WO2023134618A1 - Timbre transdermique pour inhiber la cristallisation médicamenteuse, et son procédé de préparation - Google Patents

Timbre transdermique pour inhiber la cristallisation médicamenteuse, et son procédé de préparation Download PDF

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WO2023134618A1
WO2023134618A1 PCT/CN2023/071264 CN2023071264W WO2023134618A1 WO 2023134618 A1 WO2023134618 A1 WO 2023134618A1 CN 2023071264 W CN2023071264 W CN 2023071264W WO 2023134618 A1 WO2023134618 A1 WO 2023134618A1
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drug
delivery system
povidone
acid
crystallization
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PCT/CN2023/071264
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English (en)
Chinese (zh)
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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 CN202380008871.5A priority Critical patent/CN117157062A/zh
Publication of WO2023134618A1 publication Critical patent/WO2023134618A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the invention relates to a transdermal drug delivery system. More specifically, the present invention relates to a transdermal drug delivery system containing a drug or a pharmaceutically acceptable salt thereof, its preparation method and use.
  • the transdermal drug delivery route is a drug delivery route superior to the oral drug delivery route, which keeps the drug concentration in the blood at a constant level by continuously delivering the drug to the blood system throughout the body.
  • the transdermal route of administration not only reduces the fluctuation of the drug concentration in the blood between peaks and valleys, but also avoids the first-pass effect.
  • the transdermal route of administration avoids the direct contact of the drug and the excipients with the gastrointestinal system, it significantly reduces or eliminates side effects such as nausea and vomiting often associated with the oral route of administration.
  • Another advantage of the transdermal route of delivery is that it is not affected by diet. Administration can be easily terminated by removing the transdermal patch from the skin if necessary.
  • transdermal patches improve patient compliance by reducing the frequency of dosing. This is especially important for elderly patients and pediatric patients.
  • transdermal patch formulations include transdermal patch formulations.
  • transdermal drug delivery patch preparations include but are not limited to drug reservoir type patches and matrix type patches.
  • a drug reservoir type patch preparation is a patch preparation that contains a drug in a reservoir having a drug-permeable substrate surface
  • a matrix type patch preparation is a patch preparation that dissolves or disperses a drug in a polymer matrix layer.
  • Both types of designs typically also include a backing layer and a release liner layer that is removed prior to use.
  • patches typically also contain a penetration enhancer and an adhesive layer.
  • transdermal drug delivery has enabled many drugs to be effectively administered through the transdermal route.
  • These advances include the development of many physical methods to increase skin permeability and facilitate transdermal drug delivery, eg. Using iontophoresis, electroporation, ultrasound, or microneedling.
  • drugs that can be effectively and safely administered continuously through the skin for 7 days or more without causing skin adhesion, skin irritation, or sensitization.
  • transdermal therapeutic systems TTS
  • WO 99/49852 disclose the transdermal delivery system of rotigotine
  • US 5891461 and 2007/0148218A1 disclose the olanzapine transdermal delivery system .
  • An object of the present invention is to provide a matrix type drug transdermal drug delivery system which can have good skin adhesive properties over a period of time for sustained delivery of the drug or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a matrix type drug transdermal drug delivery system which is not irritating and/or sensitizing to the skin during the period of sustained delivery of the drug or a pharmaceutically acceptable salt thereof.
  • One object of the present invention is to provide a method for preparing a matrix-type transdermal drug delivery system.
  • the method heats a wet mixture of drug and pressure sensitive adhesive to above room temperature and then coats to produce an adhesive matrix patch free of drug crystals. If the wet mixture is not heated, the drug will form crystals from the matrix.
  • Another object of the present invention is to provide a method of treating or preventing a disease, which comprises administering a therapeutically effective amount of a matrix-type transdermal drug delivery system to a subject in need.
  • Another object of the present invention is to provide a therapeutically effective dose matrix-type transdermal drug delivery system used in the preparation of medicines for treating or preventing diseases.
  • a transdermal drug delivery system comprising:
  • a matrix layer comprising a drug or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting crystallization of the drug, and a pressure-sensitive adhesive;
  • the stabilizer that inhibits drug crystallization is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer (preferably povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, copovidone VA64, crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL -SF), hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betad, alpha, ⁇ , ⁇ cyclodextrin, one or more of chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or carrageenan.
  • the drug crystallization inhibiting stabilizer is selected from an insoluble drug crystallization inhibiting stabilizer, a soluble drug crystallization inhibiting stabilizer, or a combination thereof.
  • the insoluble drug crystallization inhibiting stabilizer is selected from insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F , Crospovidone CL-SF.
  • the drug crystallization-inhibiting stabilizer further comprises a soluble drug crystallization-inhibiting stabilizer on the basis of an insoluble drug crystallization-inhibiting stabilizer; preferred soluble drug crystallization-inhibiting stabilizers are selected from soluble povidone , more preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, and copovidone VA64.
  • the matrix layer further includes other pharmaceutically acceptable excipients, and the other pharmaceutically acceptable excipients are preferably one or more of skin penetration enhancers, viscosity enhancers, and cohesion-promoting additives.
  • the matrix layer comprises the following components relative to the total weight of the matrix layer:
  • the dosage of the drug or its pharmaceutically acceptable salt is 3-30%;
  • the dosage of the stabilizer for inhibiting drug crystallization is 1.5-90%;
  • the amount of each component in the matrix layer is 100% in total.
  • the matrix layer further comprises a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following:
  • Carbohydrate polymers preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylbeta De, ⁇ , ⁇ , ⁇ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;
  • Acrylic or methacrylic polymers 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 One or more of ethylene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic acid-copolysiloxane copolymer adhesives;
  • 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 binder 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 tackifiers from Ineos ;
  • the silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400 and 7-4500,7-4600Bio-PSA SR7-4400, SRS7-4500, SRS7 -4600;
  • the acrylic acid-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 and toluene or hot melt.
  • the transdermal drug delivery system according to any one of claims 1-9, wherein the content of the drug or a pharmaceutically acceptable salt thereof is 5% to 20% of the total weight of the matrix layer, Preferably 5% to 15%, or 5% to 12%, 7.5%.
  • the content of the stabilizer for inhibiting drug crystallization is 6% to 40%, preferably 6% to 30%, 6% to 20%, 6.7%-20%, 6.70%, 8.2% of the total weight of the matrix layer. %, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.
  • the content of the insoluble drug crystallization-inhibiting stabilizer is 5 to 40% of the total weight of the matrix layer, preferably 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35%, 40%, 45%;
  • the preferred insoluble stabilizer for inhibiting drug crystallization is selected from insoluble crospovidone CL-M, crospovidone CL, crosslinked Povidone CL-F, crospovidone CL-SF.
  • the content of the soluble stabilizer for inhibiting drug crystallization is 2 to 40% of the total weight of the matrix layer, preferably 2-30%, 5-30%, 5-24%, 10-20%, 12.5% -20%, 2.5%, 3.4%, 4%, 5%; preferred soluble stabilizers for drug crystallization are selected from soluble povidone, preferably povidone K30, povidone K90, povidone K12, povidone One or more of povidone K17, povidone K25, plastone K29/32, and copovidone VA64.
  • the content of the pressure sensitive adhesive is 35% to 90%, preferably 40% to 80%, 35 to 90%, 45% to 65%, 65%, 70%, 75% of the total weight of the substrate layer. %, 80%, 90%.
  • the matrix layer further includes other pharmaceutically acceptable excipients, and the other pharmaceutically acceptable excipients are preferably one or more of skin penetration enhancers, viscosity enhancers, and cohesion-promoting additives.
  • the skin penetration enhancer includes one or more of C2 to C30 saturated or unsaturated fatty acids, surfactants, and laurocaprazine.
  • the C2 to C30 saturated or unsaturated fatty acid is selected from C2 to C20 saturated or unsaturated fatty acid, preferably one or more of oleic acid, isostearic acid or stearic acid.
  • the tackifier is selected from silicone oil, mineral oil, polybutene, terpene and mixtures thereof, preferably light mineral oil; further, the amount of tackifier is 0-50% of the total weight of the matrix layer , preferably 0-30%.
  • nonanol, isopropyl myristate, isopropyl palmitate, or lauryl lactate are absent from the matrix layer.
  • the drug is selected from the group consisting of Olanzapine, rotigotine, Donepezil, Almotriptan, Aripiprazole, Apixaban ( Apixaban), Asenapine, Baricigtinib, Bisoprolol, Blonanserin, Buprenorphine, Dextroamphetamine, Dextroamphetamine Dexmedetomidine, Eletriptan, Escitalopram, Frovatriptan, Granisetron, Indomethacin, Latex Lasmiditan, Meloxicam, Naratriptan, naproxen, Oxybutynin, Piroxicam, Pramipexole , rizatriptan, ropinirole, sumatriptan, tolubuterol, testosterone, and zolmitriptan, or their pharmaceutically acceptable of salt.
  • a method for preparing the aforementioned transdermal drug delivery system comprising the following steps:
  • Step 1 Dissolving the drug or its pharmaceutically acceptable salt in a solvent as premix A; preferably, the solvent includes but not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, One or more of dimethyl sulfoxide and ethyl acetate, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof.
  • the solvent includes but not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, One or more of dimethyl sulfoxide and ethyl acetate, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof.
  • Step 2 Mix the pressure-sensitive adhesive solution with the stabilizer for inhibiting drug crystallization to obtain premix B; the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizer for inhibiting drug crystallization, soluble stabilizer for inhibiting drug crystallization agent or combination thereof; mixing time is preferably from 0.1 hour to 24 hours.
  • Step 3 adding premix A to premix B to obtain a wet drug mixture, in which the drug or its pharmaceutically acceptable salt is dispersed in an amorphous state;
  • Step 4. coating the drug wet mixture on the release film
  • Step 5 drying to remove the solvent to obtain a release film/substrate layer laminate
  • Step 6 Laminate the substrate layer to the backing layer.
  • a method for preparing the aforementioned transdermal drug delivery system comprising:
  • Step 1 Dissolve the stabilizer that inhibits drug crystallization in a solvent and mix well; preferably, the solvent includes but is not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, acetic acid One or more of ethyl esters, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof.
  • the drug crystallization inhibiting stabilizer is selected from insoluble drug crystallization inhibiting stabilizers, soluble drug crystallization inhibiting stabilizers or combinations thereof.
  • the mixing time is preferably from 0.1 hour to 24 hours. ;
  • Step 2 Add the drug or its pharmaceutically acceptable salt, mix and dissolve until dispersed in an amorphous state;
  • Step 3 Add the pressure sensitive adhesive and mix well to obtain the drug wet mixture
  • Step 4 Coating the drug wet mixture on the release film
  • Step 5 drying to remove the solvent to obtain a release film/substrate layer laminate
  • Step 6 Laminate the substrate layer to the backing layer.
  • step 2 includes the step of heating to 30-65°C to make the drug in a dissolved state; the heating temperature is preferably 35-45, 45-55°C.
  • step 3 is to add a pressure-sensitive adhesive heated to 30-65°C and mix uniformly to obtain a drug wet mixture; the heating temperature is preferably 35-45, 45-55°C.
  • step 4 is coating the wet drug mixture on the release film at 30-65°C; the heating temperature is preferably 30-40, 35-45, 45-55°C.
  • a method for treating or preventing a disease comprises administering a therapeutically effective amount of the aforementioned transdermal drug delivery system to a subject in need.
  • a kind of olanzapine transdermal delivery system has the three-layer structure as shown in Figure 1, and it comprises:
  • a matrix layer which comprises olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer (ie, the aforementioned stabilizer for inhibiting drug crystallization), C 2 to C 30 Saturated or unsaturated fatty acids and pressure sensitive adhesives; and
  • the polymeric skin penetration enhancer is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, plastone K29/32 , Copovidone VA64, Crospovidone CL-M, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose Acetate Succinate, Hydroxypropylmethylcellulose Phthalate , hydroxypropyl betad, ⁇ , ⁇ , ⁇ cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or one or more of carrageenan.
  • the matrix layer comprises the following components relative to the total weight of the matrix layer:
  • the dosage of olanzapine or its pharmaceutically acceptable salt is 3-30%;
  • the dosage of the polymer skin penetration enhancer is 1.5-90%;
  • the amount of each component in the matrix layer is 100% in total.
  • the matrix layer also includes a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following:
  • Carbohydrate polymers preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylbeta De, ⁇ , ⁇ , ⁇ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;
  • Acrylic or methacrylic polymers preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55.
  • Polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone preferably povidone K30, povidone K90, plastone K29/32, copovidone VA64, or crospovidone CL-M.
  • the pressure sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives One or more of adhesives, styrene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives;
  • 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 binder 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, 7-4300, 7-4400 and 7-4500,7-4600Bio-PSA SR7-4400, SRS7-4500, SRS7 -4600;
  • the acrylic acid-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 and toluene or hot melt.
  • the content of olanzapine or a pharmaceutically acceptable salt thereof is 5% to 20%, preferably 5% to 15%, or 5% to 12% of the total weight of the stroma layer.
  • the content of the soluble polymer skin penetration enhancer is 5 to 40% of the total weight of the matrix layer, preferably 5-30%, 5-24, 10-20%, 12.5-20%.
  • the content of the insoluble polymer skin penetration enhancer is 5 to 60% of the total weight of the matrix layer, preferably 7.5-45%, 7.5-36, 15-36%.
  • the content of the pressure-sensitive adhesive is 40% to 80%, preferably 45% to 65%, of the total weight of the substrate layer.
  • the matrix layer further comprises one or more of small molecule skin penetration enhancers, antioxidants, and anti-skin irritation agents.
  • the small molecule skin penetration enhancer includes one or more of C2 to C30 saturated or unsaturated fatty acids, surfactants, and lauroazepine.
  • the C2 to C30 saturated or unsaturated fatty acid is selected from C2 to C20 saturated or unsaturated fatty acid, preferably one or more of oleic acid, isostearic acid or stearic acid.
  • the molar ratio of the C2 to C30 saturated or unsaturated fatty acid to olanzapine or a pharmaceutically acceptable salt thereof is 0.05 to 3.3, preferably 0.5 to 1.65.
  • an olanzapine transdermal drug delivery system which has a four-layer structure as shown in Figure 2, comprising:
  • a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, C2 to C30 saturated or unsaturated fatty acids and pressure-sensitive adhesive;
  • the skin contact adhesive layer includes, but is not limited to, acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer One or more of material adhesives, styrene-butadiene-styrene block copolymer adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives.
  • an olanzapine transdermal drug delivery system which has a five-layer structure as shown in Figure 3, comprising:
  • a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, C2 to C30 saturated or unsaturated fatty acids and pressure-sensitive Adhesive
  • the semi-permeable membrane comprises a continuous membrane or a microporous membrane.
  • the thickness of the semi-permeable membrane or woven fabric layer is from about 10 um to about 100 um, preferably from about 15 ⁇ m to about 50 ⁇ m.
  • the coating weight of the matrix layer is 100 to 1000 g/m 2 , preferably 100, 200, 300, 400, 500, 600 g/m 2 .
  • the skin penetration amount of the olanzapine or a pharmaceutically acceptable salt thereof within 7 days, 14 days, 21 or 28 days or longer is greater than or equal to 2 ⁇ g/ cm2 /hr, preferably greater than or equal to 3, 4, 5, 6, 7, 8, 9 or 10 ⁇ g/cm2/hr; or about 1 mg to about 18 mg of olanzapine or a pharmaceutically acceptable salt thereof per day
  • To the blood circulatory system of the subject preferably from about 2 mg to about 12 mg of olanzapine or a pharmaceutically acceptable salt thereof to the blood circulatory system of the subject.
  • the matrix layer does not contain nonanol, isopropyl myristate, isopropyl palmitate or lauryl lactate.
  • the solvent is selected from one or more of dimethylacetamide or dimethyl sulfoxide in the preparation process; ethanol, isopropanol or Other solvents act as co-solvents.
  • a method for preparing the olanzapine transdermal drug delivery system comprising the following steps:
  • Step 1 Dissolving olanzapine or a pharmaceutically acceptable salt thereof in a solvent as premix A;
  • Step 2 Mixing the pressure-sensitive adhesive solution with the insoluble polymer skin penetration enhancer, and optional small molecule skin penetration enhancer, surfactant, and antioxidant for 0.1 to 24 hours to obtain a premix B;
  • Step 3 adding premix A to premix B to obtain a drug wet mixture, in which olanzapine or a pharmaceutically acceptable salt thereof is dispersed in an amorphous state;
  • Step 4 Coating the drug wet mixture on the release layer
  • Step 5 Drying to remove the solvent to obtain a release layer/substrate layer laminate
  • Step 6 Laminate the substrate layer to the backing layer.
  • a method for preparing the olanzapine transdermal drug delivery system comprising the following steps:
  • Step 1 Dissolving the polymer penetration enhancer in a solvent, the solvent includes but not limited to dimethylacetamide, dimethyl sulfoxide or a mixed solvent; optionally add a small molecule skin penetration enhancer, surface active agents and antioxidants, mixed for 0.1 hour to 24 hours;
  • Step 2 Add olanzapine or its pharmaceutically acceptable acid addition salt, mix and dissolve until olanzapine or its pharmaceutically acceptable salt is dispersed in an amorphous state;
  • Step 3 Add the pressure sensitive adhesive and mix well to obtain the drug wet mixture
  • Step 4 Coating the drug wet mixture on the release layer
  • Step 5 Drying to remove the solvent to obtain a release layer/substrate layer laminate
  • Step 6 Laminate the substrate layer to the backing layer.
  • a method for preparing the olanzapine transdermal drug delivery system, when there is a skin contact adhesive component comprising the following steps:
  • Step 1 Prepare a release layer/matrix layer laminate according to any of the aforementioned steps 1 to 5, as a drug reservoir;
  • Step 2 Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates;
  • Step 3 Laminate the adhesive side of the skin contact adhesive layer/release layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.
  • a method for preparing the olanzapine transdermal drug delivery system when having a semipermeable membrane or a woven fabric layer, comprising the following steps:
  • Step 1 Prepare a release layer/matrix layer laminate according to any of the aforementioned steps 1 to 5, as a drug reservoir;
  • Step 2 Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates with an adhesive face layer laminated to a semi-permeable membrane or woven fabric layer;
  • Step 3 Laminate the semipermeable membrane or woven fabric layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.
  • a therapeutically effective amount of olanzapine transdermal drug delivery system prepared for the treatment or prevention of positive and negative symptoms of schizophrenia, or reducing chemotherapy-related and PARP inhibitor (PARPi)-induced The frequency and intensity of nausea and vomiting of the drug used in the drug.
  • PARPi chemotherapy-related and PARP inhibitor
  • said positive and negative symptoms of schizophrenia include psychosis, acute mania, and a mild anxiety state.
  • a method of treating or preventing positive and negative symptoms of schizophrenia or reducing the frequency and intensity of chemotherapy-related and PARP inhibitor (PARPi)-induced nausea and vomiting comprising administering A subject in need thereof is administered a therapeutically effective amount of the olanzapine transdermal delivery system.
  • PARPi chemotherapy-related and PARP inhibitor
  • said positive and negative symptoms of schizophrenia include psychosis, acute mania, and a mild anxiety state.
  • the olanzapine transdermal drug delivery system is administered once every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, every 28 days.
  • the olanzapine transdermal drug delivery system delivers about 1 mg to about 18 mg of olanzapine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject per day, preferably About 2 mg to about 12 mg of olanzapine base, or a pharmaceutically acceptable salt thereof, is delivered to the blood circulatory system of the subject.
  • the olanzapine transdermal drug delivery system of the present invention can continuously deliver olanzapine or a pharmaceutically acceptable salt thereof with high skin flux for about 1 day, about 3 days, about 7 days, about 10 days , about 14 days, about 21 days, about 28 days or longer.
  • the olanzapine transdermal drug delivery system of the present invention has long-lasting and good skin adhesion properties during the continuous delivery of olanzapine or a pharmaceutically acceptable salt thereof.
  • the olanzapine transdermal drug delivery system of the present invention has no irritation and sensitization to the skin during the continuous delivery of the olanzapine or a pharmaceutically acceptable salt thereof.
  • a rotigotine transdermal drug delivery system comprising:
  • a matrix layer comprising rotigotine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting 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 for inhibiting drug crystallization further comprises soluble povidone on the basis of insoluble crospovidone, and the soluble povidone is preferably povidone K30, povidone K90, povidone K12 , povidone K17, povidone K25, plastone K29/32, one or more of copovidone VA64.
  • the weight ratio of rotigotine to insoluble povidone is not 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 for inhibiting drug crystallization includes polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, and plastone K29/32, Copovidone VA64, Crospovidone CL-M, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose Acetate Succinate, Hydroxypropylmethylcellulose Phthalate , hydroxypropyl betad, ⁇ , ⁇ , ⁇ cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or one or more of carrageenan.
  • polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer preferably povidone K30, povidone K90, and plastone K29/32, Copovidone VA64, Crospovid
  • the matrix layer further contains other pharmaceutically acceptable excipients.
  • Other pharmaceutically acceptable excipients can be selected from one or more of skin penetration enhancers, thickeners, and cohesion-promoting additives.
  • the matrix layer comprises the following components relative to the total weight of the matrix layer:
  • the dosage of the stabilizer for inhibiting drug crystallization is 6-40%;
  • the amount of each component in the matrix layer is 100% in total.
  • the matrix layer further comprises a cohesion-promoting additive selected from one or more of the following:
  • Carbohydrate polymers preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylbeta De, ⁇ , ⁇ , ⁇ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;
  • Acrylic or methacrylic polymers 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 One or more of ethylene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic acid-copolysiloxane copolymer adhesives;
  • 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 binder 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 acid-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 and 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 for inhibiting drug crystallization is 6% to 40%, 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%, preferably 40% to 90%, 70% to 90%, 65%, 70%, 75%, 80%, 90%.
  • the tackifier is selected from silicone oils, mineral oils, polybutenes, terpenes, and mixtures thereof, preferably light mineral oils. In some embodiments, the amount of tackifier is 0-50%, preferably 0-30%, 0-28% of the total weight of the substrate layer.
  • the weight ratio of rotigotine to the viscosity enhancer 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 an optional surfactant.
  • the rotigotine transdermal drug 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 drug delivery system comprising the following steps:
  • Step 1 Dissolving the stabilizer that inhibits drug crystallization in a solvent and mixing for 0.1 to 24 hours;
  • Step 2 Add rotigotine or a pharmaceutically acceptable salt thereof, mix and dissolve until rotigotine or a pharmaceutically acceptable salt thereof is dispersed in an amorphous state;
  • Step 3 Add the pressure sensitive adhesive and mix well to obtain the drug wet mixture
  • Step 4 Coating the drug wet mixture on the release film
  • Step 5 drying to remove the solvent to obtain a release film/substrate layer laminate
  • the solvent in step 1 includes but not limited to one or more of toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, preferably toluene, ethanol, isopropanol propanol or its mixed solvents.
  • step 2 includes the step of heating to 30-65°C to bring the drug into solution.
  • the heating temperature in step 2 is preferably 30-35°C, 35-45°C, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C °C, 40°C, 41°C, 42°C, 43°C, 44°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 30-65°C and mix well to obtain a drug wet mixture.
  • the heating temperature in step 3 is preferably 30-35, 35-45, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.
  • step 4 is to coat the wet drug mixture on the release film at a temperature of 35-65°C.
  • the heating temperature in step 4 is preferably 30-35, 35-45, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C °C, 41°C, 42°C, 43°C, 44°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 the rotigotine transdermal drug delivery system according to the preparation of a medicament for treating or preventing a disease sensitive to the action of a dopamine receptor agonist. the use of.
  • the disease is a disease sensitive to the effects of rotigotine.
  • the disease is Parkinson's, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and loss of dopaminergic neurons.
  • a method for treating or preventing a disease sensitive to the action of a dopamine receptor agonist which comprises administering to a subject in need a therapeutically effective amount of the aforementioned rotigol transdermal drug delivery system.
  • the disease is a disease sensitive to the effects of rotigotine.
  • the disease is Parkinson's, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and loss of dopaminergic neurons.
  • the rotigotine transdermal delivery system is administered once 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 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 From about 2 mg to about 12 mg of rotigotine base or a pharmaceutically acceptable salt thereof is administered to the subject's blood circulatory system.
  • the term "pharmaceutically acceptable salt” means a salt suitable for use in contact with a subject (eg, a human subject) without undue toxicity, irritation, allergic response, etc., within reasonable medical judgment, with reasonable benefit/risk ratio and are those salts that are effective for their intended use.
  • the "pharmaceutically acceptable salt” mentioned in the present invention includes 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 can be prepared by adding the free base form of the purified compound Prepared by separate reaction with a suitable organic or inorganic acid and isolation of the salt thus formed.
  • inorganic acid addition salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates , pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, etc.
  • organic acid addition salts include saturated or unsaturated C1 to C30 fatty acid salts, including but not limited to monocarboxylates or dicarboxylates.
  • Non-limiting examples include formate, glyoxylate, oxalate, acetate, glycolate, acrylate, pyruvate, malonate, propionate, 3-hydroxypropionate, milk Glycerate, Fumarate, Maleate, Oxaloacetate, Crotonate, Acetoacetate, 2-Oxobutyrate, Methylmalonate, Succinate , malate, L-tartrate, DL-tartrate, meso-tartrate, dihydroxytartrate, butyrate, isobutyrate, hydroxybutyrate, levulinate, sorbate, coating Conate, mesaconate, ketoglutarate, glutarate, succinate, methylsuccinate, valerate, isovalerate, pivalate, cis-aconitate , trans-aconitate, ascorbate, citrate, isocitrate, adipate, caproate, benzoate, salicylate, gentisate, protocatechuate, Gallate
  • the term "therapeutically effective amount” means an amount of a compound or molecule of the invention which, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) attenuates, Ameliorate or eliminate one or more symptoms of a particular disease, disorder or condition, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder or condition described herein.
  • the term "about” refers to plus or minus 10% of the indicated figure.
  • “about 10%” can mean a range of 9% to 11%, and “about 1” can mean 0.9-1.1.
  • treatment refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, prevention of occurrence or recurrence of disease, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of disease, prevention of metastasis, reduction of the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • C2 to C30 fatty acid includes saturated or unsaturated C2 to C30 fatty acid fatty acids, including but not limited to monocarboxylic or dicarboxylic acids.
  • Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxalic acid, Acetoacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid Acid, hydroxybutyric acid, levulinic acid, sorbic acid, itaconic acid, mesaconic acid,
  • the term "backing layer” serves as the upper surface of the transdermal patch and as the main structural element provides flexibility to the patch.
  • the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions.
  • the backing layer is preferably made of a sheet or film of flexible elastic material.
  • the backing layer is preferably air impermeable.
  • the backing layer used in the patch of the invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement.
  • the non-occlusive backing layer allows the area to breathe (ie facilitates water vapor transmission from the skin surface), while the occlusive backing layer reduces air/vapor penetration.
  • the backing layer of the matrix-type transdermal delivery system Figs.
  • the backing layer comprises synthetic polymers such as polyolefins, polyesters, polyethylenes, polyvinylidene chlorides 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 delivery 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 50 g/m/24hr, more preferably, the MVTR is from about 0.3 g/m/24hr to about 30 g/m/24hr.
  • the backing layer is an occlusive polyester film layer about 2.0 mil thick (commercially available, such as 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 seal layers, the laminate is translucent, conformable, closed and heat sealable. It can be used in the matrix type transdermal drug delivery system shown in Figures 1-3.
  • the backing layer comprises a laminate comprising a layer of aluminum foil between polymeric film layers, such as Scotchpak 9738 and Scotchpak 1109. When the patch is on the skin, the aluminum layer prevents light from coming into contact with the photosensitizing medication.
  • insoluble crospovidone is a high-molecular water-insoluble polymer obtained by cross-linking N-vinyl-2-pyrrolidone. It is a white or near-white powder, odorless and tasteless, and flows Good sex, insoluble in water and various solvents, also insoluble in strong acid or alkali.
  • insoluble crospovidone include CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.
  • Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, Sodium formaldehyde sulfoxylate, chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA.
  • the antioxidant is alpha-tocopherol ( ⁇ -dl-tocopherol), ie vitamin E.
  • the content of ⁇ -tocopherol is 0.05 to 0.5%, preferably 0.1 to 0.2%, of the total weight of the adhesive layer.
  • the term "semi-permeable membrane or woven fabric layer” is used to contain a liquid or semi-solid matrix material within the matrix drug layer, which functions to control the transition of the drug or its pharmaceutically acceptable salt from the liquid or semi-solid Diffusion of a solid matrix drug layer into a skin contact adhesive layer.
  • the semi-permeable membrane or woven fabric layer and the backing layer can be sealed together around the peripheral edge.
  • Semipermeable membranes include, but are not limited to, ethylene-co-vinyl acetate copolymer membranes, polyethylene polymer membranes, polypropylene polymer membranes.
  • Non-limiting examples of ethylene-co-vinyl acetate copolymers include 3M Cotran 9702, Cotran 9712, Contan 9716, and Contran 9728.
  • Non-limiting examples of polyethylene polymer films include Solupore.
  • Non-limiting examples of polypropylene polymer films include Celgard 2400.
  • Suitable semi-permeable membranes include continuous membranes and microporous membranes, which can be made of woven or non-woven materials.
  • the semipermeable membrane is preferably made of flexible polymeric materials commonly used by those skilled in the art.
  • Polymeric membranes that can be used to make the semipermeable membrane layer include, but are not limited to, those comprising low density polyethylene, high density polyethylene, ethyl vinyl acetate copolymer, polypropylene, and other suitable polymers.
  • the semipermeable membrane layer is made from a microporous membrane made from ethylene-vinyl acetate copolymer containing from about 0.5 to about 28 wt. % vinyl acetate.
  • Suitable weaving materials include Saatifil PES, such as PES 105/52 available from Saatitech, Inc.
  • a suitable nonwoven is Sontara from DuPont Nonwovens Sontara Technologies.
  • the semipermeable membrane layer is an ethylene-vinyl acetate copolymer membrane available from 3MTM, such as Cotran 9702, Cotran 9705, Cotran 9706, Cotran 9707, Cotran 9712, Cotran 9715, Cotran 9716 and Cotran 9728 ( available from 3MTM).
  • the thickness of the semi-permeable membrane layer may generally be about 10 um to about 100 um, preferably about 15 ⁇ m to about 50 ⁇ m.
  • skin contact adhesive layer serves to adhere the transdermal drug delivery system to the skin surface. After removing the protective release layer, it can also be used to control the rate of drug delivery to the skin.
  • release liner includes, but is not limited to, silicon-coated polyester release liners, fluoropolymer-coated polyester release liners from 3M, and fluorosilicone-coated polyester release liners available from a number of suppliers Isolation liner.
  • GSM grams per square meter
  • Fig. 1 shows a schematic diagram of the three-layer matrix type transdermal drug delivery system of the present invention.
  • Fig. 2 shows a schematic diagram of the four-layer matrix type transdermal drug delivery system of the present invention.
  • Fig. 3 shows a schematic diagram of the five-layer matrix type transdermal drug delivery system of the present invention.
  • Fig. 4 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples A1, A8 and Comparative Example A1.
  • Fig. 5 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples A21, A22 and Comparative Examples A2, A3, A4, A5.
  • Figure 6 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example A24.
  • Fig. 7 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Example A25 and Comparative Example A6.
  • Fig. 8 shows the skin flux of the transdermal delivery system described in embodiment A26 (100GSM), embodiment A26 (200GSM), embodiment A26 (300GSM), embodiment A26 (400GSM), embodiment A27 (400GSM) measurement curve.
  • Fig. 9 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Example A28 and Comparative Example A7.
  • Figure 10 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example A29.
  • Fig. 11 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples A30-A33 and Comparative Examples A8-A11.
  • Fig. 12 shows the measurement curves of the skin flux of the transdermal drug delivery systems of Examples C1-C2.
  • Olanzapine (1.5 g) and dimethylacetamide (2.5 g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution.
  • Add Duro-Tak 387-2516 (17.71 g) mix to form a homogeneous suspension, and degas to remove air bubbles.
  • One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109.
  • Embodiment A1 (prescription A1)
  • Povidone K30 (0.45g), olanzapine (0.90g) and dimethylacetamide (2.25g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution.
  • Add Duro-Tak 387-2516 (15.94g) mix to form a homogeneous suspension, and degas to remove air bubbles.
  • One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109.
  • Example A1 The three-ply laminates were die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. The crystal observation results are shown in Table 1. After 18 days, no olanzapine crystals were observed under a transmitted light microscope at 100 times magnification (Table 1). Formulation 1 in Example A1 contained povidone K30 as a crystallization inhibitor, so no crystals formed on storage.
  • Embodiment A2 to embodiment A5 prescription A2 to prescription A5
  • Olanzapine (1.02g), lactic acid (0.512g) and dimethylacetamide (2.508g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution.
  • lauryl lactate (1.51 g) and Duro-Tak 387-2516 (12.74 g) mix to form a homogeneous suspension, and degas to remove air bubbles. Dry coat at 100 gsm to a siliconized polyester release liner in a 50C forced air oven for 5 minutes then in a 120C forced air oven for 15 minutes to remove solvent.
  • One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109.
  • the three-ply laminates were die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. From the crystallization observation results in Table 1, it can be seen that after the transparent Scotchpak 9733 backing patch was stored at room temperature for 10 days and 31 days or at 40°C for 31 days, no olanzapine was observed with a transmitted light microscope at a magnification of 100 times crystals.
  • Crospovidone also improves the physical properties and skin adhesion of formulations containing liquid lactic acid or other liquid excipients, as described in the Skin Adhesion, Finger Pressure, and Physical Properties section.
  • Formulations A3 to A5 in Example A3 to Example A5 were prepared similarly. It can be seen from Table 1 that due to the presence of the crystallization inhibitor crospovidone CLM and the solubilizer lactic acid, no crystals were formed after 31 days at room temperature and 40°C.
  • Embodiment A6 (prescription A6) and embodiment A7 (prescription A7)
  • Formulation 6 and Formulation A7 contained crystallization inhibitor povidone K30 and silicone binders Bio-PSA 4202 and 7-4302, and no olanzapine crystals were observed after 31 days.
  • Embodiment A8 (prescription A8) and embodiment A9 (prescription A9)
  • prescription A9 in embodiment A9 contains 22% crystallization inhibitor crospovidone CLM (22%) than prescription A8 in embodiment A8 contains more crospovidone CLM (15%), preparation 9 was more stable to crystallization than formulation 8 at day 26, as no crystals were observed in formulation 9 but a small amount of crystals were observed in formulation 8 at day 26.
  • Embodiment A10 (prescription A10) to embodiment A12 (prescription A12)
  • Formulation 10 contained the very hydrophobic silicone binder Bio-PSA 7-4302, 15% crospovidone CL-M was not sufficient to inhibit olanzapine crystallization, but it Duro-Tak 387-2516 is more formulated to inhibit crystallization.
  • Embodiment A 13 (prescription A 13) to embodiment A 17 (prescription A 17)
  • Examples A13 to A17 further demonstrate that formulations containing the acrylic binder Duro-Tak 387-2516 are more stable to olanzapine crystallization as the CLM of crospovidone is increased.
  • Embodiment A 18 (prescription A 18) to embodiment A 20 (prescription A 20)
  • Embodiment A 22 (prescription A 22) to embodiment A 24 (prescription A 24)
  • Embodiment A 25 (prescription A 25)
  • Laminate adhesive side to clear backing film ScotchPak 9733 The three-layer laminate was die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. As can be seen from the crystallization observation results in Table 1, due to the presence of both oleic acid and Eudragit E100, no crystallization was formed after 32 days at room temperature. Eudragit E100 also improves the physical properties and skin adhesion of the formulation, as described in the Skin Adhesion, Finger Adhesion and Physical Properties sections.
  • Comparative example 2 (contrast prescription A2) and comparative example 3 (contrast prescription A2)
  • Comparative formulation A2 and comparative formulation A3 contained liquid lactic acid and oleic acid in the absence of povidone, crospovidone CLM or Eudragit E100. Although no crystals formed after 48 days at room temperature, their physical properties and skin adhesion were unacceptable, as described in the Skin Adhesion, Fingertip, and Physical Properties sections.
  • the mixed solution, olanzapine solution and excipient solution were prepared according to Table 2-1, Table 2-2 and Table 2-3 respectively.
  • Wet formulation formulation A was then prepared according to Tables 2-4.
  • the final dry formulation composition Recipe A is shown in Tables 2-5.
  • Embodiment A26 (prescription A26):
  • Premix A Povidone K90 (6g), Eudragit E100 (6g), oleic acid (6g) and dimethylacetamide (24g), DL- ⁇ tocopherol (0.09g), ascorbyl palmitate NF (0.0006g), sodium metabisulfite (0.0005g) were added to a glass jar. Mix to dissolve and form a clear solution. Mix at room temperature for 24 hours to a homogeneous solution. Olanzapine (5.5 g) was added and mixed for 1 hour to form a solution.
  • Solution B Weigh the amount of Dura-Tak387-2287 (64.9g) of the adhesive Dura-Tak387-2287 of the prescription A into a glass bottle.
  • DL-alpha tocopherol (0.0825 g)
  • ascorbyl palmitate NF 0.0006 g
  • sodium metabisulfite 0.0004 g
  • hydroxybutyltoluene 0.0275 g
  • Example A27 was prepared using a similar method. At the time of writing this formulation did not form crystals. Povidone and Eudragit E100 effectively inhibited olanzapine crystal formation for 49 days at room temperature and 40 days at a storage temperature of 40°C.
  • Embodiment A28 (implementing prescription A28) and comparative example A7 (comparing prescription A7):
  • Olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) were added to a glass jar. Mix to dissolve and form a clear solution. Isopropyl palmitate (1.26g), myristyl alcohol (1.07g), glyceryl monooleate (1.74g) and Dura-Tak 87-900A (44.05g) were added. well mixed. After degassing, it was coated on a release liner with a target dry thickness of about 130 GSM. Dry at 37.8°C for 60 minutes. Apply a backing film on top of the adhesive. It was found that the release liner could not be peeled off. GC found residual DMSO at 6.52%.
  • Olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) were added to a glass jar. Mix to dissolve and form a clear solution. Add Dura-Tak 87-900A (52.06g). well mixed. After degassing, it was coated on a release liner with a target dry thickness of about 130 GSM. Dry at 37.8°C for 60 minutes. Apply a backing film on top of the adhesive. The release liner was found to be peelable. GC found residual DMSO at 7.25%.
  • Embodiment A29 (prescription A29):
  • Premix A Povidone K90 (5.5g), oleic acid (8.25g) and dimethylacetamide (22g), D-alpha tocopherol (0.2063g), ascorbyl palmitate NF (0.0413g) , a 10% aqueous solution of sodium metabisulfite (0.0062 g) and hydroxybutyltoluene (0.2063 gram) were added to a glass jar. Mix and heat at 50°C to dissolve and form a clear solution. Mix at room temperature for 24 hours to a homogeneous solution. Olanzapine (5.5 g) was added and mixed for 1 hour to form a solution.
  • Solution B Weigh the adhesive Dura-Tak 387-2510 (64.3814g) containing 0.56% polybutyl titanate into a glass bottle. D-alpha tocopherol (0.05 g), ascorbyl palmitate NF (0.01 g), 10% sodium metabisulfite (0.0015 g), and hydroxybutyl toluene (0.05 g) were added to a glass jar and mixed for 24 hours.
  • D-alpha tocopherol 0.05 g
  • ascorbyl palmitate NF 0.01 g
  • 10% sodium metabisulfite 0.0015 g
  • hydroxybutyl toluene 0.05 g
  • the receiving pool has a volume of 7ml and is filled with a pH 6.5 buffer solution with an effective skin permeability of 0.61cm2.
  • the stroma layer was placed on the stratum corneum side of human cadaver skin. Place the O-ring on top of the skin. .
  • the receiving solution was immediately analyzed by HPLC for the amount of olanzapine.
  • Formulation 23 containing 15% by weight crospovidone CL-M had higher in vitro skin flux than comparative formulation A3 and comparative formulation A5 without crospovidone CL-M or povidone K30 (Table 4, Figure 5) .
  • Crospovidone CL-M not only increased skin flux but also improved the physical properties and skin adhesion of Formulation A23 by increasing adhesive matrix cohesion and thus reducing adhesive transfer to the skin.
  • Example A1 Although the in vitro skin flux of US20070148218A1 Example A1 was good due to the presence of skin penetration enhancers, as shown in Table 11 of the present application, excessive adhesive transfer to the finger was observed and formed in the finger test Binder flow (Comparative Example A15, Table 11), therefore the physical properties of Example A in 20070148218A1 are not acceptable.
  • Comparative Example A4 4.6% fatty ester (lauryl lactate) was added to formulation A23 to obtain comparative formulation A4.
  • the average skin flux of Comparative Example A4 was low relative to Example A23, indicating that the addition of liquid lauryl lactate reduced the average skin flux (Table 4, Figure 5).
  • the addition of liquid lauryl lactate also reduced the integrity of the adhesive matrix. Therefore, there was some adhesive transfer to the finger in the finger test (Comparative Example A14, Table 11).
  • Table 5 shows that the in vitro skin flux of amorphous formulation A24 containing 9.3% oleic acid and 15% Eudragit was high from the 24 hour time point to the 168 hour time point. As shown in Table 11, there was no adhesive transfer to the finger in the finger test of Formulation A24 (Example A38, Table 11).
  • Comparative Example A6 The average epidermal flux of Comparative Example A6 was similar to that of Example A25, and the results are shown in Table 6 ( Figure 7).
  • the fatty alcohol nonanol did not increase the skin penetration of olanzapine.
  • composition of prescription A26 of embodiment A26 is: 10% olanzapine, 10% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-alpha-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% coke Sodium Sulfite NF, 0.1% BHT, 59.5965% Dura-Tak 387-2287.
  • the prescription A contains a polymer skin penetration enhancer (10% povidone K90) and 10% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1).
  • the skin penetration rate of this prescription A7 days is higher (Table 7, Figure 8), and from 100GSM (grams per square meter), 200GSM, 300GSM, 400GSM, the skin penetration rate increases with the increase of matrix thickness (coating weight) .
  • the polymeric skin penetration enhancer (10% Povidone K90) increased the cohesion of the adhesive, thereby reducing the transfer of the adhesive to the finger in the finger test (Example A39, Table 11).
  • the prescription A27 of embodiment A27 consists of: 10% olanzapine, 15% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-alpha-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.1% BHT, 54.5965 Dura-Tak 387-2287 (400GSM matrix layer).
  • This formulation A contains a polymer skin penetration enhancer (10% povidone K90) and 15% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1). Compared with Example A26, the 7-day skin penetration rate of this formulation A at 400GSM is higher (Table 7, Figure 8). At the same time the polymer skin penetration enhancer (10% Povidone K90) increased the cohesion of the adhesive, thereby reducing the transfer of the adhesive to the finger in the finger test (Example A40, Table 11).
  • composition of prescription A28 of embodiment A28 is: 9% olanzapine, 10% oleic acid, 16% DMSO (2.7% after drying), 65% Duro-Tak 87-900A (110GSM matrix layer).
  • composition of the comparative prescription A7 of comparative example A7 is: 9% olanzapine, 10% oleic acid, 16% DMSO (3.5% after drying), 3.5% isopropyl palmitate, 3% myristyl alcohol, 3.5% GMO ( Glyceryl Monooleate), 55% Duro-Tak 87-900A (120GSM matrix layer).
  • Example A28 and comparative formulation A7 did not contain the polymeric skin penetration enhancer povidone. Thus, both formulations formed olanzapine crystals on day 1. The skin flux of both formulations was much lower than that of formulations A26, 27 and 29 prepared according to preparation method 2 containing 10% povidone K90 and 10% oleic acid.
  • composition of prescription A29 of embodiment A29 is: 10% olanzapine, 15% oleic acid, 10% povidone K90, 0.5% DL-alpha tocopherol, 0.1% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.5% BHT, 63.8985% Duro-Tak 387-2510, 0.56% Polybutylate (600GSM matrix layer).
  • the formulation A29 of Example A29 contains a polymer skin penetration enhancer (10% povidone K90) and 10% to 20% oleic acid. This system was able to effectively inhibit the crystal formation of olanzapine (Table 1).
  • the 14-day skin penetration rate of this formulation A is very high (Table 9, Figure 10), and it is the first formulation among all drug transdermal systems whose skin flux can satisfy the drug effect for up to 14 days.
  • the polymer skin penetration enhancer (10% povidone K90) increased the adhesive cohesion, thereby reducing the transfer of the adhesive to the finger in the finger test (Example A40, Table 11).
  • Embodiment A30 and comparative example A8 are identical to Embodiment A30 and comparative example A8
  • composition of prescription A30 of Example A30 is: 8% olanzapine, 16% oleic acid, 5% KollidonCL-M, 0.5% butyl hydroxytoluene, 70.5% Duro-Tak87-900A.
  • composition of the comparative prescription A8 of embodiment A8 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% KollidonCL-M, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87-900A .
  • Example A30 did not contain 10% isopropyl palmitate, and Comparative Example A8 (comparative prescription A8) contained 10% isopropyl palmitate.
  • the skin flux of Example A30 was higher than that of comparative formulation A8 (Table 10, Figure 11).
  • comparative formulation A8 transferred more adhesive to the finger than formulation A30 (Table 11).
  • composition of prescription A31 of Example A31 is: 8% olanzapine, 16% oleic acid, 15% KollidonCL-M, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87-900A.
  • composition of the comparative prescription A9 of embodiment A9 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% KollidonCL-M, 0.5% butyl hydroxytoluene, 50.5% Duro-Tak87-900A .
  • Example A31 (prescription A31) did not contain 10% isopropyl palmitate, and Comparative Example A9 (comparative prescription A9) contained 10% isopropyl palmitate.
  • the skin flux of Example A31 was higher than that of Comparative Example A9 (Table 10, Figure 11).
  • Comparative Formulation A9 transferred more adhesive to the finger than Formulation A31 (Table 11).
  • composition of prescription A32 of Example A32 is: 8% olanzapine, 16% oleic acid, 5% copovidone Kollidon64, 0.5% butylhydroxytoluene, 70.5% Duro-Tak87-900A.
  • composition of the comparative prescription A10 of embodiment A10 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% copovidone Kollidon64, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87- 900A.
  • Example A32 (prescription A32) did not contain 10% isopropyl palmitate, and Comparative Example A10 (comparative prescription A10) contained 10% isopropyl palmitate.
  • the skin flux of Example A32 was higher than that of Comparative Example A10 (Table 10, Figure 11).
  • comparative formulation A10 transferred more adhesive to the finger than formulation A20 (Table 11).
  • composition of prescription A33 of embodiment A33 is: 8% olanzapine, 16% oleic acid, 15% copovidone Kollidon64, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak87-900A.
  • composition of the comparative formulation A11 of Example A11 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% copovidone Kollidon64, 0.5% 50.5% Duro-Tak87-900A.
  • Example A33 (prescription A33) did not contain 10% isopropyl palmitate, and Comparative Example A11 (comparative prescription A11) contained 10% isopropyl palmitate.
  • the skin flux of Example A33 was higher than that of Comparative Example A11 (Table 10, Figure 11).
  • Comparative Example 11 transferred more adhesive to the finger than Example A33 (Table 11).
  • formulation A8 (Example A34) and formulation A9 (Example A35) contained 15% by weight and 22% by weight of crospovidone CL-M, respectively, and no adhesive transfer to the index finger was observed.
  • Embodiment A36-37 and comparative example A12-13 are identical to Embodiment A36-37 and comparative example A12-13:
  • Formulation A22 (Example A36) and Formulation A23 (Example A37) containing 15% crospovidone CL-M also had no adhesive transfer to the fingers.
  • Comparative formulation A5 (comparative example A15) not only contained a very high content of liquid oleic acid (17.17%) and liquid isopropyl palmitate (8.59%), but also did not contain crospovidone CL-M, povidone K30 or EudragitE100, so severe adhesive transfer was observed in the finger test.
  • Embodiment A38 (prescription A24):
  • Formulation A24 contained the polymer Eudragit E100 and there was no adhesive transfer to the finger in the finger test.
  • Embodiment A39-40 (prescription A26-27):
  • formulations contain polymeric penetration enhancers (povidone and Eudragit E100) that promote adhesive cohesion, excellent physical properties, and no adhesive transfer to the finger was observed in the finger test.
  • Embodiment A41 (prescription A28) and comparative example A16 (comparison prescription A7):
  • Example A41 contained no fatty acid esters or fatty alcohols, and despite the adhesive transfer due to the presence of high amounts of DMSO, the liner was still peeled off cleanly.
  • Comparative Example A16 contained fatty acid ester isopropyl ester and fatty alcohol myristyl alcohol, and in the finger test, the release liner could not be removed and a large amount of adhesive transfer to the finger was observed.
  • Embodiment A42 (prescription A29):
  • Formulation A29 in Example A42 contained a sufficient amount of polymeric cohesion promoter that no adhesive transfer to the finger was observed in the finger test.
  • Embodiment A43 (prescription A30) and comparative example A17 (comparison prescription A8):
  • Example A43 with 5% curing agent Kolliodn CL-M i.e. crospovidone CL-M
  • Embodiment A44 (prescription A31) and comparative example A18 (comparative prescription A8):
  • Example A44 containing 15% curing agent Kolliodn CL-M did not observe adhesive transfer to the fingers, but Comparative Example A18 containing 10% isopropyl palmitate had a lot of stickiness. The mixture is transferred to the fingers.
  • Embodiment A45 (prescription A32) and comparative example A19 (comparative prescription A8):
  • Example A45 with 5% curing agent copovidone VA64 had only a small amount of adhesive transfer to the finger, but Comparative Example A19 with 10% isopropyl palmitate had a large amount of adhesive transfer to the finger.
  • Embodiment A46 (prescription A33) and comparative example A20 (comparative prescription A8):
  • Example A46 with 15% curing agent copovidone VA64 had no adhesive transfer to the finger, but Comparative Example A20 with 10% isopropyl palmitate had substantial adhesive transfer to the finger.
  • Placebo Patch Formulation A1 and Placebo Patch Formulation A2 described in Table 14 and Table 15 were prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain the olanzapine base .
  • patches were prepared in two coating weights (454 GSM (grams per square meter of olanzapine)).
  • One healthy volunteer participated in Placebo Wear Study #1 (Example A47).
  • the skin on the left and right outer arms was cleaned with wet paper towels and dried with dry paper towels.
  • the Formulation 1 patch was applied on the left upper outer arm. Apply the prescription A22 patch to the upper right outer arm. After the patches are applied, smooth them out to ensure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment.
  • Adhesion and irritation scores were recorded daily. Adhesion was scored using a five-point scale from 0 to 4, as shown in Table 12. Primary skin irritation was scored using a 0-7 point scoring system as shown in Table 13.
  • the Skin Adhesion Score and Major Skin Irritation Score for Placebo Wear Study #1 are reported in Tables 16 and 17. Both the placebo prescription A1 patch and the placebo prescription A2 patch had low cohesion because insufficient amounts of crospovidone CLM or povidone K30 were used to avoid the use of large amounts of liquid excipients (lactic acid and lauryl lactate). As a result, in the finger test, a large amount of adhesive was transferred to the index finger (Table 11). Due to the low cohesion of the adhesive layer, in the placebo wear study, the placebo prescription A1 patch was very slippery, and the patch moved by itself on the upper arm after 28 hours of wearing, while the placebo prescription A2 patch had 80 % of the patch, lift after 12 hours of wearing.
  • Placebo patch prescription A1 (backing film is Scotchpak 9733)
  • Placebo patch formulation A2 (backing film is Scotchpak 9733)
  • Placebo Patch Wearing Test 1 Scoring of Placebo Patch Prescription A1 (454GSM Adhesive Layer Thickness)
  • Placebo Patch Wearing Test 1 Scoring of Placebo Patch Prescription A2 (426GSM Adhesive Layer Thickness)
  • Embodiment A47 placebo prescription A3
  • Placebo patch formulation A3 described in Table 18 was prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain olanzapine.
  • the patches were prepared in two coat weights, 200 GSM (grams per square meter) and 400 GSM.
  • GSM grams per square meter
  • Nine healthy volunteers participated in Placebo Wear Study #1 (Example A47). Clean the outer skin of the upper arm with a damp paper towel and dry with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily.
  • the skin adhesion scores and major skin irritation scores for Placebo Wear Study #3 are reported in Tables 19 and 20.
  • the 168-hour (7-day)-skin adhesion score for most volunteers was 0 (greater than 90% of the patch adhered to the skin) or 1 (75% to 89% of the patch adhered to the skin), with few Volunteers were able to wear the patch for 12 or 13 days.
  • Major skin irritations in most volunteers were 0 (no irritation) or 1 (almost no irritation) within 168 hours (7 days).
  • Placebo patch prescription A3 (backing film is Scotchpak 9733)
  • Placebo patch prescription A4 (backing film is Scotchpak 9733)
  • Embodiment A48 placebo patch prescription A4.
  • the coating weight of the patch was 400 GSM (grams per square meter).
  • One healthy volunteer wore both patches in Placebo Wear Study #3 (Example 48).
  • the skin of the upper left foreleg was cleaned with a wet paper towel and dried with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch.
  • Adhesion and irritation scores (based on skin itching and skin appearance such as redness) were recorded daily.
  • the skin adhesion scores and major skin irritation scores for Placebo Wear Study 3 are reported in Tables 22 and 23.
  • the 28-day skin adhesion score was 0 (greater than 90% patch adhered to the skin).
  • Major skin irritation at 28 days was also 0 (no irritation).
  • the formulation with 15% crospovidone CLM maintained good cohesion and provided excellent skin adhesion for up to 28 days despite the presence of high amounts of liquid oleic acid in the formulation.
  • composition component Take each composition component by weighing according to table 24 and prepare prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50°C. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months.
  • the weight ratio of rotigotine to soluble povidone is 9:3
  • the ratio of rotigotine to insoluble povidone is 9:6.8.
  • composition component Take each composition component by weighing according to table 24 and prepare prescription.
  • Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C and mixed with insoluble crospovidone CL-M at room temperature for 24 hours.
  • the suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months.
  • the weight ratio of rotigotine to soluble povidone is 9:3
  • the weight ratio of rotigotine to insoluble povidone is 9:8.
  • composition component Take each composition component by weighing according to table 24 and prepare prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50°C. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months.
  • the weight ratio of rotigotine to soluble povidone is 9:3
  • the weight ratio of rotigotine to insoluble crospovidone is 9:9.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • the antioxidants ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in toluene at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature.
  • the suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of polyisobutylene binders Oppanol B12 and Oppanol N100 in toluene at room temperature was added and mixed.
  • the suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • the patch samples of Comparative Example B7 to Comparative Example B11 were prepared using a method similar to that of Comparative Example B6. Take each composition component by weighing according to table 25 and prepare prescription. The amount of insoluble crospovidone was increased to 10%, 13%, 16.65%, 18% and 20%, respectively. The patch samples of Comparative Example B7 to Comparative Example B11 all formed crystals, but as the amount of insoluble crospovidone increased, the formation of crystals was more and more delayed. In these Comparative Examples B, the wet mixture was maintained at room temperature, ie not heated above room temperature, to maintain the dissolution of rotigotine in the wet mixture.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • the antioxidants ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in toluene at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature.
  • the suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in toluene heated to 50°C was added and mixed.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • Example B5 was prepared using a method similar to that of Example B4. As shown in Table 25, no crystals were observed for the patch samples after 10 days of storage at 60°C and 1 month at 40°C. In this Example B, without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 7.5:20 or 9:24. In this Example B, the wet mix was maintained at 50°C to maintain rotigotine dissolved in the wet mix prior to coating.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • the antioxidants ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in isopropanol at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature.
  • the suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.
  • Example B without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 7.5:20 or 9:24. In this Example B, the wet mix was maintained at 50°C to maintain rotigotine dissolved in the wet mix prior to coating.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • Povidone K90, ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in isopropanol at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, crystallization was observed on day 3 of patch samples stored at room temperature.
  • the weight ratio of rotigotine to soluble povidone is 9:3
  • the weight ratio of rotigotine to insoluble crospovidone is 9:3.6.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • Povidone K90, ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in isopropanol at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed on the patch samples stored at 60°C for 10 days, and no crystals were observed at 40°C for 1 month.
  • the weight ratio of rotigotine to crospovidone is 9:3
  • the weight ratio of rotigotine to insoluble crospovidone is 9:12.
  • composition component Take each composition component by weighing according to table 25 and prepare prescription.
  • Povidone K90, ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in isopropanol at 50°C.
  • Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis.
  • a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed.
  • the suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed on the patch samples stored at 60°C for 10 days, and no crystals were observed at 40°C for 1 month.
  • the ratio of rotigotine to crospovidone is 9:3
  • the weight ratio of rotigotine to insoluble crospovidone is 9:18.
  • composition component Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, crystals were observed in patch samples stored at room temperature for 6 months and at 40°C on day 22. In this example B, the ratio of rotigotine to insoluble crospovidone is 7.5:6 or 9:7.2.
  • composition component Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, crystals were observed on day 62 of patch samples stored at 40°C. In this example B, the ratio of rotigotine to insoluble crospovidone is 7.5:10 or 9:12.
  • composition component Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and ⁇ -dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The solution was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, no crystals were observed for the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this Example B, the ratio of rotigotine to insoluble soluble crospovidone was 9:20.
  • Example B10 Take each composition component by weighing according to table 26 and prepare prescription.
  • the formulation in Example B10 was prepared using the same method as in Example B9. As shown in Table 26, no crystals were observed in the patch samples stored at room temperature for 6 months and at 40°C for 6 months.
  • the weight ratio of rotigotine to insoluble crospovidone is 9:22.8.
  • Example B12 to 14 were prepared using the same method as Formulation 11 of Example B11. As shown in Table 26, no crystals were observed for the patch samples stored at room temperature for 9 months and at 40°C for 6 months.
  • composition component Take each composition component by weighing according to table 27 and prepare prescription. Soluble povidone K90 was dispersed in ethyl acetate, and oleic acid and Eudragit EPO were added to form a solution. Add Crospovidone CL-M and mix for 24 hours at room temperature. Donepezil free base was added with mixing and microscopic analysis indicated complete dissolution. Add and mix Duro-Tak 387-2516. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 27, no crystals were observed in patch samples stored at room temperature for 9 days or 24 days, stored at 40°C for 1 month, and stored at 60°C for 1 month for 9-10 days.

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Abstract

L'invention concerne un système d'administration de médicaments transdermique pour inhiber la cristallisation médicamenteuse, son procédé de préparation et son utilisation. Un médicament ou un sel pharmaceutiquement acceptable de celui-ci dans le système d'administration de médicaments est dispersé de manière stable, dans un état amorphe, dans une couche de matrice d'un adhésif sensible à la pression, de telle sorte que la formation de cristallisation médicamenteuse peut être inhibée, et une libération stable du médicament est effectuée.
PCT/CN2023/071264 2022-01-12 2023-01-09 Timbre transdermique pour inhiber la cristallisation médicamenteuse, et son procédé de préparation WO2023134618A1 (fr)

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DE102012013439A1 (de) * 2012-07-03 2014-01-23 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Transdermales therapeutisches System umfassend Rotigotin und Kristallisationsinhibitor
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