Transdermal patch for inhibiting drug crystallization and its preparation method

Abstract

A transdermal drug delivery system for inhibiting drug crystallization, its preparation method and use. The drug or its pharmaceutically acceptable salt in the drug delivery system is stably dispersed in the matrix layer of the pressure-sensitive adhesive in an amorphous state, which can inhibit the formation of drug crystallization and achieve a steady release of the drug.

Description

Technical Field

[0001] The present invention relates to a transdermal drug delivery system. More specifically, the present invention relates to a transdermal drug delivery system comprising a drug or a pharmaceutically acceptable salt thereof, and a method for preparing and using the same. Background Art

[0002] The transdermal drug delivery route is a drug delivery route superior to the oral drug delivery route, which continuously delivers drugs to the systemic blood system to maintain a constant drug concentration in the blood. The transdermal drug delivery route not only reduces the fluctuation of the drug concentration in the blood between peaks and valleys, but also avoids the first-pass effect. In addition, since the transdermal drug delivery route avoids the direct contact of drugs and excipients with the gastrointestinal system, it significantly reduces or eliminates side effects such as nausea and vomiting often associated with the oral drug delivery route. Another advantage of the transdermal drug delivery route is that it is not affected by diet. When necessary, the transdermal patch can be easily removed from the skin to terminate drug administration. Moreover, the transdermal patch improves patient compliance by reducing the dosing frequency. This is particularly important for elderly patients and pediatric patients.

[0003] Common dosage forms of the transdermal drug delivery route include transdermal patch preparations. Currently common transdermal patch preparations include, but are not limited to, drug reservoir type patches and matrix type patches, etc. A drug reservoir type patch preparation is a patch preparation that contains a drug in a reservoir having a drug-permeable substrate surface, and a matrix type patch preparation is a patch preparation that dissolves or disperses a drug in a polymer matrix layer. The designs of both types usually also include a backing layer and a release liner layer that is removed before use. In addition, the patch usually also contains a penetration enhancer and an adhesive layer.

[0004] In recent years, the advantages of transdermal drug delivery have enabled many drugs to be effectively administered through the transdermal route. These advancements include the development of many physical methods for increasing skin permeability and promoting transdermal drug delivery, such as iontophoresis, electroporation, ultrasound, or microneedles. However, there are still limited drugs that can be effectively and safely continuously administered through the skin for 7 days or longer without causing skin adhesion, skin irritation, or sensitization.

[0005] To date, different transdermal therapeutic systems (TTS) have been described. For example, WO 99 / 49852), WO02 / 15903, WO 94 / 07468, WO 99 / 49852 disclose a transdermal drug delivery system for rotigotine; US 5891461 and 2007 / 0148218A1 disclose a transdermal drug delivery system for olanzapine.

[0006] It has recently been found that the above-described system unfortunately exhibits long-term stability problems. If drug crystals form in the self-adhesive matrix during long-term storage, crystal growth can lead to a reduced drug release rate, with the risk of eventually falling below the specified value. Stabilizing the amorphous state of the medicinal substance in a drug dosage form, including a transdermal system, is very difficult. The amorphous form is only relatively stable and easily converts into crystals. Summary of the Invention

[0007] One object of the present invention is to provide a matrix-type transdermal drug delivery system that can continuously deliver a drug or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration over an extended period of time.

[0008] One object of the present invention is to provide a matrix-type transdermal drug delivery system that can have good skin adhesion properties during the period of continuously delivering a drug or a pharmaceutically acceptable salt thereof.

[0009] Another object of the present invention is to provide a matrix-type transdermal drug delivery system that is non-irritating and / or non-sensitizing to the skin during the period of continuously delivering a drug or a pharmaceutically acceptable salt thereof.

[0010] 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 a drug and a pressure-sensitive adhesive above room temperature and then coats it to produce an adhesive matrix patch without drug crystals. If the wet mixture is not heated, the drug will form crystals in the matrix.

[0011] Another object of the present invention is to provide a method for 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 thereof.

[0012] Another object of the present invention is to provide the use of a therapeutically effective amount of a matrix-type transdermal drug delivery system in the preparation of a drug for treating or preventing a disease. Detailed Description of the Invention

[0014] In one class of embodiments of the present invention, a transdermal drug delivery system comprises:

[0015] 1) a backing layer;

[0016] 2) a matrix layer, which contains a drug or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer that inhibits drug crystallization, and a pressure-sensitive adhesive;

[0017] 3) a release liner.

[0018] In some embodiments, the stabilizer for inhibiting drug crystallization is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer (preferably povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, copovidone VA64, crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF), hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan, or one or more thereof. In the technical solution of olanzapine, it is also called a polymer skin penetration enhancer.

[0019] In some embodiments, the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizers for inhibiting drug crystallization, soluble stabilizers for inhibiting drug crystallization, or a combination thereof.

[0020] In some embodiments, the insoluble stabilizer for inhibiting drug crystallization is selected from insoluble cross-linked polyvinylpyrrolidone, preferably insoluble cross-linked polyvinylpyrrolidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.

[0021] In some embodiments, the stabilizer for inhibiting drug crystallization further comprises a soluble stabilizer for inhibiting drug crystallization on the basis of the insoluble stabilizer for inhibiting drug crystallization; preferably, the soluble stabilizer for inhibiting drug crystallization is selected from soluble polyvinylpyrrolidone, more preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, copovidone VA64.

[0022] In some embodiments, the matrix layer further comprises other pharmaceutically acceptable excipients, and the other pharmaceutically acceptable excipients are preferably one or more of a skin penetration enhancer, a tackifier, and a cohesion promoting additive.

[0023] In some embodiments, relative to the total weight of the matrix layer, the matrix layer comprises the following components:

[0024] 1) The dosage of the drug or its pharmaceutically acceptable salt is 3-30%;

[0025] 2) The dosage of the stabilizer for inhibiting drug crystallization is 1.5-90%;

[0026] 3) The dosage of the pressure-sensitive adhesive is 30-90%;

[0027] 4) The dosage of the tackifier is 0-50%;

[0028] 5) Skin penetration enhancer 0 - 30%;

[0029] 6) Cohesion promoting additive 0 - 20%;

[0030] The total amount of each component used in the substrate layer is 100%.

[0031] In some embodiments, the substrate layer further comprises a cohesion promoting additive selected from one or more of the following:

[0032] 1) Carbohydrate polymers, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl betadex, α, β, λ - cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;

[0033] 2) Acrylic or methacrylic acid polymers, preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L - 55.

[0034] In some embodiments, the pressure - sensitive adhesive is selected from one or more of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene - isoprene - styrene block copolymer adhesives, styrene - butadiene - styrene copolymer adhesives, silicone adhesives, acrylic - copolysiloxane copolymer adhesives;

[0035] 1) The acrylic adhesives are selected from Henkel's Duro - Tak adhesives 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 GMS9073, Gelva 737, Gelva 2655, Polythick 410 - SA (Sanyo Chemical Industries, Ltd.);

[0036] 2) The polyisobutylene adhesives are 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;

[0037] 3) The silicone adhesives are selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400, 7-4500, 7-4600, Bio-PSA SR7-4400, SRS7-4500, SRS7-4600;

[0038] 4) The acrylic-co-polysiloxane copolymer adhesives are selected from DuPont Bio-PSA 7-6100, 7-6200, and 7-6300; The Bio-PSA adhesives are dissolved in different solvents, and the solvents are selected from one or more of n-heptane, ethyl acetate, toluene, or a hot melt.

[0039] In some embodiments, for the transdermal delivery system according to any one of claims 1-9, wherein the content of the drug or its pharmaceutically acceptable salt is 5% to 20% of the total weight of the matrix layer, preferably 5% to 15%, or 5% to 12%, 7.5%.

[0040] In some embodiments, 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%.

[0041] In some embodiments, the content of the insoluble stabilizer that inhibits drug crystallization 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 that inhibits drug crystallization is selected from insoluble cross-linked povidone CL-M, cross-linked povidone CL, cross-linked povidone CL-F, cross-linked povidone CL-SF.

[0042] In some embodiments, the content of the soluble stabilizer that inhibits 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%; The preferred soluble stabilizer that inhibits drug crystallization is selected from soluble povidone, preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, copovidone VA64.

[0043] In some embodiments, the content of the pressure-sensitive adhesive is 35% to 90%, preferably 40% to 80%, 35 to 90%, 45% to 65%, 65%, 70%, 75%, 80%, 90% of the total weight of the matrix layer.

[0044] In some embodiments, the matrix layer further contains other pharmaceutically acceptable excipients, and the other pharmaceutically acceptable excipients are preferably one or more of a skin penetration enhancer, a tackifier, and a cohesion promoting additive.

[0045] In some embodiments, the skin penetration enhancer includes one or more of C2 to C30 saturated or unsaturated fatty acids, surfactants, and laurocapram.

[0046] In some embodiments, the C2 to C30 saturated or unsaturated fatty acid is selected from C2 to C20 saturated or unsaturated fatty acids, preferably one or more of oleic acid, isostearic acid, or stearic acid.

[0047] In some embodiments, the tackifier is selected from silicone oil, mineral oil, polybutene, terpene, and mixtures thereof, preferably light mineral oil; further, the dosage of the tackifier is 0-50%, preferably 0-30% of the total weight of the matrix layer.

[0048] In some embodiments, the matrix layer does not contain nonyl alcohol, isopropyl myristate, isopropyl palmitate, or lauryl lactate.

[0049] In some embodiments, the drug is selected from Olanzapine, rotigotine, Donepezil, Almotriptan, Aripiprazole, Apixaban, Asenapine, Baricigtinib, bisoprolol, Blonanserin, Buprenorphine, Dextroamphetamine, Dexmedetomidine, Eletriptan, Escitalopram, Frovatriptan, Granisetran, indomethacin, Lasmiditan, Meloxicam, Naratriptan, naproxen, Oxybutynin, Piroxicam, Pramipexole, rizatriptan, Ropinirole, Sumatriptan, Tolubuterol, Testosterone, and Zolmitriptan or a pharmaceutically acceptable salt thereof.

[0050] In another class of embodiments of the present invention, a method for preparing the aforementioned transdermal drug delivery system is provided, comprising the following steps:

[0051] Step 1. Dissolve the drug or a pharmaceutically acceptable salt thereof in a solvent to obtain a premix A; preferably, the solvent includes, but is not limited to, one or more of water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and ethyl acetate, and the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate, or a mixed solvent thereof.

[0052] Step 2. Mix the pressure-sensitive adhesive solution with a stabilizer that inhibits drug crystallization evenly to obtain a premix B; the stabilizer that inhibits drug crystallization is selected from an insoluble stabilizer that inhibits drug crystallization, a soluble stabilizer that inhibits drug crystallization, or a combination thereof; the mixing time is preferably from 0.1 hour to 24 hours.

[0053] Step 3. Add the premix A to the premix B to obtain a wet drug mixture, in which the drug or a pharmaceutically acceptable salt thereof is dispersed in a non-crystalline state;

[0054] Step 4. Coating the wet drug mixture onto a release film;

[0055] Step 5. Drying to remove the solvent, obtaining a release film / matrix layer laminate;

[0056] Step 6. Laminating the matrix layer onto a backing layer.

[0057] In another class of embodiments of the present invention, there is provided a method for preparing the aforementioned transdermal delivery system, comprising:

[0058] Step 1. Dissolving a stabilizer for inhibiting drug crystallization in a solvent and mixing evenly; preferably, the solvent includes but is not limited to one or more of water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, and the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof. The stabilizer for inhibiting drug crystallization is selected from insoluble stabilizers for inhibiting drug crystallization, soluble stabilizers for inhibiting drug crystallization or a combination thereof. The mixing time is preferably 0.1 hour to 24 hours.

[0059] Step 2. Adding a drug or a pharmaceutically acceptable salt thereof and mixing and dissolving until it is dispersed in a non-crystalline state;

[0060] Step 3. Adding a pressure-sensitive adhesive and mixing evenly to obtain a wet drug mixture;

[0061] Step 4. Coating the wet drug mixture onto a release film;

[0062] Step 5. Drying to remove the solvent, obtaining a release film / matrix layer laminate;

[0063] Step 6. Laminating the matrix layer onto a backing layer.

[0064] In some embodiments, Step 2 includes a step of heating to 30 - 65 °C to make the drug in a dissolved state; the heating temperature is preferably 35 - 45 °C, 45 - 55 °C.

[0065] In some embodiments, Step 3 is adding a pressure-sensitive adhesive heated to 30 - 65 °C and mixing evenly to obtain a wet drug mixture; the heating temperature is preferably 35 - 45 °C, 45 - 55 °C.

[0066] In some embodiments, Step 4 is coating the wet drug mixture onto a release film while keeping it at 30 - 65 °C; the heating temperature is preferably 30 - 40 °C, 35 - 45 °C, 45 - 55 °C.

[0067] In another class of embodiments of the present invention, there is provided the use of a therapeutically effective amount of the aforementioned transdermal delivery system in the preparation of a drug for treating or preventing a disease.

[0068] In another class of embodiments of the present invention, a method for treating or preventing a disease is provided, which comprises administering to a subject in need a therapeutically effective amount of the aforementioned transdermal delivery system.

[0069] In one embodiment of the present invention, an olanzapine transdermal delivery system is provided, having a three-layer structure as Figure 1 described, which comprises:

[0070] 1) A backing layer;

[0071] 2) A matrix layer, which contains olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer (i.e., the aforementioned stabilizer that inhibits drug crystallization), C2 to C 30 saturated or unsaturated fatty acid, and a pressure-sensitive adhesive; and

[0072] 3) A release liner.

[0073] In a further embodiment, the polymer skin penetration enhancer is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or a vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, plasdone K29 / 32, copovidone VA64, crospovidone CL-M, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan, or one or more thereof.

[0074] In a further embodiment, relative to the total weight of the matrix layer, the matrix layer contains the following components:

[0075] 1) The amount of olanzapine or a pharmaceutically acceptable salt thereof is 3-30%;

[0076] 2) The amount of the polymer skin penetration enhancer is 1.5-90%;

[0077] 3) C2 to C 30 The amount of saturated or unsaturated fatty acid is 3-30%;

[0078] 4) The amount of the pressure-sensitive adhesive is 30-90%;

[0079] The total amount of the components in the matrix layer is 100%.

[0080] In a further embodiment, the matrix layer further contains a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following:

[0081] 1) Carbohydrate polymers, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, ethylcellulose, methylcellulose, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, carrageenan;

[0082] 2) Acrylic or methacrylic acid polymers, preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55.

[0083] 3) Polyvinylpyrrolidone or crosslinked polyvinylpyrrolidone, preferably povidone K30, povidone K90, plasdone K29 / 32, copovidone VA64, or crospovidone CL-M.

[0084] In a further embodiment, the pressure-sensitive adhesive is selected from one or more of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, styrene-butadiene-styrene copolymer adhesives, silicone adhesives, and acrylic-copolymer silicone copolymer adhesives;

[0085] 1) The acrylic adhesives are selected from Henkel's Duro-Tak adhesives 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 GMS9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industries, Ltd.);

[0086] 2) The polyisobutylene adhesives are 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;

[0087] 3) The silicone adhesives are selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400, 7-4500, 7-4600, Bio-PSA SR7-4400, SRS7-4500, SRS7-4600;

[0088] 4) The acrylic-co-polysiloxane copolymer adhesives are selected from DuPont Bio-PSA 7-6100, 7-6200, and 7-6300; the Bio-PSA adhesives are dissolved in different solvents selected from one or more of n-heptane, ethyl acetate, toluene, or a hot melt.

[0089] In a further embodiment, the content of olanzapine or its pharmaceutically acceptable salt is 5% to 20% of the total weight of the matrix layer, preferably 5% to 15%, or 5% to 12%.

[0090] In a further embodiment, the content of the soluble polymeric 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%.

[0091] In a further embodiment, the content of the insoluble polymeric skin penetration enhancer is 5 to 60% of the total weight of the matrix layer, preferably 7.5 - 45%, 7.5 - 36, 15 - 36%.

[0092] In a further embodiment, the content of the pressure-sensitive adhesive is 40% to 80% of the total weight of the matrix layer, preferably 45% to 65%.

[0093] In a further embodiment, the matrix layer further comprises one or more of a small molecule skin penetration enhancer, an antioxidant, and an anti-skin irritant.

[0094] In a further embodiment, the small molecule skin penetration enhancer includes one or more of C2 to C 30 saturated or unsaturated fatty acids, surfactants, and azone.

[0095] In a further embodiment, the C2 to C30 saturated or unsaturated fatty acids are selected from C2 to C20 saturated or unsaturated fatty acids, preferably one or more of oleic acid, isostearic acid, or stearic acid.

[0096] In a further embodiment, the molar ratio of the C2 to C30 saturated or unsaturated fatty acid to olanzapine or its pharmaceutically acceptable salt is 0.05 to 3.3, preferably 0.5 to 1.65.

[0097] In another embodiment, there is provided a transdermal delivery system for olanzapine having asFigure 2 The four-layer structure described above includes:

[0098] 1) A backing layer;

[0099] 2) A matrix reservoir layer, which contains olanzapine or a pharmaceutically acceptable salt thereof, a polymeric skin penetration enhancer, a C2 to C 30 saturated or unsaturated fatty acid, and a pressure-sensitive adhesive, dispersed in the matrix layer in an amorphous state;

[0100] 3) A skin contact adhesive layer; and

[0101] 4) A release layer.

[0102] In a further embodiment, the skin contact adhesive layer includes, but is not limited to, one or more of an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a styrene-butadiene-styrene block copolymer adhesive, a silicone adhesive, and an acrylic-copolymer silicone copolymer adhesive.

[0103] In another embodiment, there is provided a transdermal drug delivery system for olanzapine, having the five-layer structure as Figure 3 described above, including:

[0104] 1) A backing layer;

[0105] 2) A matrix reservoir layer, which contains olanzapine or a pharmaceutically acceptable salt thereof, a polymeric skin penetration enhancer, a C2 to C 30 saturated or unsaturated fatty acid, and a pressure-sensitive adhesive

[0106] 3) A semipermeable membrane or a woven fabric layer;

[0107] 4) A skin contact adhesive layer; and

[0108] 5) A release layer.

[0109] In a further embodiment, the semipermeable membrane includes a continuous membrane or a microporous membrane.

[0110] In a further embodiment, the thickness of the semipermeable membrane or the woven fabric layer is about 10 μm to about 100 μm, preferably about 15 μm to about 50 μm.

[0111] In any of the transdermal drug delivery systems for olanzapine, the coating weight of the matrix layer is 100 to 1000 g / m 2 , preferably 100, 200, 300, 400, 500, 600 g / m 2 .

[0112] In any olanzapine transdermal delivery system, the skin permeation amount of the olanzapine or a pharmaceutically acceptable salt thereof within 7 days, 14 days, 21 days or 28 days or longer is greater than or equal to 2 μg / cm 2 / hr, preferably greater than or equal to 3, 4, 5, 6, 7, 8, 9 or 10 μg / cm2 / hr; or about 1 mg to about 18 mg of olanzapine or a pharmaceutically acceptable salt thereof is delivered to the blood circulation system of the subject per day, preferably about 2 mg to about 12 mg of olanzapine or a pharmaceutically acceptable salt thereof is delivered to the blood circulation system of the subject.

[0113] In any olanzapine transdermal delivery system, the matrix layer does not contain nonyl alcohol, isopropyl myristate, isopropyl palmitate or lauryl lactate.

[0114] In any olanzapine transdermal delivery system, the solvent selected during the preparation process is one or more of dimethylacetamide or dimethyl sulfoxide; ethanol, isopropanol or other solvents can be further selected as co-solvents.

[0115] In another embodiment, a method for preparing the olanzapine transdermal delivery system is provided, including the following steps:

[0116] Step 1. Dissolve olanzapine or a pharmaceutically acceptable salt thereof in a solvent to obtain a premix A;

[0117] Step 2. Mix the pressure-sensitive adhesive solution with an insoluble polymer skin penetration enhancer, and optionally a small molecule skin penetration enhancer, a surfactant, and an antioxidant for 0.1 hour to 24 hours to obtain a premix B;

[0118] Step 3. Add the premix A to the premix B to obtain a drug wet mixture, in which the olanzapine or a pharmaceutically acceptable salt thereof is dispersed in a non-crystalline state;

[0119] Step 4. Coat the drug wet mixture on a release liner;

[0120] Step 5. Dry to remove the solvent to obtain a release liner / matrix layer laminate;

[0121] Step 6. Laminate the matrix layer onto the backing layer.

[0122] In another embodiment, a method for preparing the olanzapine transdermal delivery system is provided, including the following steps:

[0123] Step 1. Dissolve a polymer penetration enhancer in a solvent, the solvent including but not limited to dimethylacetamide, dimethyl sulfoxide or a mixed solvent; optionally add a small molecule skin penetration enhancer, a surfactant and an antioxidant, and mix for 0.1 hour to 24 hours;

[0124] Step 2. Add olanzapine or a pharmaceutically acceptable acid addition salt thereof, and mix and dissolve until olanzapine or a pharmaceutically acceptable salt thereof is dispersed in a non-crystalline state;

[0125] Step 3. Add a pressure-sensitive adhesive and mix uniformly to obtain a wet drug mixture;

[0126] Step 4. Coat the wet drug mixture on a release layer;

[0127] Step 5. Dry to remove the solvent to obtain a release layer / substrate layer laminate;

[0128] Step 6. Laminate the substrate layer onto a backing layer.

[0129] In another embodiment, there is provided a method for preparing the olanzapine transdermal delivery system, which, when having a skin contact adhesive component, comprises the following steps:

[0130] Step 1. Prepare a release layer / substrate layer laminate as a drug reservoir according to any of the foregoing Steps 1 to 5;

[0131] Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally a skin penetration enhancer, an antioxidant, and other additives, coat it onto the release layer, and dry to form a skin contact adhesive layer / release layer laminate;

[0132] Step 3. Laminate the adhesive surface layer of the skin contact adhesive layer / release layer prepared in Step 2 onto the substrate reservoir layer of the material prepared in Step 1.

[0133] In another embodiment, there is provided a method for preparing the olanzapine transdermal delivery system, which, when having a semi-permeable membrane or a woven fabric layer, comprises the following steps:

[0134] Step 1. Prepare a release layer / substrate layer laminate as a drug reservoir according to any of the foregoing Steps 1 to 5;

[0135] Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally a skin penetration enhancer, an antioxidant, and other additives, coat it onto the release layer, and dry to form a skin contact adhesive layer / release layer laminate, and laminate the adhesive surface layer onto a semi-permeable membrane or a woven fabric layer;

[0136] Step 3. Laminate the semi-permeable membrane or the woven fabric layer of the material prepared in Step 2 onto the substrate reservoir layer of the material prepared in Step 1.

[0137] In another embodiment, there is provided the use of a therapeutically effective amount of an olanzapine transdermal delivery system in the preparation of a medicament for treating or preventing the positive and negative symptoms of schizophrenia, or reducing the frequency and intensity of nausea and vomiting associated with chemotherapy and caused by poly (ADP-ribose) polymerase inhibitors (PARPi).

[0138] In a further embodiment, the positive and negative symptoms of schizophrenia include psychosis, acute mania, and mild anxiety states.

[0139] In another embodiment, there is provided a method for treating or preventing the positive and negative symptoms of schizophrenia or reducing the frequency and intensity of nausea and vomiting associated with chemotherapy and caused by poly (ADP-ribose) polymerase inhibitors (PARPi), which comprises administering to a subject in need thereof a therapeutically effective amount of an olanzapine transdermal delivery system.

[0140] In a further embodiment, the positive and negative symptoms of schizophrenia include psychosis, acute mania, and mild anxiety states.

[0141] In a further embodiment, the olanzapine transdermal delivery system is administered once every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, or every 28 days.

[0142] In a further embodiment, the olanzapine transdermal 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 to the blood circulation system of the subject per day.

[0143] Surprisingly, the olanzapine transdermal delivery system of the present invention can continuously deliver olanzapine or a pharmaceutically acceptable salt thereof at a 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.

[0144] In addition, the olanzapine transdermal delivery system of the present invention has durable and good skin adhesion properties during the continuous delivery of olanzapine or a pharmaceutically acceptable salt thereof.

[0145] Moreover, the olanzapine transdermal delivery system of the present invention is not irritating and sensitizing to the skin during the continuous delivery of olanzapine or a pharmaceutically acceptable salt thereof.

[0146] In one class of embodiments of the present invention, there is provided a rotigotine transdermal delivery system, which comprises:

[0147] 1) A backing layer;

[0148] 2) A matrix layer, which contains 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;

[0149] 3) A release layer.

[0150] In some embodiments, the inhibitor of drug crystallization comprises insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.

[0151] In some embodiments, the stabilizer for inhibiting drug crystallization further comprises soluble povidone on the basis of insoluble crospovidone, and the soluble povidone is preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, copovidone VA64.

[0152] In some embodiments, 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.

[0153] In some embodiments, the weight ratio of rotigotine to soluble povidone is 9:0.5 - 9:4, preferably 9:1, 9:2, 9:3, 9:4.

[0154] In some embodiments, the stabilizer for inhibiting drug crystallization comprises polyvinylpyrrolidone or crosslinked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, plasdone K29 / 32, copovidone VA64, crosslinked povidone CL-M, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan.

[0155] In some embodiments, the matrix layer further comprises other pharmaceutically acceptable excipients. The other pharmaceutically acceptable excipients are optionally one or more of skin penetration enhancers, tackifiers, and cohesion-promoting additives.

[0156] In some embodiments, relative to the total weight of the matrix layer, the matrix layer comprises the following components:

[0157] 1) The dosage of rotigotine or a pharmaceutically acceptable salt thereof is 3 - 30%;

[0158] 2) The dosage of the stabilizer for inhibiting drug crystallization is 6-40%;

[0159] 3) The dosage of the pressure-sensitive adhesive is 30-90%;

[0160] 4) The tackifier is 0-50%;

[0161] 5) The skin penetration enhancer is 0-30%;

[0162] 6) The cohesion-promoting additive is 0-20%;

[0163] The total dosage of each component in the matrix layer is 100%.

[0164] In some embodiments, the matrix layer further comprises a cohesion-promoting additive selected from one or more of the following:

[0165] 1) Carbohydrate polymers, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, ethylcellulose, methylcellulose, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, carrageenan;

[0166] 2) Acrylic or methacrylic acid polymers, preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55.

[0167] In some embodiments, the pressure-sensitive adhesive is selected from one or more of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, styrene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic-copolymer silicone copolymer adhesives;

[0168] 1) The acrylic adhesives are selected from Henkel's Duro-Tak adhesives 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 GMS9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industries, Ltd.);

[0169] 2) The polyisobutene adhesive is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12, low molecular weight polybutene from Ineos, and mineral oil tackifiers;

[0170] 3) The silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4202, 7-4300, 7-4302, 7-4400, 7-4500, 7-4502, 7-4600, Bio-PSA SR7-4400, SRS7-4500, SRS7-4600;

[0171] 4) 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 selected from one or more of n-heptane, ethyl acetate, and toluene or a hot melt.

[0172] In some embodiments, 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.

[0173] In some embodiments, 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% of the total weight of the matrix layer.

[0174] In some embodiments, the content of the pressure-sensitive adhesive is 35% to 90%, preferably 40% to 90%, 70% to 90%, 65%, 70%, 75%, 80%, 90% of the total weight of the matrix layer.

[0175] In some embodiments, the tackifier is selected from silicone oil, mineral oil, polybutene, terpene, and mixtures thereof, preferably light mineral oil. In some embodiments, the amount of the tackifier is 0 - 50%, preferably 0 - 30%, 0 - 28% of the total weight of the matrix layer.

[0176] In some embodiments, the weight ratio of rotigotine to the tackifier is 9:25 - 9:40, preferably 9:30 - 9:35.

[0177] In some embodiments, the content of the skin penetration enhancer is 0 to 30%, preferably 5 - 30%, 5 - 24%, 10 - 20%, 12.5 - 20% of the total weight of the matrix layer.

[0178] In some embodiments, the skin penetration enhancer includes an optional surfactant.

[0179] In some embodiments, the rotigotine transdermal delivery system may further include structures such as a skin contact adhesive layer, a semi-permeable membrane, or an organic fabric layer.

[0180] In another class of embodiments of the present invention, a method for the aforementioned rotigotine transdermal delivery system is provided, comprising the following steps:

[0181] Step 1. Dissolve a stabilizer that inhibits drug crystallization in a solvent and mix for 0.1 hour to 24 hours;

[0182] Step 2. Add rotigotine or a pharmaceutically acceptable salt thereof and mix until dissolved so that rotigotine or a pharmaceutically acceptable salt thereof is dispersed in a non-crystalline state;

[0183] Step 3. Add a pressure-sensitive adhesive and mix evenly to obtain a wet drug mixture;

[0184] Step 4. Coat the wet drug mixture on a release film;

[0185] Step 5. Dry to remove the solvent to obtain a release film / matrix layer laminate;

[0186] Step 6. Laminate the matrix layer onto the backing layer.

[0187] In some embodiments, the solvent in Step 1 includes, but is not limited to, one or more of toluene, ethanol, isopropanol, dimethylacetamide, and dimethyl sulfoxide, preferably toluene, ethanol, isopropanol, or a mixed solvent thereof.

[0188] In some embodiments, Step 2 includes a step of heating to 30 - 65 °C to dissolve the drug. 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, 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.

[0189] In some embodiments, step 3 is to add a pressure-sensitive adhesive heated to 30 - 65°C and mix evenly to obtain a wet drug 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.

[0190] In some embodiments, step 4 is to coat the wet drug mixture on a release film while keeping it at 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, 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.

[0191] In another class of embodiments of the present invention, there is provided the use of a therapeutically effective amount of the foregoing rotigotine transdermal delivery system in the preparation of a medicament for treating or preventing a disease sensitive to the action of a dopamine receptor agonist.

[0192] In some embodiments, the disease is a disease sensitive to the action of rotigotine.

[0193] In some embodiments, the disease is Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and dopaminergic neuronal loss.

[0194] In another class of embodiments of the present invention, there is provided 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 thereof a therapeutically effective amount of the foregoing rotigotine transdermal delivery system.

[0195] In some embodiments, the disease is a disease sensitive to the action of rotigotine.

[0196] In some embodiments, the disease is Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and dopaminergic neuronal loss.

[0197] In some embodiments, 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, or every 28 days.

[0198] In some embodiments, the rotigotine transdermal delivery system delivers from about 1 mg to about 18 mg of rotigotine or a pharmaceutically acceptable salt thereof to the bloodstream of the subject, preferably from about 2 mg to about 12 mg of rotigotine base or a pharmaceutically acceptable salt thereof to the bloodstream of the subject per day.

[0199] Definitions

[0200] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are within the scope of sound medical judgment, suitable for contact with a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, etc., having a reasonable benefit / risk ratio, and effective for their intended use.

[0201] The "pharmaceutically acceptable salts" of the present invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final separation and purification process of the compound, or by reacting the purified compound in free base form with a suitable organic or inorganic acid separately and isolating the salt thus formed. Examples of inorganic acid addition salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, hydroiodides, phosphites, borates, etc. Examples of 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 formates, glyoxylates, oxalates, acetates, glycolates, acrylates, pyruvates, malonates, propionates, 3-hydroxypropionates, lactates, glycerates, fumarates, maleates, oxaloacetates, crotonates, acetoacetates, 2-oxobutyrates, methylmalonates, succinates, malates, L-tartrates, DL-tartrates, meso-tartrates, ditartrates, butyrates, isobutyrates, hydroxybutyrates, acetylpropionates, sorbates, itaconates, mesaconates, ketoglutarates, glutarates, succinates, methylsuccinates, valerates, isovalerates, pivalates, cis-aconitates, trans-aconitates, ascorbates, citrates, isocitrates, adipates, hexanoates, benzoates, salicylates, gentisates, protocatechualtes, gallates, cyclohexanecarboxylates, pimelates, benzoates, chlorobenzoates, phthalates, isophthalates, terephthalates, terephthalates, phenylacetates, toluates, o-toluenates, m-toluenates, p-toluenates, dinitrobenzoates, benzenesulfonates, toluenesulfonates, citrates, methanesulfonates, oleates, toluenesulfonates, naphthalenemethanesulfonates, glucoheptonates, lacturonates, lauryl sulfonates and hydroxyethyl sulfonates, mandelates, homogentisates, octanedioates, octanoates, decanoates, laurates, palmitates, stearates, isostearates, oleates, elaidates, gondoates, erucates, nervonates, and cetates, hexadecatrienoates, linoleates, α-linolenates, γ-linolenates, calendulates, stearates, meadates, eicosadienoates, eicosatrienoates, dihomo-γ-linolenates, arachidonates, docosadienoates, etc. and combinations thereof.

[0202] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or molecule of the present invention which, when administered to a subject, (i) treats or prevents a specific disease, disorder or condition, (ii) diminishes, ameliorates or eliminates one or more symptoms of a specific disease, disorder or condition, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, disorder or condition described herein.

[0203] As used herein, the term "about" refers to plus or minus 10% of the indicated number. For example, "about 10%" can represent a range from 9% to 11%, and "about 1" can represent 0.9 - 1.1.

[0204] As used herein, the term "treatment" refers to a clinical intervention that attempts to alter the natural course of the individual being treated and can be prophylactic or in the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and relieving or improving the prognosis.

[0205] As used herein, the term "C2 to C 30 fatty acid" includes saturated or unsaturated C2 to C 30 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, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxy tartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, levulinic acid, sorbic acid, itaconic acid, methylenesuccinic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitic acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, hexanoic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentisic acid, suberic acid, octanoic acid, decanoic acid, lauric acid, palmitic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, gondoic acid, erucic acid, nervonic acid, and calendic acid, hexadecatrienoic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, stearidonic acid, eicosadienoic acid, eicosatrienoic acid, dihomo-γ-linolenic acid, arachidonic acid, docosadienoic acid and combinations thereof. Preferably oleic acid, isostearic acid, or stearic acid.

[0206] As used herein, the term "backing layer" serves as the upper surface of a transdermal patch and, as a primary structural element, provides flexibility to the patch. Preferably, the backing layer is substantially impermeable to the pharmaceutical composition for transdermal delivery. The backing layer is preferably made of a sheet or film of a flexible elastic material. The backing layer is preferably airtight. The backing layer for 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. A non-occlusive backing layer allows the area to breathe (i.e., promotes the transport of water vapor across the skin surface), while an occlusive backing layer reduces air / steam permeation. Preferably, the backing layer of a matrix-type transdermal delivery system ( Figures 1 - 3 ) is occlusive. Preferably, the backing layer comprises a synthetic polymer such as polyolefin, polyester, polyethylene, polyvinylidene chloride, and polyurethane. Preferably, the backing layer has a thickness of about 0.5 mils to about 5 mils; more preferably, the backing layer has a thickness of about 1 mil to about 3 mils. Preferably, the oxygen transmission rate is about 2 cc / m / 24 hr to about 100 cc / m / 24 hr. Preferably, the MVTR is about 0.1 g / m / 24 hr to about 50 g / m / 24 hr, and more preferably, the MVTR is about 0.3 g / m / 24 hr to about 30 g / m / 24 hr. In a preferred embodiment, the backing layer is an occlusive polyester film layer about 2.0 mils thick (commercially available, e.g., Scotchpak 9733, Scotchpak 9735, and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul Minn.). Scotchpak 9733 consists of a polyester and a medium-density polyethylene / ethylene vinyl acetate heat-seal layer, and the laminate is translucent, conformable, occlusive, and heat-sealable. It can be used for Figures 1 - 3 the matrix-type transdermal delivery system shown. More preferably, the backing layer comprises a laminate including an aluminum foil layer between polymer film layers, such as Scotchpak 9738 and Scotchpak 1109. When the patch is applied to the skin, the aluminum layer prevents light from contacting photosensitive drugs.

[0207] As used herein, the term "insoluble crosslinked polyvinylpyrrolidone" is a high molecular weight water-insoluble polymer obtained by crosslinking N-vinyl-2-pyrrolidone, and is a white or near-white powder, odorless and tasteless, with good fluidity, insoluble in water and various solvents, and also insoluble in strong acids or strong bases. Non-limiting examples of "insoluble crosslinked polyvinylpyrrolidone" include CL-M, crosslinked polyvinylpyrrolidone CL, crosslinked polyvinylpyrrolidone CL-F, and crosslinked polyvinylpyrrolidone CL-SF.

[0208] Non-limiting examples of antioxidants include tocopherols, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate. Chelating agents used as co-antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA. Preferably, the antioxidant is α-tocopherol (α-dl-tocopherol), i.e., vitamin E. The content of α-tocopherol is 0.05 to 0.5% of the total weight of the adhesive layer, preferably 0.1% to 0.2%.

[0209] As used herein, the term "semipermeable membrane or woven fabric layer" is used to contain a liquid or semi-solid matrix material within the matrix drug layer, and its function is to control the diffusion of the drug or its pharmaceutically acceptable salt from the liquid or semi-solid matrix drug layer to the skin contact adhesive layer. The semipermeable membrane or woven fabric layer and the backing layer can be sealed together around the peripheral edge.

[0210] Semipermeable membranes include, but are not limited to, ethylene-co-vinyl acetate copolymer membranes, polyethylene polymer membranes, and 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 membranes include Solupore. Non-limiting examples of polypropylene polymer membranes include Celgard 2400.

[0211] Suitable semipermeable membranes include continuous membranes and microporous membranes, and can be made of woven or non-woven materials. The semipermeable membrane is preferably made of a flexible polymeric material commonly used by those skilled in the art. Polymer membranes that can be used to manufacture the semipermeable membrane layer include, but are not limited to, those containing low-density polyethylene, high-density polyethylene, ethylene-vinyl acetate copolymer, polypropylene, and other suitable polymers. In one embodiment, the semipermeable membrane layer is made of a microporous membrane prepared from an ethylene-vinyl acetate copolymer containing about 0.5 to about 28 wt.% vinyl acetate. Suitable woven materials include Saatifil PES, such as PES 105 / 52 available from Saatitech, Inc. A suitable non-woven fabric is Sontara from DuPont Nonwovens Sontara Technologies. In a preferred embodiment, the semipermeable membrane layer is an ethylene-vinyl acetate copolymer membrane available from 3M™, such as Cotran 9702, Cotran 9705, Cotran 9706, Cotran 9707, Cotran 9712, Cotran 9715, Cotran 9716, and Cotran 9728 (available from 3M™).

[0212] The thickness of the semi-permeable membrane layer can generally be from about 10 μm to about 100 μm, preferably from about 15 μm to about 50 μm.

[0213] As used herein, the term "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.

[0214] As used herein, the term "release layer" 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 release liners.

[0215] As used herein, the term "GSM" refers to the grams of the solid matrix layer contained in the transdermal system per square meter, with the specific unit being "grams per square meter" or (g / m 2 ) Brief Description of the Drawings

[0216] Figure 1 A schematic diagram of the three-layer matrix type transdermal drug delivery system according to the present invention is shown.

[0217] Figure 2 A schematic diagram of the four-layer matrix type transdermal drug delivery system according to the present invention is shown.

[0218] Figure 3 A schematic diagram of the five-layer matrix type transdermal drug delivery system according to the present invention is shown.

[0219] Figure 4 Measurement curves of the skin flux of the transdermal drug delivery systems described in Example A1, A8 and Comparative Example A1 are shown.

[0220] Figure 5 Measurement curves of the skin flux of the transdermal drug delivery systems described in Example A21, A22 and Comparative Examples A2, A3, A4, A5 are shown.

[0221] Figure 6 Measurement curves of the skin flux of the transdermal drug delivery system described in Example A24 are shown.

[0222] Figure 7 Measurement curves of the skin flux of the transdermal drug delivery systems described in Example A25 and Comparative Example A6 are shown.

[0223] Figure 8 Measurement curves of the skin flux of the transdermal drug delivery systems described in Example A26 (100 GSM), Example A26 (200 GSM), Example A26 (300 GSM), Example A26 (400 GSM), Example A27 (400 GSM) are shown.

[0224] Figure 9 Shows the measurement curves of the skin fluxes of the transdermal delivery systems described in Example A28 and Comparative Example A7.

[0225] Figure 10 Shows the measurement curve of the skin flux of the transdermal delivery system described in Example A29.

[0226] Figure 11 Shows the measurement curves of the skin fluxes of the transdermal delivery systems described in Examples A30 - A33 and Comparative Examples A8 - A11.

[0227] Figure 12 Shows the measurement curves of the skin fluxes of the transdermal delivery systems of Examples C1 - C2. Detailed implementation manners

[0228] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are a module embodiment of the present invention, rather than all the embodiments. The elements and features described in one embodiment of the present invention can be combined with the elements and features shown in one or more other embodiments. It should be noted that for the sake of clarity, the representation and description of components and processes unrelated to the present invention and known to those of ordinary skill in the art are omitted. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0229] Anti - crystallization Stability Experiment

[0230] Table 1. Olanzapine anti-crystallization stability

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] Comparative Example A1

[0237] Olanzapine (1.5 g) and dimethylacetamide (2.5 g) were added to a glass jar. They were mixed and heated at 85 °C to dissolve and form a clear solution. Duro-Tak 387-2516 (17.71 g) was added and mixed into a uniform suspension, and degassed to remove bubbles. It was dried and coated onto a silicated polyester release liner at 100 gsm, dried in a forced-air oven at 50 °C for 5 minutes, and then dried in a forced-air oven at 120 °C for 15 minutes to remove the solvent. The adhesive layer of a part of the dried two-layer laminate was laminated onto a transparent backsheet ScotchPak 9733, and another part was laminated onto an aluminized backsheet Scotchpak 1109. The three-layer laminate was die-cut into 10-square centimeter patches and each patch was heat-sealed into an aluminized bag for stability studies. The bagged patches were stored at room temperature. Microscopic analysis was performed on the 7th day after patch manufacturing. From the crystal observation results in Table 1, many crystals were observed in the transparent Scotchpak 9733-backed patches at 100-fold magnification on the 7th day and the 28th day. Because the comparative formulation 1 in Comparative Example 1 did not contain a crystallization inhibitor, the dissolved olanzapine crystallized rapidly.

[0238] Example A1 (Formulation A1)

[0239] Povidone K30 (0.45 g), olanzapine (0.90 g), and dimethylacetamide (2.25 g) were added to a glass jar. They were mixed and heated at 85 °C to dissolve and form a clear solution. Duro-Tak 387-2516 (15.94 g) was added and mixed into a uniform suspension, and degassed to remove bubbles. It was dried and coated onto a silicated polyester release liner at 100 gsm, dried in a forced-air oven at 50 °C for 5 minutes, and then dried in a forced-air oven at 120 °C for 15 minutes to remove the solvent. The adhesive layer of a part of the dried two-layer laminate was laminated onto a transparent backsheet ScotchPak 9733, and another part was laminated onto an aluminized backsheet Scotchpak 1109. The three-layer laminate was die-cut into 10-square centimeter patches and each patch was heat-sealed into an aluminized bag for stability studies. The bagged patches were stored at room temperature. The crystal observation results are shown in Table 1. No olanzapine crystals were observed under a transmission light microscope at 100-fold magnification after 18 days (Table 1). Formulation 1 in Example A1 contained povidone K30 as a crystallization inhibitor, so no crystals were formed during storage.

[0240] Examples A2 to A5 (Formulations A2 to A5)

[0241] Add olanzapine (1.02 g), lactic acid (0.512 g) and dimethylacetamide (2.508 g) to a glass jar. Mix and heat at 85 °C to dissolve and form a clear solution. Add crospovidone CL-M (1.04 g) and mix well. Add lauryl lactate (1.51 g) and Duro-Tak 387-2516 (12.74 g), mix into a homogeneous suspension, and degas to remove air bubbles. Dry coat onto a siliconized polyester release liner at 100 gsm, dry in a forced-air oven at 50 °C for 5 minutes, and then dry in a forced-air oven at 120 °C for 15 minutes to remove the solvent. Laminate the adhesive layer of a part of the dried two-layer laminate onto a transparent backsheet ScotchPak 9733, and laminate another part onto an aluminized backsheet Scotchpak 1109. Die-cut the three-layer laminate into 10 cm² patches and heat-seal each patch into an aluminized bag for stability studies. The bagged patches are stored at room temperature. From the crystallization observation results in Table 1, no olanzapine crystals were observed under a transmission light microscope at 100-fold magnification after storing the transparent Scotchpak 9733 backsheet patches at room temperature for 10 days and 31 days or at 40 °C for 31 days. This is because the crystallization inhibitor crospovidone CL-M and the solubilizer lactic acid are present. As described in the skin adhesion, finger pressure and physical properties section, crospovidone can also improve the physical properties and skin adhesion of formulations containing liquid lactic acid or other liquid excipients.

[0242] Formulations A3 to A5 in Examples A3 to A5 were prepared similarly. As can be seen from Table 1, due to the presence of the crystallization inhibitor crospovidone CL-M and the solubilizer lactic acid, no crystallization occurred after 31 days at room temperature and 40 °C.

[0243] Example A6 (Formulation A6) and Example A7 (Formulation A7)

[0244] Formulation 6 and Formulation A7 contain the crystallization inhibitor polyvinylpyrrolidone K30 and the silicone adhesives Bio-PSA 4202 and 7-4302, and no olanzapine crystals were observed after 31 days.

[0245] Example A8 (Formulation A8) and Example A9 (Formulation A9)

[0246] As can be seen from Table 1, Formulation A9 in Example A9 contains 22% of the crystallization inhibitor crospovidone CL-M (22%), which is more than the crospovidone CL-M (15%) in Formulation A8 in Example A8. Formulation 9 is more stable against crystallization than Formulation 8 on the 26th day because no crystals were observed in Formulation 9 on the 26th day, but a small amount of crystals were observed in Formulation 8.

[0247] Example A10 (Formulation A10) to Example A12 (Formulation A12)

[0248] Since formulation 10 contains the very hydrophobic silicone adhesive Bio-PSA 7-4302, 15% crospovidone CL-M is not sufficient to inhibit olanzapine crystallization, but is more sufficient to inhibit crystallization in formulations containing a silicone adhesive and the acrylic adhesive Duro-Tak 387-2516.

[0249] Examples A13 (Formulation A13) to A17 (Formulation A17)

[0250] Examples A13 to A17 further showed that as the amount of crospovidone CLM increased, the formulations containing the acrylic adhesive Duro-Tak 387-2516 were more stable against olanzapine crystallization.

[0251] Examples A18 (Formulation A18) to A20 (Formulation A20)

[0252] When the adhesive was changed from the hydroxyethyl-functional acrylic adhesive Duro-Tak 387-2516 to the carboxy-functional acrylic adhesive Duro-Tak 387-2504, no olanzapine crystals formed in the patch even at 10% crospovidone CL-M after 3 months at room temperature and 40 °C.

[0253] Examples A22 (Formulation A22) to A24 (Formulation A24)

[0254] For Formulations A22 to 24 containing a liquid solubilizer (lactic acid or oleic acid) that dissolves part of the olanzapine and a crystallization inhibitor (micronized solid powder crospovidone CL-M), no crystals were observed after 48 days at room temperature. This means that crospovidone CL-M enhances the stability against olanzapine crystallization. As described in the Skin Adhesion, Finger Tack and Physical Properties section, crospovidone CL-M also improves the physical properties and skin adhesion of formulations containing a liquid solubilizer.

[0255] Example A25 (Formulation A25)

[0256] Eudragit E100 (6 g), oleic acid (4 g), and dimethylacetamide (16 g), DL-α-tocopherol (0.12 g), ascorbyl palmitate NF (0.04 g), and sodium metabisulfite (0.002 g) were added to a glass jar. The mixture was heated at 50 °C to dissolve and form a clear solution. Duro-Tak 387-2516 (54 g) was added and mixed for 24 hours to form a homogeneous suspension. Olanzapine (4 g) was added, and after mixing for 2 hours, the mixture was degassed to remove air bubbles. It was dried and coated onto a silicated polyester release liner at 100 gsm, dried in a forced-air oven at 50 °C for 4 minutes, and then dried in a forced-air oven at 90 °C for 6 minutes to remove the solvent. The adhesive side was laminated onto a transparent backsheet ScotchPak 9733. The three-layer laminate was die-cut into 10 cm² patches, and each patch was heat-sealed into an aluminized bag for stability studies. The bagged patches were stored at room temperature. From the crystal observation results in Table 1, no crystal formation was observed after 32 days at room temperature due to the presence of both oleic acid and Eudragit E100. As described in the skin adhesion, finger tack, and physical properties sections, Eudragit E100 also improved the physical properties and skin adhesion of the formulation.

[0257] Comparative Example 2 (Comparative Formulation A2) and Comparative Example 3 (Comparative Formulation A2)

[0258] Comparative Formulation A2 and Comparative Formulation A3 contain liquid lactic acid and oleic acid and do not contain 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, finger tack, and physical properties sections.

[0259] Comparative Example A4 (Comparative Formulation A4)

[0260] To prepare Comparative Formulation A4, a mixed solution, an olanzapine solution, and an excipient solution were prepared according to Tables 2-1, 2-2, and 2-3, respectively. Then, the wet formulation Formulation A was prepared according to Table 2-4. The final dry formulation composition Formulation A is shown in Table 2-5.

[0261] Table 2-1. Mixed Solvents

[0262] Components gram acetone 19.019 methanol 4.76 trifluoroacetic acid 0.29 Total 24.062

[0263] Table 2-2. Olanzapine Solution

[0264] Components gram w / w% mixed solvent 21.06 96.28 olanzapine 0.81 3.72 Total 21.88 100.00

[0265] Table 2-3. Excipient Solution

[0266] Components gram w / w% oleic acid 2.68 57.13 isopropyl myristate 1.35 28.79 olanzapine 0.66 14.08 Total 4.69 100.00

[0267] Table 2-4. Wet Prescription A

[0268]

[0269]

[0270] Table 2-5. Dry Prescription A

[0271]

[0272] Example A26 (Prescription A26):

[0273] Premix A: Add polyvinylpyrrolidone K90 (6 g), Eudragit E100 (6 g), oleic acid (6 g), and dimethylacetamide (24 g), DL-α-tocopherol (0.09 g), ascorbyl palmitate NF (0.0006 g), and sodium metabisulfite (0.0005 g) to a glass jar. Mix to dissolve and form a clear solution. Mix at room temperature for 24 hours to form a homogeneous solution. Add olanzapine (5.5 g) and mix for 1 hour to form a solution.

[0274] Solution B: Weigh the amount of binder Dura-Tak 387-2287 (64.9 g) according to Prescription A into a glass bottle. Add DL-α-tocopherol (0.0825 g), ascorbyl palmitate NF (0.0006 g), sodium metabisulfite (0.0004 g), and hydroxytoluene (0.0275 g) to a glass jar. Mix at room temperature for 24 hours.

[0275] Add 48 g of Premix A to Solution B and homogenize for 7 minutes. Coat onto a siliconized polyester release liner at 50 gsm and dry in a forced-air oven at 50°C for 4 minutes, then dry in a forced-air oven at 90°C for 6 minutes to remove the solvent. Laminate the adhesive side onto a transparent backsheet ScotchPak 9733. Die-cut the three-layer laminate into 10 cm² patches and heat-seal each patch into an aluminized bag for stability studies.

[0276] Prepare Example A27 using a similar method. At the time of writing this invention, this formulation did not form crystals. Polyvinylpyrrolidone and Eudragit E100 effectively inhibited the formation of olanzapine crystals at room temperature for 49 days and at a storage temperature of 40°C for 40 days.

[0277] Example A28 (Implementation Prescription A28) and Comparative Example A7 (Comparative Prescription A7):

[0278] Add olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) into a glass jar. Mix and dissolve to form a clear solution. Add isopropyl palmitate (1.26 g), myristyl alcohol (1.07 g), glyceryl monooleate (1.74 g) and Dura-Tak 87-900A (44.05 g). Mix well. After degassing, coat it on a release liner with a target dry thickness of about 130 GSM. Dry at 37.8 °C for 60 minutes. Apply a back film on top of the adhesive. It was found that the release liner could not be peeled off. GC found that the residual DMSO was 6.52%.

[0279] In another coating, a wet coating was dried at 50 °C for 5 minutes and at 90 °C for 3.5 minutes. GC analysis found that the residual DMSO was 2.70%. Microscopic analysis of the patch showed that a large number of olanzapine crystals were formed on the first day.

[0280] Another wet coating was dried at 50 °C for 5 minutes and at 90 °C for 7 minutes. GC found that the residual DMSO was 0.25%.

[0281] Comparative Example A7 (Comparative Prescription A7):

[0282] Add olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) into a glass jar. Mix and dissolve to form a clear solution. Add Dura-Tak 87-900A (52.06 g). Mix well. After degassing, coat it on a release liner with a target dry thickness of about 130 GSM. Dry at 37.8 °C for 60 minutes. Apply a back film on top of the adhesive. It was found that the release liner could be peeled off. GC found that the residual DMSO was 7.25%.

[0283] In another coating, a wet coating was dried at 50 °C for 5 minutes and at 90 °C for 3.5 minutes. GC found that the residual DMSO was 3.52%. Microscopic analysis of the patch showed that a large number of olanzapine crystals were formed on the first day. Microscopic analysis of the patch showed that a large number of olanzapine crystals were formed on the first day.

[0284] Another wet coating was dried at 50 °C for 5 minutes and at 90 °C for 7 minutes. GC found that the residual DMSO was 0.92%.

[0285] Example A29 (Prescription A29):

[0286] Premixed Solution A: Add polyvinylpyrrolidone K90 (5.5 g), oleic acid (8.25 g), dimethylacetamide (22 g), D-α-tocopherol (0.2063 g), ascorbyl palmitate NF (0.0413 g), 10% aqueous sodium metabisulfite (0.0062 g), and butylated hydroxytoluene (0.2063 g) 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 form a homogeneous solution. Add olanzapine (5.5 g) and mix for 1 hour to form a solution.

[0287] Solution B: Weigh 64.3814 g of binder Dura-Tak 387-2510 containing 0.56% titanium butoxide into a glass bottle. Add D-α-tocopherol (0.05 g), ascorbyl palmitate NF (0.01 g), 10% sodium metabisulfite (0.0015 g), and butylated hydroxytoluene (0.05 g) to a glass jar and mix for 24 hours.

[0288] Add 30.33 g of Premixed Solution A to Solution B and homogenize and mix for 7 minutes. Dry coat at 50 gsm onto a siliconized polyester release liner, dry in a forced-air oven at 50 °C for 4 minutes, and then dry in a forced-air oven at 90 °C for 6 minutes to remove the solvent. Laminate the adhesive side onto a transparent backsheet ScotchPak 9733.

[0289] In Vitro Skin Flux Experiment

[0290] Perform in vitro permeation testing using a vertically static modified Franz cell. The volume of the receptor cell is 7 ml, filled with a buffer solution at pH 6.5, and the effective skin permeability is 0.61 cm2. Mount human cadaver skin on the receptor cell with the dermal layer facing the receptor cell. Place the matrix layer on the stratum corneum side of the human cadaver skin. Place an O-ring on top of the skin.. Fix the donor cell on top of the receptor cell. Place the Franz cell in a 32 °C incubator on a magnetic stirrer plate. Take 2 ml of solution at each pre-arranged time point, pour out the remaining solution, and replenish with fresh receptor solution. Immediately analyze the amount of olanzapine in the receptor solution by HPLC.

[0291] Since there is no crystallization inhibitor such as polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90, the olanzapine dissolved by crospovidone CL-M crystallizes after formulation. As shown in Table 3 ( Figure 4 ), the in vitro skin flux of the crystalline preparation (comparative formulation A1 in Comparative Example 1) rapidly decreases from the 48-hour time point to the 168-hour time point. From the 48-hour time point to the 168-hour time point, the in vitro skin fluxes of the two non-crystalline preparations (Formulation A2 and Formulation A8) are still much higher than that of Comparative Formulation A1.

[0292] Table 3. Skin Permeation Flux (μg / cm2 / hr): Example A1, Example A8, and Comparative Example A1

[0293]

[0294] The in vitro skin flux of the amorphous formulation A22 containing 15 wt% crospovidone CL-M is higher than that of the comparative formulation A2 without crospovidone CL-M or povidone K30 (Table 4, Figure 5 ). As will be described in the skin adhesion, finger test, and physical properties sections, some adhesive transfer to the finger was observed in the finger test for comparative formulation A2 (Comparative Example A12, Table 11), and its physical properties and skin adhesion were unacceptable. Crospovidone CL-M not only increases skin flux but also improves the physical properties and skin adhesion of formulation A22 by increasing the cohesive force within the adhesive matrix, thereby reducing adhesive transfer to the skin.

[0295] The in vitro skin flux of formulation 23 containing 15 wt% crospovidone CL-M is higher than that of comparative formulations A3 and A5 without crospovidone CL-M or povidone K30 (Table 4, Figure 5 ). As will be described in the skin adhesion, finger test, and physical properties sections, the physical properties (some adhesive transfer to the finger was observed in the finger test, see Comparative Example A13, Table 11) and skin adhesion of comparative formulations A3 and A5 were unacceptable. Crospovidone CL-M not only increases skin flux but also improves the physical properties and skin adhesion of formulation A23 by increasing the cohesive force within the adhesive matrix, thereby reducing adhesive transfer to the skin.

[0296] Although the in vitro skin flux of Example A1 of US Patent US20070148218A1 is good due to the presence of a skin penetration enhancer, as shown in Table 11 of this application, excessive adhesive transfer to the finger was observed, and an adhesive flow was formed in the finger test (Comparative Example A15, Table 11). Therefore, the physical properties of Example A in 20070148218A1 are unacceptable.

[0297] 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 is lower than that of Example A23, indicating that the addition of liquid lauryl lactate reduces the average skin flux (Table 4, Figure 5 ). The addition of liquid lauryl lactate also reduces the integrity of the adhesive matrix. Therefore, some adhesive transfer to the finger was observed in the finger test (Comparative Example A14, Table 11).

[0298] Table 4. Skin Permeation Flux (g / cm 2 / hr): Examples A22 - 23, Comparative Examples A2 - 5

[0299]

[0300] Table 5( Figure 6 ) shows that the in vitro skin flux of the amorphous formulation A24 containing 9.3% oleic acid and 15% Eudragit is high from the 24 - hour time point to the 168 - hour time point. As shown in Table 11, no adhesive transfer to the finger occurred in the finger test of formulation A24 (Example A38, Table 11).

[0301] Table 5. Skin permeation flux (μg / cm 2 / hr): Example A24

[0302]

[0303] The average epidermal flux of Comparative Example A6 is similar to that of Example A25, as shown in Table 6( Figure 7 ). The fatty alcohol nonanol did not increase the skin permeation of olanzapine.

[0304] Table 6. Skin permeation flux (μg / cm 2 / hr): Example A25 and Comparative Example A6

[0305]

[0306] Example A26

[0307] The composition of formulation A26 of Example A26 is: 10% olanzapine, 10% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-α-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.1% BHT, 59.5965% Dura-Tak387 - 2287.

[0308] This formulation A contains a polymeric skin penetration enhancer (10% polyvinylpyrrolidone K90) and 10% oleic acid. This system effectively inhibits the crystal formation of olanzapine (Table 1). The skin permeability of this formulation is high for 7 days (Table 7, Figure 8 ), and from 100 GSM (grams per square meter), 200 GSM, 300 GSM, 400 GSM, the skin permeability increases with the increase in the matrix thickness (coating weight). At the same time, the polymeric skin penetration enhancer (10% polyvinylpyrrolidone K90) improves the cohesion of the adhesive, thus reducing the adhesive transfer to the finger in the finger test (Example A39, Table 11).

[0309] Example A27

[0310] The formulation of Example A27, Formulation A27, consists of: 10% olanzapine, 15% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-α-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.1% BHT, 54.5965 Dura-Tak 387-2287 (400 GSM substrate layer).

[0311] This Formulation A contains a polymeric skin penetration enhancer (10% polyvinylpyrrolidone K90) and 15% oleic acid. This system effectively inhibits the crystal formation of olanzapine (Table 1). Compared to Example A26, Formulation A has a higher 7-day skin permeability at 400 GSM (Table 7, Figure 8 ). At the same time, the polymeric skin penetration enhancer (10% polyvinylpyrrolidone K90) improves the cohesion of the adhesive, thus reducing adhesive transfer to the finger during the finger test (Example A40, Table 11).

[0312] Table 7. Skin penetration flux (μg / cm 2 / hr): Example A26, Example A27

[0313]

[0314]

[0315] Example A28 and Comparative Example A7

[0316] The formulation of Example A28, Formulation A28, consists of: 9% olanzapine, 10% oleic acid, 16% DMSO (2.7% after drying), 65% Duro-Tak 87-900A (110 GSM substrate layer).

[0317] The formulation of Comparative Example A7, Comparative Formulation A7, consists of: 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 (120 GSM substrate layer).

[0318] The average epidermal flux of Comparative Example A7 is similar to that of Example A28, as shown in Table 8 ( Figure 9 ). Isopropyl palmitate (fatty acid ester) and myristyl alcohol (fatty alcohol) do not increase the skin penetration of olanzapine. On the contrary, they reduce the integrity of the adhesive matrix. Therefore, there is some adhesive transfer to the finger during the finger test (Comparative Example A12, Table 11).

[0319] Example A28 and Comparative Formulation A7 did not contain the polymeric skin penetration enhancer povidone. Therefore, on day 1, olanzapine crystals were formed in both formulations. The skin fluxes of both formulations were much lower than those of Formulations A26, 27, and 29 containing 10% povidone K90 and 10% oleic acid prepared by Preparation Method 2.

[0320] Table 8. Skin Permeation Flux (μg / cm 2 / hr): Example A28 and Comparative Example A7

[0321]

[0322] Example A29

[0323] The composition of Formulation A29 of Example A29 was: 10% olanzapine, 15% oleic acid, 10% povidone K90, 0.5% DL-α-tocopherol, 0.1% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.5% BHT, 63.8985% Duro-Tak 387-2510, 0.56% polybutyl acrylate (600 GSM backing layer).

[0324] Formulation A29 of Example A29 contained a polymeric 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 permeability of Formulation A was very high (Table 9, Figure 10 ), and it was the first formulation among all transdermal drug delivery systems whose skin flux could meet the pharmacodynamic effect for up to 14 days. At the same time, the polymeric skin penetration enhancer (10% povidone K90) increased the cohesive force of the adhesive, thus reducing the transfer of the adhesive to the fingers during the finger test (Example A40, Table 11).

[0325] Table 9. Skin Permeation Flux (μg / cm 2 / hr): Example A29

[0326]

[0327] Example A30 and Comparative Example A8

[0328] The composition of Formulation A30 of Example A30 was: 8% olanzapine, 16% oleic acid, 5% Kollidon CL-M, 0.5% butylated hydroxytoluene, 70.5% Duro-Tak 87-900A.

[0329] The composition of Comparative Formulation A8 of Example A8 was: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% Kollidon CL-M, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak 87-900A.

[0330] Example A30 (Formulation A30) does not contain 10% isopropyl palmitate, and Comparative Example A8 (Comparative Formulation A8) contains 10% isopropyl palmitate. The skin flux of Example A30 is higher than that of Comparative Formulation A8 (Table 10, Figure 11 ). In the finger test, more adhesive was transferred to the finger from Comparative Formulation A8 than from Formulation A30 (Table 11).

[0331] Example A31 and Comparative Example A9

[0332] The composition of Formulation A31 in Example A31 is: 8% olanzapine, 16% oleic acid, 15% Kollidon CL-M, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak 87-900A.

[0333] The composition of Comparative Formulation A9 in Example A9 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% Kollidon CL-M, 0.5% butylated hydroxytoluene, 50.5% Duro-Tak 87-900A.

[0334] Example A31 (Formulation A31) does not contain 10% isopropyl palmitate, and Comparative Example A9 (Comparative Formulation A9) contains 10% isopropyl palmitate. The skin flux of Example A31 is higher than that of Comparative Example A9 (Table 10, Figure 11 ). In the finger test, more adhesive was transferred to the finger from Comparative Formulation A9 than from Formulation A31 (Table 11).

[0335] Example A32 and Comparative Example A10

[0336] The composition of Formulation A32 in Example A32 is: 8% olanzapine, 16% oleic acid, 5% copovidone Kollidon 64, 0.5% butylated hydroxytoluene, 70.5% Duro-Tak 87-900A.

[0337] The composition of Comparative Formulation A10 in Example A10 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% copovidone Kollidon 64, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak 87-900A.

[0338] Example A32 (Formulation A32) does not contain 10% isopropyl palmitate, and Comparative Example A10 (Comparative Formulation A10) contains 10% isopropyl palmitate. The skin flux of Example A32 is higher than that of Comparative Example A10 (Table 10, Figure 11 ). In the finger test, more adhesive was transferred to the finger from Comparative Formulation A10 than from Formulation A20 (Table 11).

[0339] Example A33 and Comparative Example A11

[0340] The formulation of Formulation A33 of Example A33 consisted of: 8% olanzapine, 16% oleic acid, 15% copovidone Kollidon 64, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak 87-900A.

[0341] The composition of the comparative formulation A11 of Comparative Example A11 was: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% copovidone Kollidon 64, 0.5% 50.5% Duro-Tak 87-900A.

[0342] Example A33 (Formulation A33) did not contain 10% isopropyl palmitate, and Comparative Example A11 (Comparative Formulation A11) contained 10% isopropyl palmitate. The skin flux of Example A33 was higher than that of Comparative Example A11 (Table 10, Figure 11 ). In the finger test, more adhesive was transferred to the finger in Comparative Example 11 than in Example A33 (Table 11).

[0343] Table 10. Skin Permeation Flux (ug / cm 2 / hr): Examples A30 - 33, Comparative Examples A9 - 11

[0344]

[0345] Physical Properties and Skin Adhesion - Finger Test

[0346] Place the patch on the workbench with the adhesive layer facing up. Press the adhesive with the index finger for 5 seconds, then lift it while holding a part of the patch with the fingers of the other hand. Observe and touch in front of the index finger with the thumb to see if the finger is sticky. If adhesive is transferred to the index finger after lifting it from the adhesive layer of the patch, then the finger is sticky. The softer the adhesive and the lower the rheological cohesion, the more adhesive is expected to be transferred from the patch adhesive to the finger and the lower the adhesiveness. The finger test results for each Example A are shown in Table 11.

[0347] Examples A34 and 35:

[0348] As shown in Table 11, Formulation A8 (Example A34) and Formulation A9 (Example A35) contained 15 wt% and 22 wt% of crospovidone CL-M respectively, and no adhesive was observed to be transferred to the index finger.

[0349] Examples A36 - 37 and Comparative Examples A12 - 13:

[0350] Formulation A22 (Example A36) and Formulation A23 (Example A37) containing 15% crospovidone CL-M also had no adhesive transfer to the fingers. In contrast, Comparative Formulation A2 (Comparative Example A12) and Comparative Formulation A3 (Comparative Example A13) without crospovidone CL-M, povidone K30 or Eudragit E100 had adhesive transfer to the fingers.

[0351] Comparative Example A14 (Comparative Formulation A4):

[0352] Compared with Example A37 (Formulation A23), the 4.6% lauryl lactate in Comparative Formulation A4 (Comparative Example A14) increased the adhesive transfer to the fingers.

[0353] Comparative Example A15 (Comparative Formulation A5):

[0354] Comparative Formulation A5 (Comparative Example A15) not only contained very high levels of liquid oleic acid (17.17%) and liquid isopropyl palmitate (8.59%), but also did not contain crospovidone CL-M, povidone K30 or Eudragit E100, and thus severe adhesive transfer was observed in the finger test.

[0355] Example A38 (Formulation A24):

[0356] Formulation A24 contains the polymer Eudragit E100 and no adhesive transfer to the fingers was observed in the finger test.

[0357] Examples A39 - 40 (Formulations A26 - 27):

[0358] These formulations contain polymer penetration enhancers (povidone and Eudragit E100), which can promote the cohesion of the adhesive, have excellent physical properties, and no adhesive transfer to the fingers was observed in the finger test.

[0359] Example A41 (Formulation A28) and Comparative Example A16 (Comparative Formulation A7):

[0360] Example A41 does not contain fatty acid esters or fatty alcohols. Although there was adhesive transfer due to the presence of a large amount of DMSO, the liner could still be peeled off cleanly. In contrast, Comparative Example A16 contains the fatty acid ester isopropyl ester and the fatty alcohol myristyl alcohol. In the finger test, the liner could not be removed and a large amount of adhesive transfer to the fingers was observed.

[0361] Example A42 (Formulation A29):

[0362] Formulation A29 in Example A42 contains a sufficient amount of polymeric cohesion promoter and no adhesive transfer to the fingers was observed in the finger test.

[0363] Example A43 (Formulation A30) and Comparative Example A17 (Comparative Formulation A8):

[0364] In Example A43 containing 5% curing agent Kolliodn CL-M (i.e., crosslinked povidone CL-M), only a small amount of adhesive was transferred to the finger, but in Comparative Example A17 containing 10% isopropyl palmitate, a large amount of adhesive was transferred to the finger.

[0365] Example A44 (Formulation A31) and Comparative Example A18 (Comparative Formulation A8):

[0366] In Example A44 containing 15% curing agent Kolliodn CL-M (i.e., crosslinked povidone CL-M), no adhesive transfer to the finger was observed, but in Comparative Example A18 containing 10% isopropyl palmitate, a large amount of adhesive was transferred to the finger.

[0367] Example A45 (Formulation A32) and Comparative Example A19 (Comparative Formulation A8):

[0368] In Example A45 containing 5% curing agent copovidone VA64, only a small amount of adhesive was transferred to the finger, but in Comparative Example A19 containing 10% isopropyl palmitate, a large amount of adhesive was transferred to the finger.

[0369] Example A46 (Formulation A33) and Comparative Example A20 (Comparative Formulation A8):

[0370] In Example A46 containing 15% curing agent copovidone VA64, no adhesive was transferred to the finger, but in Comparative Example A20 containing 10% isopropyl palmitate, a large amount of adhesive was transferred to the finger.

[0371] Table 11. Summary of Finger Test Results

[0372]

[0373]

[0374]

[0375] Placebo Patch Wear Test

[0376] The placebo patch prescriptions A1 and A2 described in Tables 14 and 15 were prepared using the same procedure as the olanzapine-containing patch formulations described earlier, except that it did not contain the olanzapine matrix. For placebo prescription A1, the patches were made with two coating weights (454 GSM (grams per square meter of olanzapine)). One healthy volunteer participated in placebo wear study #1 (Example A47). The skin of the left and right outer arms was cleaned with a wet tissue and dried with a dry tissue. The formulation 1 patch was applied to the upper left outer arm. The prescription A22 patch was applied to the upper right outer arm. After patch application, they were smoothed to ensure no air bubbles were under the patch surface. The start date and time of the experiment were recorded. Adhesion and irritation scores were recorded daily. As shown in Table 12, a five-point scoring method of 0 - 4 was used to score adhesion. As shown in Table 13, a 0 - 7 scoring system was used to score primary skin irritation.

[0377] The skin adhesion scores and primary skin irritation scores for placebo wear study #1 (Example A47) are recorded in Tables 16 and 17. Due to insufficient amounts of crospovidone CLM or povidone K30, it was not possible to avoid using large amounts of liquid excipients (lactic acid and lauryl lactate), and both the placebo prescription A1 patches and the placebo prescription A2 patches had very low cohesive forces. As a result, in the finger test, a large amount of adhesive transferred to the index finger (Table 11). Due to the low cohesive force of the adhesive layer, in the placebo wear study, the placebo prescription A1 patches were very slippery, and the patches moved their position on the upper arm by themselves after 28 hours of wear, while 80% of the placebo prescription A2 patches lifted after 12 hours of wear.

[0378] Table 12. Skin Adhesion Scoring

[0379] Degree of Adhesion Score ≥90% (Basically does not lift from the skin) 0 ≥75% to <90% (only some edges are lifted from the skin) 1 ≥50% to <75% (less than half of the patch lifts from the skin) 2 >0% to <50% (more than half of the patch has lifted from the skin but has not detached) 3 0% (The patch completely separates from the skin) 4

[0380] Table 13. Skin Irritation Scoring

[0381] Skin Appearance Score No evidence of irritation 0 Minimal erythema that is hardly visible 1 Visibly obvious erythema, slight edema or slight papules 2 Erythema and papules 3 Definite edema 4 Erythema, swelling and papules 5 Vesicles 6 Strong reaction within the patch area 7

[0382] Table 14. Placebo Patch Prescription A1 (Backing film is Scotchpak 9733)

[0383] Components Dry, w / w% crospovidone CLM 15.00 lactic acid 3.00 lauryl lactate 15.00 polyacrylic acid Duro - Tak 87 - 2516 67.00 Total 100.00

[0384] Table 15. Placebo Patch Prescription A2 (Backing film is Scotchpak 9733)

[0385]

[0386]

[0387] Table 16. Placebo Patch Wear Experiment 1: Scoring of Placebo Patch Prescription A1 (Adhesive Layer Thickness of 454 GSM)

[0388]

[0389] *The test was stopped due to the patch slipping and shifting automatically.

[0390] Table 17. Placebo Patch Wear Experiment 1: Scoring of Placebo Patch Prescription A2 (Adhesive Layer Thickness of 426 GSM)

[0391]

[0392] *The test was stopped because 80% of the patches peeled off the skin.

[0393] Placebo Patch Wear Test

[0394] Example A47 (Placebo Prescription A3)

[0395] The placebo patch prescription A3 described in Table 18 was prepared using the same procedure as the olanzapine-containing patch formulation described earlier, except that it did not contain olanzapine. For placebo prescription A3, the patches were made with two coating weights, 200 GSM (grams per square meter) and 400 GSM, respectively. Nine healthy volunteers participated in the placebo wear study #1 (Example A47). The outer skin of the upper arm was cleaned with a wet tissue and dried with a dry tissue. After applying the placebo patch, it was smoothed to ensure that there were no air bubbles under the patch surface. The start date and time of the experiment were recorded. Adhesion and irritation scores were recorded daily.

[0396] The skin adhesion scores and primary skin irritation scores for the placebo wear study #3 (Example A47) are recorded in Tables 19 and 20. The 168-hour (7-day) skin adhesion scores for most volunteers were 0 (more than 90% of the patches adhered to the skin) or 1 (75% to 89% of the patches adhered to the skin), and several volunteers were able to wear the patches for 12 or 13 days. The primary skin irritation for most volunteers was 0 (no irritation) or 1 (almost no irritation) within 168 hours (7 days).

[0397] Table 18. Placebo Patch Prescription A3 (Backing Film is Scotchpak 9733)

[0398]

[0399]

[0400]

[0401] Table 21. Placebo Patch Prescription A4 (Backing Film is Scotchpak 9733)

[0402]

[0403] Example A48 (Placebo Patch Prescription A4)

[0404] For the placebo prescription A4, the coating weight of the patch was 400 GSM (grams per square meter). A healthy volunteer wore two patches in the placebo wear study #3 (Example 48). The skin of the left upper front leg was cleaned with a wet tissue and dried with a dry tissue. After applying the placebo patch, it was smoothed to ensure that there were no air bubbles under the patch surface. The adhesion and irritation scores (based on whether the skin itched and the appearance of the skin, such as whether it was red) were recorded daily.

[0405] The skin adhesion scores and the primary skin irritation scores for the placebo wear study 3 (Example A48) are recorded in Tables 22 and 23. The 28-day skin adhesion scores were all 0 (more than 90% of the patches adhered to the skin). The primary skin irritation for 28 days was also 0 (no irritation). Despite the large amount of liquid oleic acid in the prescription, the prescription with 15% crosslinked povidone CLM could still maintain good cohesion and provided excellent skin adhesion for up to 28 days.

[0406]

[0407] Example B1

[0408] Weigh each composition component according to Table 24 and prepare the prescription. Dissolve soluble povidone, the antioxidant ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C. The insoluble crosslinked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50 °C, and rotigotine was added and completely dissolved as shown by microscopic analysis. The silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202, heated to 50 °C, were added and mixed. The suspension was kept 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 24, no crystal formation occurred when the patch samples were stored at room temperature for 9 months and at 40 °C for 6 months. In this Example B, the weight ratio of rotigotine to soluble povidone was 9:3, and the ratio of rotigotine to insoluble crosslinked povidone was 9:6.8.

[0409] Example B2

[0410] Weigh each component of the composition according to Table 24 and prepare the formulation. Dissolve soluble polyvinylpyrrolidone, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol in ethanol at 50 °C, and mix with insoluble cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50 °C. Keep the suspension at 50 °C, coat it on the release film and dry it at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 24, no crystal formation occurred when the patch samples were stored at room temperature for 9 months and at 40 °C for 6 months. In this Example B, the weight ratio of rotigotine to soluble polyvinylpyrrolidone is 9:3, and the weight ratio of rotigotine to insoluble cross-linked polyvinylpyrrolidone is 9:8.

[0411] Example B3

[0412] Weigh each component of the composition according to Table 24 and prepare the formulation. Dissolve soluble polyvinylpyrrolidone, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol in ethanol at 50 °C. Mix insoluble cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50 °C. Keep the suspension at 50 °C, coat it on the release film and dry it at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 24, no crystal formation occurred when the patch samples were stored at room temperature for 9 months and at 40 °C for 6 months. In this Example B, the weight ratio of rotigotine to soluble polyvinylpyrrolidone is 9:3, and the weight ratio of rotigotine to insoluble cross-linked polyvinylpyrrolidone is 9:9.

[0413] Table 24. Comparative Examples B1 to B5, Examples B1 to B3

[0414]

[0415]

[0416] Comparative Example B6

[0417] Weigh each component of the composition according to Table 25 and prepare the formulation. Dissolve the antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in toluene at 50 °C. Mix the insoluble crospovidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix the solution of polyisobutene binders Oppanol B12 and Oppanol N100 in toluene at room temperature. Coat the suspension on a release film and dry at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, crystal formation was observed as early as the 8th day when the patch samples were stored at 40 °C. In this Example B, there is no soluble polyvinylpyrrolidone, and the ratio of rotigotine to insoluble crospovidone is 9:3. In this Comparative Example B, the wet mixture was maintained at room temperature, i.e., not heated above room temperature, to keep rotigotine dissolved in the wet mixture.

[0418] Comparative Examples B7 to B11

[0419] Prepare the patch samples of Comparative Examples B7 to B11 using a method similar to that of Comparative Example B6. Weigh each component of the composition according to Table 25 and prepare the formulation. The amount of insoluble crospovidone was increased to 10%, 13%, 16.65%, 18%, and 20% respectively. Crystal formation occurred in the patch samples of Comparative Examples B7 to B11, but the formation of crystals was increasingly delayed as the amount of insoluble crospovidone increased. In these Comparative Examples B, the wet mixture was maintained at room temperature, i.e., not heated above room temperature, to keep rotigotine dissolved in the wet mixture.

[0420] Example B4

[0421] Weigh each component of the composition according to Table 25 and prepare the formulation. Dissolve the antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in toluene at 50 °C. Mix the insoluble crospovidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix the solution of polyisobutene binders Oppanol B12 and Oppanol N100 in toluene heated to 50 °C. Keep the suspension at 50 °C, coat it on a release film and dry 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 when the patch samples were stored at 60 °C for 10 days and at 40 °C for 1 month. In this Example B, there is no soluble polyvinylpyrrolidone, and the ratio of rotigotine to insoluble crospovidone is 9:21. In this Example B, the wet mixture was maintained at 50 °C to keep rotigotine dissolved in the wet mixture before coating.

[0422] Example B5

[0423] Weigh each composition component according to Table 25 and prepare the formulation. Example B5 was prepared using a method similar to that of Example B4. As shown in Table 25, no crystals were observed in the patch samples after storage at 60 °C for 10 days and after storage at 40 °C for 1 month. In this Example B, there is no soluble povidone, and the ratio of rotigotine to insoluble crospovidone is 7.5:20 or 9:24. In this Example B, the wet mixture was maintained at 50 °C to maintain the dissolution of rotigotine in the wet mixture before coating.

[0424] Example B6

[0425] Weigh each composition component according to Table 25 and prepare the formulation. The antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in isopropanol at 50 °C. The insoluble crospovidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50 °C, and rotigotine was added and completely dissolved as shown by microscopic analysis. The solutions of polyisobutene binders Oppanol B12 and Oppanol N100 in n-heptane, heated to 50 °C, were added and mixed. The suspension was kept 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 in the patch samples after storage at 60 °C for 10 days. In this Example B, there is no soluble povidone, and the ratio of rotigotine to insoluble crospovidone is 7.5:20 or 9:24. In this Example B, the wet mixture was maintained at 50 °C to maintain the dissolution of rotigotine in the wet mixture before coating.

[0426] Comparative Example B12

[0427] Weigh each composition component according to Table 25 and prepare the formulation. Povidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in isopropanol at 50 °C. The insoluble crospovidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50 °C, and rotigotine was added and completely dissolved as shown by microscopic analysis. The solutions of polyisobutene binders Oppanol B12 and Oppanol N100 in n-heptane, heated to 50 °C, were added and mixed. The suspension was kept 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 in the patch samples after storage at room temperature for 3 days. In this Example B, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:3.6.

[0428] Example B7

[0429] Weigh each component of the composition according to Table 25 and prepare the formulation. Dissolve polyvinylpyrrolidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in isopropanol at 50 °C. Mix the insoluble crosslinked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix the solution of polyisobutene adhesives Oppanol B12 and Oppanol N100 in n-heptane heated to 50 °C. Keep the suspension at 50 °C, coat it on the release film, and dry it 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 in the patch samples stored at 60 °C on the 10th day, and no crystals were observed after storage at 40 °C for 1 month. In this Example B, the weight ratio of rotigotine to crosslinked polyvinylpyrrolidone is 9:3, and the weight ratio of rotigotine to insoluble crosslinked polyvinylpyrrolidone is 9:12.

[0430] Example B8

[0431] Weigh each component of the composition according to Table 25 and prepare the formulation. Dissolve polyvinylpyrrolidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in isopropanol at 50 °C. Mix the insoluble crosslinked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix the solution of polyisobutene adhesives Oppanol B12 and Oppanol N100 in n-heptane heated to 50 °C. Keep the suspension at 50 °C, coat it on the release film, and dry it 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 in the patch samples stored at 60 °C on the 10th day, and no crystals were observed after storage at 40 °C for 1 month. In this Example B, the ratio of rotigotine to crosslinked polyvinylpyrrolidone is 9:3, and the weight ratio of rotigotine to insoluble crosslinked polyvinylpyrrolidone is 9:18.

[0432] Table 25. Comparative Examples B6 to 12, Examples B4 to B8

[0433]

[0434]

[0435]

[0436] Comparative Example B13

[0437] Weigh each component of the composition according to Table 26 and prepare the formulation. Dissolve ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C. Mix insoluble cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and completely dissolve it as shown by microscopic analysis. Add and mix Bio-PSA 7-4502. Coat the suspension on a release film and dry it 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 the patch samples stored at room temperature for 6 months and on the 22nd day of storage at 40 °C. In this Example B, the ratio of rotigotine to insoluble cross-linked polyvinylpyrrolidone is 7.5:6 or 9:7.2.

[0438] Comparative Example B14

[0439] Weigh each component of the composition according to Table 26 and prepare the formulation. Dissolve ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C. Mix insoluble cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and completely dissolve it as shown by microscopic analysis. Add and mix Bio-PSA 7-4502. Coat the suspension on a release film and dry it 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 the patch samples on the 62nd day of storage at 40 °C. In this Example B, the ratio of rotigotine to insoluble cross-linked polyvinylpyrrolidone is 7.5:10 or 9:12.

[0440] Comparative Example B15

[0441] Weigh each component of the composition according to Table 26 and prepare the formulation. Dissolve soluble polyvinylpyrrolidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C, and then mix at room temperature for 24 hours. Heat the solution to 50 °C, add rotigotine, and completely dissolve it as shown by microscopic analysis. Add and mix Bio-PSA 7-4502. Coat the suspension on a release film and dry it 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 the patch samples stored at room temperature for 6 months. In this Example B, the weight ratio of rotigotine to soluble polyvinylpyrrolidone is 9:4.

[0442] Example B9

[0443] Weigh each component of the composition according to Table 26 and prepare the formulation. Dissolve ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C. Mix insoluble cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the solution to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix Bio-PSA 7-4502. Coat the suspension on a release film and dry it 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 when the patch samples were 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 cross-linked polyvinylpyrrolidone is 9:20.

[0444] Example B10

[0445] Weigh each component of the composition according to Table 26 and prepare the formulation. Prepare the formulation in Example B10 using the same method as in Example B9. As shown in Table 26, no crystals were observed when the patch samples were stored at room temperature for 6 months and at 40 °C for 6 months. In this Example B, the weight ratio of rotigotine to insoluble cross-linked polyvinylpyrrolidone is 9:22.8.

[0446] Example B11

[0447] Weigh each component of the composition according to Table 26 and prepare the formulation. Dissolve soluble polyvinylpyrrolidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in ethanol at 50 °C. Mix cross-linked polyvinylpyrrolidone CL-M at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine, and dissolve completely as shown by microscopic analysis. Add and mix Bio-PSA 7-4502 and Duro-Tak 387-2287. Coat the suspension on a release film and dry it 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 when the patch samples were stored at room temperature for 11 months and at 40 °C for 6 months. In this Example B, the weight ratio of rotigotine to insoluble polyvinylpyrrolidone is 9:5, and the weight ratio of rotigotine to soluble polyvinylpyrrolidone is 9:3.

[0448] Examples B12 to B14

[0449] Weigh each component of the composition according to Table 26 and prepare the formulation. Prepare the formulations in Examples B12 to 14 using the same method as in Formulation 11 of Example B11. As shown in Table 26, no crystals were observed when the patch samples were stored at room temperature for 9 months and at 40 °C for 6 months.

[0450] Table 26. Comparative Examples B13 to 15 and Examples B9 to B14

[0451]

[0452]

[0453]

[0454]

[0455] Example C1

[0456] Weigh each composition component according to Table 27 and prepare the prescription. Dissolve soluble polyvinylpyrrolidone K90 and disperse it in ethyl acetate, add oleic acid and Eudragit EPO to form a solution. Add cross-linked polyvinylpyrrolidone CL-M and mix at room temperature for 24 hours. Add donepezil free base and mix, and it is shown to be completely dissolved by microscopic analysis. Add and mix Duro-Tak 387-2516. Coat the suspension on the release film and dry it 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 the patch samples stored at room temperature for 9 days or 24 days, at 40 °C for 1 month, and at 60 °C for 1 month and 9-10 days.

[0457] Example C2

[0458] Weigh each composition component according to Table 27 and prepare the prescription. Dissolve HPMC K15M in a mixture of isopropanol and water (90:10), add oleic acid and Eudragit EPO to form a solution. Add cross-linked polyvinylpyrrolidone CL-M and mix at room temperature for 24 hours. Add donepezil free base and mix, and it is shown to be completely dissolved by microscopic analysis. Add and mix Duro-Tak 387-2516. Coat the suspension on the release film and dry it 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 the patch samples stored at room temperature for 9 days or 24 days, at 40 °C for 1 month, and at 60 °C for 1 month and 9-10 days

[0459] Table 27

[0460]

[0461] Example C3

[0462] An in vitro permeation test was carried out using the same vertically static modified Franz cell as olanzapine. The measurement results of the skin permeation flux of donepezil are shown in Table 28, and the measurement curve of the skin flux is shown in Figure 12 .

[0463] Table 28 Skin permeation flux (ug / cm 2 / hr): Examples C1-C2

[0464]

[0465]

Claims

1. A transdermal drug delivery system, comprising: 1) A backing layer; 2) A matrix layer, which contains a drug 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; 3) A release liner; Relative to the total weight of the matrix layer, the matrix layer contains the following components: 1) The dosage of the drug or a pharmaceutically acceptable salt thereof is 3-30%, and the drug is selected from olanzapine, rotigotine or donepezil; 2) The stabilizer for inhibiting drug crystallization is selected from 17.5-40% of insoluble cross-linked povidone, or a combination of 10 to 40% of insoluble cross-linked povidone and 2-10% of soluble povidone; 3) The dosage of the pressure-sensitive adhesive is 35-65%, and the pressure-sensitive adhesive is selected from one or more of acrylic adhesives or polyisobutene adhesives; 4) The dosage of the tackifier is 25.3482-50% provided that the pressure-sensitive adhesive is a polyisobutene adhesive, or the dosage of the tackifier is 0-50% provided that the pressure-sensitive adhesive is an acrylic adhesive; and the tackifier is selected from silicone oil, mineral oil, polybutene, terpenes and mixtures thereof; 5) The skin penetration enhancer is 0-30%; 6) The cohesive-promoting additive is 0-20%, and the cohesive-promoting additive is selected from one or more of Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55, hydroxypropyl methylcellulose; The matrix layer does not contain isopropyl palmitate, isopropyl myristate or lauryl lactate; The total dosage of each component in the matrix layer is 100%.

2. The transdermal drug delivery system according to claim 1, wherein the insoluble cross-linked povidone is selected from insoluble cross-linked povidone CL-M, cross-linked povidone CL, cross-linked povidone CL-F, cross-linked povidone CL-SF.

3. The transdermal drug delivery system according to claim 1, wherein the soluble povidone is selected from one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, copovidone VA64.

4. The transdermal drug delivery system according to any one of claims 1-3, wherein the cohesive-promoting additive is selected from one or two of Eudragit E100 and Eudragit PO.

5. The transdermal drug delivery system according to any one of claims 1-3, wherein 1) The acrylic adhesive is selected from Henkel's Duro-Tak adhesives 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 GMS9073, Gelva 737, Gelva 2655, Polythick 410-SA; 2) The polyisobutene 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 tackifiers from Ineos.

6. The transdermal delivery system according to any one of claims 1-3, wherein the content of the drug or its pharmaceutically acceptable salt is 5% to 20% of the total weight of the matrix layer.

7. The transdermal delivery system according to any one of claims 1-3, wherein the content of the drug or its pharmaceutically acceptable salt is 5% to 15% of the total weight of the matrix layer.

8. The transdermal delivery system according to any one of claims 1-3, wherein the content of the drug or its pharmaceutically acceptable salt is 5% to 12% of the total weight of the matrix layer.

9. The transdermal delivery system according to any one of claims 1-3, wherein the content of the drug or its pharmaceutically acceptable salt is 7.5% of the total weight of the matrix layer.

10. The transdermal delivery system according to any one of claims 1-3, wherein the content of the stabilizer for inhibiting drug crystallization is 12.5% to 40% of the total weight of the matrix layer.

11. The transdermal delivery system according to any one of claims 1-3, wherein the content of the stabilizer for inhibiting drug crystallization is 12.5%, 16.65%, 17.50%, 19.00% or 20.00% of the total weight of the matrix layer.

12. The transdermal delivery system according to any one of claims 1-2, wherein when the stabilizer for inhibiting drug crystallization is only selected as insoluble crosslinked polyvinylpyrrolidone, the content of insoluble crosslinked polyvinylpyrrolidone is 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35% or 40% of the total weight of the matrix layer.

13. The transdermal delivery system according to any one of claims 1-3, wherein when the stabilizer for inhibiting drug crystallization is selected from the combination of insoluble crosslinked polyvinylpyrrolidone and soluble polyvinylpyrrolidone, the dosage of insoluble crosslinked polyvinylpyrrolidone is 10 to 40%, and the content of soluble polyvinylpyrrolidone is 2%, 2.5%, 3.4%, 4% or 5% of the total weight of the matrix layer.

14. The transdermal drug delivery system according to any one of claims 1 - 3, wherein the content of the pressure - sensitive adhesive is 45% to 65% of the total weight of the matrix layer.

15. The transdermal drug delivery system according to any one of claims 1 - 3, wherein the skin penetration enhancer comprises one or more of C2 - C30 saturated or unsaturated fatty acids, surfactants, and azone.

16. A method for preparing the transdermal drug delivery system according to any one of claims 1 - 15, comprising the following steps: Step 1. Dissolve the drug or its pharmaceutically acceptable salt in a solvent to form a premix A; the solvent is selected from one or more of water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and ethyl acetate; Step 2. Mix the pressure - sensitive adhesive solution evenly with a stabilizer that inhibits drug crystallization to obtain a premix B; the stabilizer that inhibits drug crystallization is selected from insoluble cross - linked povidone or a combination of insoluble cross - linked povidone and soluble povidone; the mixing time is 0.1 hour to 24 hours; Step 2 also includes the step of heating to 30 - 65°C; Step 3. Add premix A to premix B to obtain a wet drug mixture, in which the drug or its pharmaceutically acceptable salt is dispersed in a non - crystalline state; Step 4. Coat the wet drug mixture on a release film; Step 5. Dry to remove the solvent to obtain a release film / matrix layer laminate; Step 6. Laminate the matrix layer onto the backing layer.

17. The method according to claim 16, wherein the solvent in Step 1 is selected from water, toluene, ethanol, isopropanol, ethyl acetate, or a mixed solvent thereof.

18. The method according to claim 16 or 17, wherein Step 2 includes heating to 35 - 60°C to keep the drug in a dissolved state.

19. The method according to claim 16 or 17, wherein Step 3 is to add a pressure - sensitive adhesive heated to 35 - 65°C and mix evenly to obtain a wet drug mixture.

20. The method according to claim 16 or 17, wherein Step 4 is to coat the wet drug mixture on a release film while keeping it at 35 - 65°C.

21. A method for preparing the transdermal drug delivery system according to any one of claims 1 - 15, comprising: Step 1. Dissolve the stabilizer that inhibits drug crystallization in a solvent and mix evenly, the solvent is selected from one or more of water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and ethyl acetate; the stabilizer that inhibits drug crystallization is selected from insoluble cross - linked povidone or a combination of insoluble cross - linked povidone and soluble povidone; the mixing time is 0.1 hour to 24 hours; Step 2. Add the drug or its pharmaceutically acceptable salt and mix until dissolved and dispersed in a non - crystalline state; Step 2 also includes the step of heating to 30 - 65°C, Step 3. Add the pressure - sensitive adhesive and mix evenly to obtain a wet drug mixture; Step 4. Coat the wet drug mixture on a release film; Step 5. Dry to remove the solvent to obtain a release film / matrix layer laminate; Step 6. Laminate the matrix layer onto the backing layer.

22. The method according to claim 21, wherein the solvent in step 1 is selected from water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof.

23. The method according to claim 21 or 22, wherein step 2 comprises heating to 35 - 60 °C to dissolve the drug.

24. The method according to claim 21 or 22, wherein step 3 is to add a pressure - sensitive adhesive heated to 35 - 65 °C and mix evenly to obtain a wet drug mixture.

25. The method according to claim 21 or 22, wherein step 4 is to coat the wet drug mixture on a release film while keeping it at 35 - 65 °C.

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