WO2024040860A1 - Système d'administration de médicament transdermique de rotigotine inhibant la cristallisation, son procédé de préparation et son utilisation - Google Patents

Système d'administration de médicament transdermique de rotigotine inhibant la cristallisation, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024040860A1
WO2024040860A1 PCT/CN2023/071273 CN2023071273W WO2024040860A1 WO 2024040860 A1 WO2024040860 A1 WO 2024040860A1 CN 2023071273 W CN2023071273 W CN 2023071273W WO 2024040860 A1 WO2024040860 A1 WO 2024040860A1
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Prior art keywords
rotigotine
delivery system
povidone
adhesive
matrix layer
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PCT/CN2023/071273
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English (en)
Chinese (zh)
Inventor
唐俭生
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新领医药技术(深圳)有限公司
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Priority to CN202380009081.9A priority Critical patent/CN117120095A/zh
Publication of WO2024040860A1 publication Critical patent/WO2024040860A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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

Definitions

  • the present invention relates to a system for transdermal drug delivery. More specifically, the present invention relates to a transdermal drug delivery system comprising rotigotine or a pharmaceutically acceptable salt thereof that inhibits crystallization, and a preparation method and use thereof.
  • the transdermal route of drug administration is a route of drug administration that is superior to the oral route of drug administration. It maintains the drug concentration in the blood at a constant level by continuously delivering drugs to the systemic blood system.
  • the transdermal delivery route not only reduces the fluctuations in drug concentration in the blood between peaks and troughs, but also avoids the first-pass effect.
  • the transdermal route of administration avoids direct contact between drugs and excipients and the gastrointestinal system, side effects such as nausea and vomiting that are often associated with the oral route of administration are significantly reduced or eliminated.
  • Another advantage of the transdermal route of administration is that it is not affected by diet. Administration can be easily terminated when necessary by removing the transdermal patch from the skin. Furthermore, transdermal patches improve patient compliance by reducing dosing frequency. This is particularly important for elderly patients and pediatric patients.
  • transdermal patch preparations include, but are not limited to, drug reservoir type patches and matrix type patches.
  • Drug reservoir-type patch formulations are patch formulations in which the drug is contained in a reservoir with a drug-permeable substrate surface
  • matrix-type patch formulations are patch formulations in which the drug is dissolved or dispersed in a polymer matrix layer. Both types of designs also typically include a backing layer and a release film layer that is removed before use.
  • patches often contain penetration enhancers and adhesive layers.
  • transdermal delivery has enabled many drugs to be effectively administered via the transdermal route.
  • These advances include the development of many physical methods to increase skin permeability and facilitate transdermal drug delivery, e.g. Use iontophoresis, electroporation, ultrasound, or microneedling.
  • drugs that can be effectively and safely administered through the skin for 7 days or longer without causing skin adhesion, skin irritation, or sensitization are still limited.
  • Rotigotine is a compound with the following structure (-)-5,6,7,8-tetrahydro-6-[propyl-[2-( 2-Thienyl)ethyl]-amino]-1-naphthol (INN):
  • Rotigotine is a non-ergolinic D1/D2/D3 dopamine receptor agonist. It has similar receptor characteristics to dopamine in structure, but has higher receptor affinity. Compared with other non-ergot dopamine agonists, rotigotine has significant D1 activity, which contributes to stronger physiological effects. Compared with ergolinic compounds, rotigotine has a very low affinity for the 5HT2B receptor and therefore has a low risk of causing fibrosis. Actions on non-dopaminergic receptors (eg, 5- HT1A agonism and A2B antagonism) may contribute to other beneficial effects, such as antidyskinetic activity, neuroprotective activity, and antidepressant effects.
  • non-dopaminergic receptors eg, 5- HT1A agonism and A2B antagonism
  • Rotigotine is disclosed as a treatment for patients with Parkinson's disease (described in WO 2002/089777), Parkinson's plus syndrome (described in WO 2005/092331), depression (described in WO 2005/092331) 009424) and restless legs syndrome (described in WO 2003/092677) as well as treatment or prevention of dopaminergic neuron loss (described in WO 2005/063237) and pain treatment (described in PCT/EP2007/005381 description) active agent.
  • compositions containing rotigotine include: transdermal therapeutic systems or patches (TTS) (described inter alia in WO 99/49852), depot forms (described in WO 02/15903), Iontophoresis devices (described in WO 2004/050083) and intranasal formulations (described in WO 2005/063236).
  • TTS transdermal therapeutic systems or patches
  • WO 02/15903 depot forms
  • Iontophoresis devices described in WO 2004/050083
  • intranasal formulations described in WO 2005/063236
  • TTS transdermal therapeutic systems
  • WO 94/07468 discloses a TTS containing rotigotine hydrochloride as the active substance in a two-phase matrix consisting essentially of a hydrophobic polymer material as a continuous phase and dispersed hydrophilic materials contained therein. A phase is formed, the hydrophilic phase containing essentially the drug and hydrated silica. Silica is said to increase the maximum possible loading of TTS on the hydrophilic salt. Furthermore, the formulations of WO 94/07468 usually contain additional hydrophobic solvents, penetration-promoting substances, dispersants and especially emulsifiers for emulsifying the aqueous solution of the active ingredient in the lipophilic polymer phase. TTS prepared using such a system have been tested in healthy subjects and Parkinson's disease patients. However, satisfactory plasma levels of the drug were not achieved.
  • TTSs have been described in WO 99/49852.
  • Various other transdermal therapeutic systems have been described in WO 99/49852.
  • the TTS used in this patent application consists of a liner layer that is inert with respect to the matrix components, a self-adhesive matrix layer containing an effective amount of rotigotine or rotigotine hydrochloride, and a protective film that is to be removed before use.
  • the matrix system consists of a non-aqueous polymeric adhesive system based on acrylates or silicones.
  • TTS for the delivery of rotigotine are disclosed, for example, in EP1 256 339 and WO 2004/012730. These systems use a mixture of at least one high-viscosity and at least one medium-viscosity amine-compatible silicone pressure-sensitive adhesive as the primary adhesive component of the self-adhesive matrix. They will provide better flux rates and adequate rotigotine plasma levels.
  • the amorphous state of pharmaceutical substances in pharmaceutical dosage forms including transdermal systems.
  • the amorphous form is only relatively Stable and easily converted into crystals.
  • the self-adhesive matrix as a whole represents a relatively stable solid dispersion.
  • US 9925150B2 discloses a solid dispersion, which is composed of a silicone pressure-sensitive adhesive as a dispersant and a soluble polyvinylpyrrolidone and rotigotine as a dispersed phase, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is between In the range of about 9:3.5 to about 9:6.
  • the solid dispersion was found to be unstable as rotigotine frequently crystallized out of the solid dispersion. Additionally, the silicone pressure-sensitive adhesive base did not adhere as well to the skin as expected.
  • An object of the present invention is to provide a matrix-type rotigotine transdermal delivery system that inhibits crystallization, which can inhibit the crystallization of rotigotine in the pressure-sensitive adhesive matrix layer. Achieve stable and sustained delivery of rotigotine or a pharmaceutically acceptable salt thereof at a therapeutically effective amount of blood concentration over an extended period of time.
  • An object of the present invention is to provide a method for preparing a matrix type rotigotine transdermal delivery system.
  • the method heats a wet mixture of rotigotine and pressure-sensitive adhesive to above room temperature and then coats it to produce an adhesive matrix patch that is free of rotigotine crystals. If the wet mixture is not heated, rotigotine will form crystals from the matrix.
  • An object of the present invention is to provide a matrix-type rotigotine transdermal delivery system that inhibits crystallization.
  • the matrix layer is composed of rotigotine, a stabilizer that inhibits drug crystallization, and a polybutylene adhesive.
  • the matrix layer composed of a stabilizer that inhibits drug crystallization and a styrene-isoprene adhesive has better skin adhesion.
  • Another object of the present invention is to provide a method for treating or preventing Parkinson's, Parkinson's superimposed syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss, which includes administering to a subject in need A therapeutically effective amount of a matrix-type crystallization-inhibiting rotigotine transdermal delivery system is administered.
  • Another object of the present invention is to provide a therapeutically effective amount of a matrix type rotigotine transdermal delivery system that inhibits crystallization in the preparation of a medicament for the treatment or prevention of diseases sensitive to the effects of dopamine receptor agonists. the use of.
  • Another object of the present invention is to provide a therapeutically effective amount of a matrix-type rotigotine transdermal delivery system that inhibits crystallization in the preparation of a medicament for the treatment or prevention of diseases that are sensitive to the effects of rotigotine. use.
  • Another object of the present invention is to provide a therapeutically effective amount of a matrix-type rotigotine transdermal delivery system that inhibits crystallization and is prepared for the treatment or prevention of Parkinson's disease, Parkinson's superimposed syndrome, depression, and restlessness. Use in medicines for leg syndrome, pain, and dopaminergic neuron loss.
  • a rotigotine transdermal delivery system which includes:
  • a matrix layer which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in an amorphous state in the matrix layer, a stabilizer that inhibits drug crystallization, and a pressure-sensitive adhesive;
  • the inhibitory drug crystallization comprises insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone Ketone CL-SF.
  • the stabilizer that inhibits drug crystallization further contains soluble povidone on the basis of insoluble cross-linked povidone, and the soluble povidone is preferably povidone K30, povidone K90, povidone K12 , one or more of povidone K17, povidone K25, prastone K29/32, and copovidone VA64.
  • the weight ratio of rotigotine to insoluble povidone is no higher than 9:40, preferably 9:1-9:24, 9:5-9:22.8, 9:5, 9:6.8, 9:8, 9:10, 9:12, 9:18, 9:20, 9:21, 9:22.8, 9:24.
  • the weight ratio of rotigotine to soluble povidone is 9:0.5-9:4, preferably 9:1, 9:2, 9:3, 9:4.
  • the stabilizer that inhibits drug crystallization includes polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, prasitone K29/32, Copovidone VA64, crospovidone CL-M, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate , hydroxypropyl betaide, ⁇ , ⁇ , ⁇ cyclodextrin, one or more of chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan.
  • polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer preferably povidone K30, povidone K90, prasitone K29/32, Copovidon
  • the matrix layer further contains other pharmaceutically acceptable excipients.
  • Other pharmaceutically acceptable excipients may be one or more of skin penetration enhancers, thickeners, and cohesion-promoting additives.
  • the matrix layer includes the following components relative to the total weight of the matrix layer:
  • the total dosage of each component in the matrix layer is 100%.
  • the matrix layer further includes a cohesion-promoting additive selected from one or more of the following:
  • Carbohydrate polymer preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl beta German, ⁇ , ⁇ , ⁇ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;
  • Acrylic or methacrylic polymer preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55.
  • the pressure-sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, benzene adhesives, One or more of ethylene-butadiene-styrene copolymer adhesive, silicone adhesive, and acrylic-copolysiloxane copolymer adhesive;
  • the acrylic adhesive is selected from Henkel's Duro-Tak adhesive 387-2051, 387-2054, 387-2353, 87-235A, 87-2852, 87-2074, 87-2677, 387-2516, 387-2287, 387-4287, 387-2510, crosslinked 387-2510, 87-900A, 87-9301, 87-4098, 87-2194, Gelva GMS788, Gelva GMS 9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industry Co., Ltd.);
  • the polyisobutylene adhesive is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene and mineral oil tackifier from Ineos ;
  • the silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4202, 7-4300, 7-4302, 7-4400 and 7-4500, 7-4502, 7- 4600Bio-PSA SR7-4400,SRS7-4500,SRS7-4600;
  • the acrylic-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA 7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, The solvent is selected from one or more of n-heptane, ethyl acetate, toluene or hot melt.
  • the content of rotigotine or a pharmaceutically acceptable salt thereof is 5% to 20%, preferably 5% to 15%, or 5% to 12% of the total weight of the matrix layer.
  • the content of the stabilizer that inhibits drug crystallization is 6% to 40% of the total weight of the matrix layer, preferably 6% to 30%, 6% to 20%, 6.7%-20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.
  • the content of the pressure-sensitive adhesive is 35% to 90% of the total weight of the matrix layer, preferably 40% to 90%, 70% to 90%, 65%, 70%, 75%, 80%, 90%.
  • the tackifier is selected from silicone oil, mineral oil, polybutene, terpenes, and mixtures thereof, preferably light mineral oil. In some embodiments, the amount of tackifier is 0-50%, preferably 0-30%, 0-28% of the total weight of the matrix layer.
  • the weight ratio of rotigotine to the tackifier is 9:25-9:40, preferably 9:30-9:35.
  • the content of the skin penetration enhancer is 0 to 30% of the total weight of the matrix layer, preferably 5-30%, 5-24%, 10-20%, 12.5-20%.
  • the skin penetration enhancer includes optional surfactants.
  • the rotigotine transdermal delivery system may further include structures such as a skin contact adhesive layer, a semipermeable membrane, or an organic fabric layer.
  • a method for the aforementioned rotigotine transdermal delivery system comprising the following steps:
  • Step 1 Dissolve the stabilizer in the solvent and mix for 0.1 to 24 hours;
  • Step 2 Add rotigotine or its pharmaceutically acceptable salt, mix and dissolve until the rotigotine or its pharmaceutically acceptable salt is dispersed in a non-crystalline state;
  • Step 3 Add pressure-sensitive adhesive and mix evenly to obtain a wet drug mixture
  • Step 4 Coat the wet drug mixture on the release film
  • Step 5 Dry to remove the solvent to obtain a release film/matrix layer laminate
  • Step 6 Laminate the matrix layer to the backing layer.
  • the solvent in step 1 includes but is not limited to one or more of toluene, ethanol, isopropyl alcohol, dimethylacetamide, and dimethyl sulfoxide, preferably toluene, ethanol, isopropanol, Propanol or its mixed solvents.
  • step 2 includes heating to 35-65°C to bring the drug into solution.
  • the heating temperature in step 2 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.
  • step 3 is to add a pressure-sensitive adhesive heated to 35-65°C and mix evenly to obtain a wet drug mixture.
  • the heating temperature in step 3 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.
  • step 4 is to coat the wet drug mixture on the release film while maintaining the temperature at 35-65°C.
  • the heating temperature in step 4 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.
  • a therapeutically effective amount of a rotigotine transdermal delivery system according to the foregoing is provided in the preparation of a medicament for treating or preventing diseases that are sensitive to the effects of dopamine receptor agonists. the use of.
  • the disease is a disease that is sensitive to the effects of rotigotine.
  • the disease is Parkinson's disease, Parkinson's disease superimposed syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss.
  • a method for treating or preventing diseases that are sensitive to the effects of dopamine receptor agonists which includes administering to a subject in need a therapeutically effective amount of the aforementioned rotigool transdermal drug delivery system.
  • the disease is a disease that is sensitive to the effects of rotigotine.
  • the disease is Parkinson's disease, Parkinson's disease superimposed syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss.
  • the rotigotine transdermal delivery system is administered every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, every 28 days.
  • the rotigotine transdermal delivery system delivers from about 1 mg to about 18 mg of rotigotine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject per day, preferably daily. About 2 mg to about 12 mg of rotigotine base or a pharmaceutically acceptable salt thereof is added to the blood circulation system of the subject.
  • the term "pharmaceutically acceptable salt” means a salt suitable for use in contact with a subject (e.g., a human subject) without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, with reasonable benefit/risk ratio and are effective for their intended use.
  • “Pharmaceutically acceptable salts” as described in the present invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final isolation and purification of the compound, or by converting the purified compound in the free base form (eg rotigotine) is prepared by reacting alone with a suitable organic or inorganic acid and isolating the salt thus formed.
  • the term "therapeutically effective amount” means an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorate or eliminate one or more symptoms of a particular disease, disorder, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder, or disorder described herein.
  • the term “about” means plus or minus 10% of the indicated number.
  • “about 10%” may represent a range of 9% to 11%, and “about 1” may represent 0.9-1.1.
  • treatment refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or in the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis.
  • insoluble cross-linked povidone is a high-molecular water-insoluble polymer obtained by cross-linking reaction of N-vinyl-2-pyrrolidone. It is a white or nearly white powder, odorless, flowing It has good properties and is insoluble in water and various solvents, as well as in strong acids or alkalis.
  • insoluble crospovidone include CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.
  • the term "backing layer” serves as the upper surface of a transdermal patch and serves as the primary structural element that provides flexibility to the patch.
  • the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions.
  • the backing layer is preferably made from a sheet or film of flexible elastic material.
  • the backing layer is preferably air-impermeable.
  • the backing layer used in the patch of the present invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement. Non-occlusive backing layers allow the area to breathe (i.e. promote water vapor transmission across the skin surface), whereas occlusive backing layers reduce air/vapor penetration.
  • the backing layer of matrix-type transdermal delivery systems is occlusive.
  • the backing layer contains synthetic polymers such as polyolefins, polyesters, polyethylene, polyvinylidene chloride and polyurethanes.
  • the thickness of the backing layer is from about 0.5 mil to about 5 mils; more preferably, the thickness of the backing layer is from about 1 mil to about 3 mils.
  • the oxygen transmission rate is from about 2 cc/m/24hr to about 100 cc/m/24hr.
  • the MVTR is from about 0.1 g/m/24hr to about 50g/m/24hr, more preferably, the MVTR is from about 0.3g/m/24hr to about 30g/m/24hr.
  • the backing layer is an approximately 2.0 mil thick layer of occlusive polyester film (commercially available, e.g., Scotchpak 9733, Scotchpak 9735, and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul Minn.).
  • Scotchpak 9733 consists of polyester and medium density polyethylene/ethylene vinyl acetate heat sealable laminates that are translucent, conformable, occlusive and heat sealable.
  • the backing layer includes a laminate including an aluminum foil layer between polymer film layers, such as Scotchpak 9738 and Scotchpak 1109.
  • the aluminum layer prevents light from coming into contact with the photosensitive rotigotine.
  • release liner includes, but is not limited to, silicone-coated polyester release liners available from many suppliers, fluoropolymer-coated polyester release liners from 3M, and fluorosilicone-coated polyester Isolation liner.
  • PVP K90 povidone K90
  • Crospovidone crospovidone CL-M
  • Ascorbyl Palmitate ascorbyl palmitate
  • Sodium Metasulfite sodium metabisulfite
  • Alpha-dl-tocopherol ⁇ -dl-tocopherol
  • BHT Butylated hydroxytoluene
  • Rotigotine rotigotine
  • Bio-PSA 7-4502 is a pressure-sensitive adhesive
  • Duro-Tak 387-2287 is a pressure-sensitive adhesive
  • Oppanol B12 SFN polyisobutylene adhesive Agent
  • Oppanol N100 Polyisobutylene Adhesive
  • Bio-PSA 7-4502 is a pressure sensitive adhesive.
  • the patch samples of Comparative Examples 7 to 11 were prepared using a method similar to Comparative Example 6. Weigh the components of each composition according to Table 2 and prepare the prescription. The amount of insoluble crospovidone was increased to 10%, 13%, 16.65%, 18% and 20% respectively. The patch samples of Comparative Examples 7 to 11 all formed crystals, but as the amount of insoluble crospovidone increased, the formation of crystals became more and more delayed. In these comparative examples, the wet mixture was maintained at room temperature, ie, was not heated above room temperature, to maintain dissolution of rotigotine in the wet mixture.
  • Example 5 was prepared using a method similar to Example 4. As shown in Table 2, no crystals were observed on the patch samples on the 10th day of storage at 60°C and after 1 month of storage at 40°C. In this example, there is no soluble povidone and the ratio of rotigotine to insoluble crospovidone is 7.5:20 or 9:24. In this example, the wet mixture was maintained at 50°C to maintain dissolution of rotigotine in the wet mixture prior to coating.
  • the weight ratio of rotigotine to crospovidone is 9:3
  • the weight ratio of rotigotine to insoluble crospovidone is 9:18.
  • Example 10 was prepared using the same method as Example 9. As shown in Table 3, no crystals were observed in the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this example, the weight ratio of rotigotine to insoluble crospovidone is 9:22.8.

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Abstract

La présente invention concerne un système d'administration de médicament transdermique de rotigotine inhibant la cristallisation de médicament, un procédé de préparation de celui-ci et une utilisation de celui-ci. La rotigotine ou un sel pharmaceutiquement acceptable de celle-ci dans le système d'administration de médicament est dispersé de manière stable dans une couche de matrice d'un adhésif sensible à la pression dans un état amorphe, de sorte que la formation de cristaux de rotigotine peut être inhibée, de façon à obtenir une libération stable du médicament.
PCT/CN2023/071273 2022-08-24 2023-01-09 Système d'administration de médicament transdermique de rotigotine inhibant la cristallisation, son procédé de préparation et son utilisation WO2024040860A1 (fr)

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CN202380009081.9A CN117120095A (zh) 2022-08-24 2023-01-09 抑制结晶的罗替高汀透皮给药系统及其制备方法和用途

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