the above prescription and process, and 0.6 g of sulfonic acid was added, and the pH was measured to be 4.7. The mixed glue was applied to siliconized paper by an automatic coater (Shanghai Haokai Co., Ltd., Model TB-04) to a coating thickness of 0.4 mm. After drying at 60 ° C for 5 minutes, the support layer is covered and transferred, and the patch is die cut or cut into the final sheet. A schematic view of the prepared patch is shown in Fig. 1. The prepared patch was subjected to the method of Example 1 to calculate the cumulative permeation amount of rasagiline. The results are shown in Table 5 below. The rasagiline time-cumulative permeation amount curve is shown in Fig. 9. - - Table 5 rasagiline patch time-cumulative permeation data table with lauryl ketone

It can be seen that the patch prepared by using polyvinylpyrrolidone and polyethylene glycol composite matrix pressure sensitive adhesive has a cumulative permeation amount of 150 (^g or more at the 48th hour, and the cumulative penetration is compared with the embodiment 1 of the patent CN101032474A. The amount is higher, and due to the addition of sulfonic acid, rasagiline is no longer in a free state, so the stability is better. Example 4: controlled release film polyvinylpyrrolidone-polyethylene containing rasagiline A diol composite matrix patch with a ruthenium ketone as a skin penetration osmotic agent. To control the release of rasagiline, a controlled release film was added on the basis of Example 3 (pH 4.7). The preparation method was the same as that in Example 3 except that the controlled release film was compounded in the last step, and then the vinylpyrrolidone-polyethylene glycol composite matrix drug-loaded self-adhesive layer was added. - - A schematic diagram of the profile of the patch is shown in Figure 2. The following controlled release membranes are used: CoTrans9702, CoTrans9707, CoTrans9726, CoTrans9728, CoTrans9720, CoTrans9701 (all produced by 3M Company of the United States), the first four are polyethylene-polyvinyl acetate controlled release membranes, and CoTrans9720 is controlled release of polyethylene. The membrane and CoTrans9701 are polyurethane controlled release membranes. The prepared patch was subjected to a Franz cell with a volume of 17 ml and a receiving area of 2.54 cm ² . The sampling time was: 2h, 4h, 6h, 8h, 16h, 24h, 48h, 72h, 96h, 120h, the results are shown in Tables 6, 7, 8, 9, 10 and Table 11, respectively. The rasagiline time-cumulative permeation curve is shown in Figure 10. For six formulations with controlled release membranes, their release rate is positively correlated with their wet vapor permeability, but there is no strict linear relationship (especially after the vinyl acetate content exceeds 10%). The best release effect of these six controlled release membranes is CoTrans9701, which also has the highest wet steam permeability. It can be seen that the wet steam permeability is too small, the release of rasagiline is too slow, and the release amount is too small, but the wet steam permeability is not as large as possible, because it is too large to reach the rasagiline. Controlled release effect. Table 6. Time-cumulative permeation data table for rasagiline patch with CoTrans9702 as controlled release membrane

- -

Table 7. Time-cumulative permeation data of rasagiline patch with CoTrans9707 as controlled release membrane

Table 8. Time-cumulative permeation data of rasagiline patch with CoTrans9720 as controlled release membrane

Table 9. Time-cumulative permeation data of rasagiline patch with CoTrans9726 as controlled release membrane

- -

Table 10, rasagiline patch time-cumulative permeation data table with CoTrans9728 as controlled release membrane

Table 11. Time-cumulative permeation data table for rasagiline patch with CoTrans9701 as controlled release membrane

It can be seen that the cumulative release of CoTrans9701 is the largest. In the pharmacokinetic experiments of rabbits mentioned later, it can also be seen that CoTrans9701 can achieve a better controlled release effect and maintain a certain blood concentration. The wet steam permeability can be selected from 100 g/m 2 /day to 3000 g/m 2 /day, considering that the release of the drug can be affected by controlling the controlled release area and the drug loading. For films having a wet vapor permeability of less than 100 g/m 2 /day, it can be used as a backing material for the patch and as a film for controlling the release area. Example 5: Composite layer patch containing rasagiline bismuth sulfonate, the first layer of quercetin as a skin penetration permeable agent: 24 g of polyvinylpyrrolidone PVP-K90D (ISP Technologies, INC) was sprinkled into 120 In anhydrous ethanol, stir it to swell completely, - -

16 g of polyethylene glycol 400 (Nanjing Weil Chemical) was added thereto, and the mixture was stirred and mixed to obtain a blank rubber. 15 g of the prepared glue was taken, and 1.0 g of rasagiline sulfonate was added, and the mixture was stirred and dissolved to dissolve. 0.3 g of lauropyridone was added, and after stirring well, the pH was measured to be 6.6. Prepared according to the above prescription and process, and added 0.05 g of sulfonic acid, and the pH value was 4.8. The mixed glue was coated on siliconized paper by an automatic coating machine (Shanghai Yukai Co., Ltd., TB-04 type). The coating thickness is 0.6 mm. After drying at 60 ° C for 5 minutes, cover the support layer and transfer. The second layer: 0.25 g of rasagiline sulfonate was dissolved in 1.0 g of propylene glycol, and then added to 20 g of silicone rubber (Model 3M, PSA 7-4302, USA). Add 0.4 g of laurel, and after mixing evenly, use automatic coating machine (Shanghai Yukai Company,

Type TB-04) The mixed glue was applied to siliconized paper to a thickness of 0.6 mm.

After drying at 60 ° C for 5 minutes, transfer to the first layer and then die cut or cut into the final sheet. A schematic cross-section of the resulting patch is shown in Figure 3. The prepared patch was subjected to the cumulative permeation amount of rasagiline according to the method of Example 1, and the results are shown in Table 12. The rasagilan time-cumulative permeation curve is shown in Figure 11. Table 12: Composite layer patch time with rasagiline - cumulative penetration data table

- -

Example 6: Controlled release area patch containing rasagiline bismuth sulfonate, using 24 g of polyvinylpyrrolidone PVP-K90D (ISP Technologies, INC) as a skin penetration enhancer In the water ethanol, the mixture was stirred to completely swell, and 16 g of polyethylene glycol 400 (Nanjing Weil Chemical) was added thereto, and the mixture was stirred and mixed to obtain a white glue. 15 g of the prepared glue was taken, 1.0 g of rasagiline sulfonate was added, and the mixture was stirred and dissolved to dissolve. 0.3 g of lauropyridone was added, and after stirring well, the pH was measured to be 5.9. Compared with the PH value measured before the addition of sulfonic acid, this example and Example 5 are reduced to meet the requirement of pH not exceeding 6.5. This difference is mainly due to polyvinylpyrrolidone and polyethylene glycol 400 polymer. Caused by differences in materials. The mixed glue was applied to siliconized paper by an automatic coater (Shanghai Haokai Co., Ltd., Model TB-04) to a coating thickness of 0.6 mm. After drying at 60 ° C for 5 minutes, the support layer was covered, and then transferred, and the patch was coated with CoTrans9720 film with a hole in the middle, and the hole area and patch area ratio was 1:5. A schematic cross-sectional view of the obtained patch is shown in Fig. 4, and a plan view is shown in Fig. 5. Due to the prescription, process and Example 3 used, the pharmacokinetics were directly verified. - - Example 7: A reservoir containing thiolactam sulfonate sulfonate-based sulfhydryl cellulose-carbomer 940-based patch, with ruthenium ketone as the first step of the skin penetration agent: 2 The ketone cellulose was sprinkled into 100 g of cold water containing 30% (WV) of ethanol, stirred to completely swell, and the pH was measured to be 8.0. 1 gram of carbomer 940 was added thereto, stirred and mixed, and then allowed to stand. The solution was allowed to swell completely, and a pH of 5.5 was measured to obtain a blank gum. 15 g of the prepared glue was taken, 1.0 g of rasagiline sulfonate was added, and the mixture was stirred and dissolved to dissolve. 0.3 g of lauropyridone was added, and after stirring, a drug-containing gel was obtained. The pH was measured to be 5.0. Part 2: CoTrans9720 film and CoTrans97201 film were taken, heat-sealed to form a 2 cm*2 cm pouch with one opening, and 0.25 g of drug-containing glue was added to the bag, and the opening was heat-sealed to obtain a patch. A schematic cross-sectional view of the obtained patch is shown in Fig. 6. The prepared patch was subjected to the method of Example 1 to calculate the cumulative permeation amount of rasagiline. The results are shown in Table 13. The rasagiline time-cumulative permeation curve is shown in Figure 12. Table 13. Time-cumulative permeation data for the reservoir-type patch containing rasagiline bismuth sulfonate

- -

Therefore, according to the patch of the present invention, a patch having a size of about 4 to 10 square centimeters using different substrates and processes can be absorbed through the skin for a therapeutic amount of 1-3 days, and can be prepared by a multilayer patch. To control the rate of penetration of rasagiline, since the drug patch material is widely available, readily available, and easy to manufacture, and can deliver rasagiline to skin absorption via the entire surface of the substrate, relative to the system described in US2004013620 It has the advantages of simple preparation method, wide availability of raw materials, smoother release, longer release time, and more complete absorption through the skin. Compared with CN101032474A, the release time is longer and more stable, and the preparation process is more environmentally friendly and safer. In the above seven examples, Examples 1, 2, 3, 5, 6, and 7 all relate to the influence of pH on the stability of rasagiline (Example 4 is controlled release on the basis of Example 3). membrane). The inventors examined changes in rasagiline after 10 days of standing at 40 ° C under different pH conditions. The content of the main drug rasagiline and related substances (impurities) was determined by high performance liquid chromatography (HPLC). The HPLC color column was a C18 column and an AD column from Daicel. The results are shown in Table 14 below. The data shows that when the pH is less than 7.0, especially less than 6.5, the rasagiline in the patch remains stable, which is beneficial for long-term storage, and the pH is greater than 6.5, especially when it is greater than 7.0. Geeland is unstable, not conducive to - - Long-term storage.

Table 14. Effect of pH on the stability of rasagiline in the patch

In the above seven examples, five of them were selected for in vivo pharmacokinetic studies: Comparative Example: rasagiline tablets of sulfonate, administered in an amount of 1.0 mg/mouse. Example 2: A single layer silicone matrix patch containing rasagiline, with azone as a skin penetration enhancer, administered in an amount of 0.503 mg/head.

Example 3: Single layer polyvinylpyrrolidone-polyvinyl alcohol composite containing rasagiline - - Quality patch, with ruthenium ketone as a skin penetration osmotic agent, administered at a dose of 3.3m _g / only. Example 4: A polyvinylpyrrolidone-polyvinyl alcohol composite matrix patch containing rasagiline plus a Cotrans9701 controlled release membrane, using a ruthenium ketone as a skin penetration osmotic agent at a dose of 13.2 mg/head. Example 5: a composite layer of rasagiline patch Yue acid, lauryl nitrogen to promote transdermal permeabilizing agent is one castor, a dose of 8m _g / only. Example 6: A controlled release area patch containing rasagiline bismuth sulfonate, with a quercetin dermal penetration enhancer administered at a dose of 8.4 m _g /mouse. The subjects were New Zealand white rabbits weighing 1.5 kg ~ 2 kg. The plasma concentrations were monitored at different times using a high performance liquid chromatography-mass spectrometer (Agilent, 200, Triple Quad LC/MS). The results of the assay are shown in Table 15 below, and the blood concentration-time curve in vivo is shown in Figure 13. Table 15 In vivo pharmacokinetics determination dose AUC(ot) AUC o-oo) MRT(ot) C _m ax max ti/ ₂ a ti/ιβ AUC(ot) number

Mg (ng L*h) (ng L*h) (h) (ng L) (h) (h) (h) t test

124.71 237.12 7.30 127.72

One room tl/2:

ORAL 1 士士士士 0.25

0.23 + 0.17h

17.21 63.3 1.84 63.97

201.28 487.46 32.19 9.66 1.67

Example 2 0.503 士士士士士 5932.32 166546.46 P < 0.05

44.04 153.87 3.29 4.14 1.16

261.55 428.20 8.65 25.32 4.33 5.81

Example 3 3.3 11.54 + 5.95 > 0.05

Saints - -

According to the data of Table 5, Table 12 - 13, Table 14 and Table 15, the transdermal patch of the present invention not only maintains a good transdermal effect, but also overcomes the disadvantage of instability, and the blood drug concentration is also ideal, and the controlled release effect is achieved. Obviously, better than oral preparations. The invention has been described above by way of illustration. However, it should be understood that the present invention is by no means limited to these specific embodiments. A person skilled in the art can make various modifications and changes to the invention without departing from the spirit and scope of the invention.

Claims

Rights request

A stable release-controlled rasagiline transdermal patch, wherein the transdermal patch comprises a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof and at least one hydrophilic A polymeric matrix, and the patch has a pH of no greater than 7.0.

The rasagiline transdermal patch according to claim 1, wherein the pH is between not less than 3.0 and not more than 6.5.

3. The rasagiline transdermal patch of claim 1, wherein the pharmaceutically acceptable salt of rasagiline comprises rasagiline hydrochloride, sulfonate, para-phenylene a sulfonate, a besylate or a sulfate.

4. The rasagiline transdermal patch according to claim 1, wherein the hydrophilic polymer matrix is selected from one or more of two or more of the following: polyvinylpyrrolidone and derivatives thereof. , polyethylene glycol and its derivatives, ethylene-vinyl acetate copolymer and its derivatives, cellulose and its derivatives, and carboxyvinyl and its derivatives.

The rasagiline transdermal patch according to any one of claims 1 to 4, further comprising at least one hydrophobic polymer matrix comprising a polyacrylic resin and Derivatives or silicones and their derivatives.

The rasagiline transdermal patch according to any one of claims 1 to 4, further comprising a controlled release membrane, wherein the membrane material of the controlled release membrane has a wet vapor permeability of 100 g/m 2 / Day to 3000 g / square meter / day.

7. The rasagiline transdermal patch of claim 6, wherein the film material is selected from at least one of the group consisting of polyethylene and its derivatives, ethylene vinyl acetate. Copolymers and derivatives thereof, polyurethanes and derivatives thereof, polyvinyl chloride and derivatives thereof.

The rasagiline transdermal patch according to any one of claims 1 to 4, further comprising a membrane having at least one pore smaller than a patch area, the membrane material of the membrane being a pair of Rasha Gelier's relatively low permeability polymer characterized by a wet vapor permeability of the membrane material of less than 100 grams per square meter per day.

9. A rasagiline transdermal patch according to any one of claims 1 to 4, optionally further comprising a pH adjusting agent or buffer.

10. The rasagiline transdermal patch of claim 9, wherein the pH adjusting agent is selected from at least one of the following acidic substances: adipic acid, caproic acid, propionic acid, benzoic acid, benzene Acetic acid, phthalic acid, citric acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, hydrazine Sulfonic acid, tartaric acid, succinic acid, boric acid, sorbic acid, silicic acid, p-toluenesulfonic acid and benzenesulfonic acid, preferably hydrochloric acid, sulfonic acid and p-toluenesulfonic acid.

11. The rasagiline transdermal patch of claim 9, wherein the buffer is selected from at least one of the following solutions: citrate buffer, acetate buffer, phosphate Buffer, citrate buffer and phthalate buffer.

12. The rasagiline transdermal patch of any of claims 1 - 4, optionally further comprising at least one transdermal enhancer.

13. The rasagiline transdermal patch of claim 12, wherein said transdermal enhancer is selected from at least one of the group consisting of: ethanol, propylene glycol, oleic acid, oleyl alcohol, linoleic acid, Lauryl alcohol, lauric acid, isopropyl myristate and lauryl ketone.

A method of preparing a rasagiline transdermal patch according to any one of claims 1 to 13, comprising:

Providing the at least one hydrophilic polymer matrix;

- mixing a therapeutically effective amount of rasagiline or a pharmaceutically acceptable salt thereof with said matrix;

- adjusting the pH of the substrate to not more than 7.0, preferably adjusting the pH to

3.0 - 6.5.

The method according to claim 14, wherein the pH of the substrate is adjusted to not more than 7.0 by adding a pH adjuster or a buffer to the matrix.

16. The method according to claim 15, wherein said pH adjusting agent is selected from at least one of the following acidic substances: adipic acid, caproic acid, propionic acid, benzoic acid, phenylacetic acid, phthalic acid, hydrazine Acid, hypophosphorous acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glacial acetic acid, acetic acid, lactic acid, malic acid, citric acid, hydrochloric acid, sulfuric acid, nitric acid, sulfonic acid, sulfonic acid, tartaric acid, succinic acid, boric acid , sorbic acid, silicic acid, p-toluenesulfonic acid and benzenesulfonic acid, preferably hydrochloric acid, sulfonic acid and p-toluenesulfonic acid.

17. The method according to claim 15, wherein said buffer is selected from at least one of the following solutions: citrate buffer, acetate buffer, phosphate buffer, citrate Flush and phthalate buffer.

The rasagiline transdermal patch according to any one of claims 1 to 13 for treating or preventing Parkinson's disease, Alzheimer's disease, depression, pediatric hyperactivity disorder, restless legs syndrome , the use of multiple sclerosis and withdrawal syndrome.