WO2009152777A1 - Patch transdermique stable et à libération prolongée de rasagiline et procédé de préparation associé - Google Patents

Patch transdermique stable et à libération prolongée de rasagiline et procédé de préparation associé Download PDF

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Publication number
WO2009152777A1
WO2009152777A1 PCT/CN2009/072352 CN2009072352W WO2009152777A1 WO 2009152777 A1 WO2009152777 A1 WO 2009152777A1 CN 2009072352 W CN2009072352 W CN 2009072352W WO 2009152777 A1 WO2009152777 A1 WO 2009152777A1
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Prior art keywords
acid
rasagiline
patch
transdermal patch
derivatives
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PCT/CN2009/072352
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English (en)
Chinese (zh)
Inventor
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
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Publication of WO2009152777A1 publication Critical patent/WO2009152777A1/fr

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Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • 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

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • MAOB monoamine oxidase B
  • the primary outcome measure was the change in the score for the Unified Parkinson's Disease Comprehensive Rating Scale (UPDRS).
  • UPDRS Unified Parkinson's Disease Comprehensive Rating Scale
  • 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.
  • rasagiline is similar to other anti-shock palsy drugs, the incidence of toxic side effects (mainly including insomnia, nausea, and hallucinations) is lower.
  • rasagiline is very potent, when it is administered orally, eating peaks will reduce the peak concentration of blood by 60%.
  • 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.
  • 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
  • MAOB monoamine oxidase B
  • cheese reaction taking irreversible non-selection
  • 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.
  • 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.
  • 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.
  • acidic conditions such as a pH of not more than 7.0, especially a pH of not more than 6.5
  • 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.
  • the pH of the patch is preferably not less than 3.0 to not more than
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the area of the hole The patch area is 1:2 ⁇ 10.
  • the pore area of the rasagiline transdermal patch patch area
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a method of preparing the rasagiline transdermal patch of any of the above embodiments, comprising:
  • 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.
  • 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
  • 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.
  • the above-described rasagiline transdermal patch has an application area of from 1 cm 2 to 50 cm 2 via skin treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • the above-mentioned rasagiline transdermal patch may be added with a pH adjuster or a buffer.
  • 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.
  • 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.
  • 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.
  • 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.
  • the rasagiline transdermal patch comprises oxalate sulfonate of rasagiline.
  • 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
  • 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.
  • 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.
  • polyvinylpyrrolidone may preferably be of the K90D type
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • the rasagiline transdermal patch of the present invention can also be controlled release release by controlling the release area.
  • 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.
  • 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.
  • 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.
  • rasagiline or a pharmaceutically acceptable salt thereof such as rasagiline sulfonate
  • an alkali regulator such as sodium hydroxide or triethanolamine
  • 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
  • Rasagiline free base is contained in the main drug content of 7.0 ⁇ 8.0 main drug - -
  • 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.
  • 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.
  • rasagiline 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.
  • rasagiline patch may exist in various forms other than the free base.
  • the patch can be prepared in different ways.
  • rasagiline when it 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.
  • an organic solvent such as ethanol, propylene glycol or glycerin
  • the skin penetration enhancer or the like is mixed to form a patch.
  • rasagiline or a pharmaceutically acceptable salt thereof when it 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.
  • 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.
  • a patch may be prepared by a melt method.
  • rasagiline and refined polyethylene glycol 4000 are uniformly mixed and heated to 40 ⁇ 60 ° C to melt.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • 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.
  • an automatic coater Shanghai Yukai Co., Ltd., type TB-04
  • 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
  • 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.
  • 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.
  • 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, - -
  • 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.
  • 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.
  • polyvinylpyrrolidone PVP-K90D ISP Technologies, INC
  • 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.
  • 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.
  • 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 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
  • 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.
  • 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.
  • 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).
  • 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.
  • 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/ ⁇ AUC(ot) number
  • 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.

Abstract

L’invention concerne un patch transdermique de rasagiline ou de sels pharmaceutiquement acceptables correspondants, permettant de traiter ou de prévenir les maladies du système nerveux. L’invention porte en particulier sur un patch transdermique stable et à libération prolongée de rasagiline, ledit patch contenant de la rasagiline ou des sels pharmaceutiquement acceptables correspondants et au moins une matrice en polymère hydrophile, la valeur du pH du patch étant en outre inférieure à 7.0. Le patch présente une stabilité prédominante et permet aisément de contrôler les caractéristiques liées à la libération transdermique de la rasagiline.
PCT/CN2009/072352 2008-06-20 2009-06-19 Patch transdermique stable et à libération prolongée de rasagiline et procédé de préparation associé WO2009152777A1 (fr)

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US7855233B2 (en) 2009-01-23 2010-12-21 Teva Pharmaceutical Industries, Ltd. Citrate salt of Rasagiline
US7968749B2 (en) 2008-06-19 2011-06-28 Teva Pharmaceutical Industries, Ltd. Process for preparing and drying solid rasagiline base
WO2011139420A3 (fr) * 2010-04-30 2012-01-12 Teikoku Pharma Usa, Inc. Compositions transdermiques de propynylaminoindane
US8188149B2 (en) 2007-09-17 2012-05-29 Teva Pharmaceutical Industries, Ltd. Use of R(+)-N-propargy1-1-aminoindan to treat or prevent hearing loss
EP2494966A1 (fr) * 2009-10-29 2012-09-05 Chongqing Pharmaceutical Research Institute Co., Ltd. Composition stable de rasagiline
US8809310B2 (en) 2006-02-21 2014-08-19 Teva Pharmaceutical Industries, Ltd. Use of rasagiline for the treatment of multiple system atrophy
US8946300B2 (en) 2006-04-03 2015-02-03 Teva Pharmaceutical Industries, Ltd. Use of rasagilline for the treatment of restless legs syndrome
US9119799B2 (en) 2011-03-24 2015-09-01 Teikoku Pharma Usa, Inc. Transdermal compositions comprising an active agent layer and an active agent conversion layer
US9205061B2 (en) 2012-11-02 2015-12-08 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions
US9913812B2 (en) 2011-11-09 2018-03-13 Teikoku Pharma Usa, Inc. Methods for the treatment of skin neoplasms

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CN103315983B (zh) * 2012-12-20 2015-06-03 上海中西制药有限公司 一种雷沙吉兰制剂及其制备方法
CN104510628A (zh) * 2013-09-27 2015-04-15 金红叶纸业集团有限公司 生活用纸
CN116077419B (zh) * 2023-02-24 2023-10-27 丽珠集团新北江制药股份有限公司 一种犬用盐酸司来吉兰透皮吸收剂及其制备方法
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US8809310B2 (en) 2006-02-21 2014-08-19 Teva Pharmaceutical Industries, Ltd. Use of rasagiline for the treatment of multiple system atrophy
US8946300B2 (en) 2006-04-03 2015-02-03 Teva Pharmaceutical Industries, Ltd. Use of rasagilline for the treatment of restless legs syndrome
US8188149B2 (en) 2007-09-17 2012-05-29 Teva Pharmaceutical Industries, Ltd. Use of R(+)-N-propargy1-1-aminoindan to treat or prevent hearing loss
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US7968749B2 (en) 2008-06-19 2011-06-28 Teva Pharmaceutical Industries, Ltd. Process for preparing and drying solid rasagiline base
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US9017723B2 (en) 2010-04-30 2015-04-28 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions
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US9597301B2 (en) 2010-04-30 2017-03-21 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions
US9119799B2 (en) 2011-03-24 2015-09-01 Teikoku Pharma Usa, Inc. Transdermal compositions comprising an active agent layer and an active agent conversion layer
US9913812B2 (en) 2011-11-09 2018-03-13 Teikoku Pharma Usa, Inc. Methods for the treatment of skin neoplasms
US9205061B2 (en) 2012-11-02 2015-12-08 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions
US9827207B2 (en) 2012-11-02 2017-11-28 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions
US10918607B2 (en) 2012-11-02 2021-02-16 Teikoku Pharma Usa, Inc. Propynylaminoindan transdermal compositions

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