Risperidone transdermal delivery system and its manufacturing method and use

Abstract

The present invention relates to a transdermal delivery system for risperidone. More specifically, the present invention relates to a transdermal delivery system for sustained delivery of risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days, and a method for producing and using the same.

Description

[Technical Field]

[0001] The present invention relates to a transdermal delivery system for risperidone. More specifically, the present invention relates to a transdermal delivery system for sustained delivery of risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days, and to a method for producing and using the same. [Background technology]

[0002] The transdermal route of administration is superior to oral administration, maintaining a consistent blood drug concentration by continuously delivering the drug to the systemic bloodstream. The transdermal route not only reduces fluctuations in blood drug concentrations between peaks and valleys, but also avoids the first-pass effect. Furthermore, because the transdermal route avoids direct contact of the drug and excipients with the gastrointestinal system, it significantly reduces or eliminates side effects often associated with oral administration, such as nausea and vomiting. Another advantage of the transdermal route is that it is not affected by food. Administration can be easily terminated by simply removing the transdermal patch from the skin when necessary. Furthermore, transdermal patches improve patient compliance by reducing the frequency of administration. In other words, whereas patients tend to forget to take tablets or capsules, transdermal patches can be more reliably administered. This is especially important for geriatric and pediatric patients. For example, if the patch is designed for 24-hour wear, patients can easily remember to change the patch every day at 8:00 a.m. For example, if a patch is designed to be worn for 3.5 days, patients can easily remember to change the patch every Monday morning at 8:00 AM and every Thursday night at 8:00 PM. For example, if a patch is designed to be worn for 7 days, patients can easily remember to change the patch every Monday morning at 8:00 AM. Transdermal patches are clearly superior to injectables because administration of transdermal patches is painless, whereas administration of injectables is painful. Furthermore, some injectable drugs are only available in hospitals.

[0003] Common dosage forms for transdermal administration include transdermal patch formulations. Currently, common transdermal patch formulations include, but are not limited to, drug reservoir-type patches and matrix-type patches. Drug reservoir-type patches are patches containing a drug in a reservoir with a drug-permeable substrate surface, while matrix-type patches are patches in which a drug is dissolved or dispersed in a polymer matrix layer. The two designs typically further include a backing layer and a release film layer that is removed before use. Furthermore, patches typically further include a permeation enhancer and an adhesive layer.

[0004] In recent years, the advantages of transdermal administration have made it possible to effectively transdermally administer many drugs.These advances include the development of many physical methods to increase skin permeability and promote transdermal administration, such as iontophoresis, electroporation, ultrasound or microneedle.However, the drugs that can be effectively and safely administered through the skin for more than 7 days without causing skin adhesion, skin irritation or sensitization are still limited.

[0005] The present invention relates to risperidone, whose general formula is 3-[2-[4-{6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The preparation method and pharmacological activity of this drug are described in U.S. Patent No. 4,804,663 (corresponding to EP-0,196,132 (1984)).

[0006] Currently, this drug is widely used clinically as an anti-schizophrenic drug. Risperidone treats or prevents schizophrenia, mania, and dementia. Risperidone is a selective monoaminergic antagonist with unique properties. It has high affinity for 5-serotonergic 5-HT2 receptors and dopaminergic D2 receptors, can also bind to α1-adrenergic receptors, has low affinity for H1 histaminergic receptors and α-2 adrenergic receptors, but cannot bind to cholinergic receptors. Risperidone treats or prevents the positive or negative symptoms of schizophrenia. Risperidone's treatment or prevention of the positive or negative symptoms of schizophrenia includes hallucinations, delusions, emotional withdrawal, and apathy. It also has the characteristic of causing fewer pyramidal side effects (such as chills and rigidity) than typical antipsychotics. Therefore, risperidone is considered to be a very useful anti-schizophrenic drug, and can significantly improve the quality of life of patients.

[0007] Risperidone is administered to patients orally in the form of tablets, fine granules, or liquid. However, oral administration has several drawbacks, such as sensitivity to the first-pass effect in the liver after drug absorption and the observation of temporary and undesirable high blood drug concentrations after administration. Furthermore, oral administration has been reported to cause many side effects, such as gastrointestinal disorders, nausea, and anorexia. It is believed that approximately 75% of schizophrenic patients have difficulty regularly taking oral preparations. Therefore, to solve these problems associated with oral administration and to prepare preparations that patients can easily and safely take continuously, transdermal patch formulations have been used. This method can solve the various problems associated with oral administration and has the advantages of reducing the frequency of administration, improving compliance, and facilitating administration or discontinuation. Therefore, transdermal patches are expected to be a useful administration method.

[0008] In practice, risperidone is typically administered as a tablet, oral solution, or intramuscular injection solution to produce an antipsychotic effect or to alleviate behavioral disorders associated with neurodegenerative diseases. For various reasons, non-invasive administration of risperidone is desirable, particularly when administered as a transdermal patch, allowing for controlled drug release rates.

[0009] Risperidone is a highly effective drug with a relatively narrow therapeutic index. Overdose can cause adverse side effects, most notably extrapyramidal syndrome (EPS) and minor hypotension (attributed to peripheral α-adrenergic activity). To produce antipsychotic effects in patients, the total daily dose of risperidone ranges from about 2 to about 8 mg. To alleviate behavioral disturbances associated with neurodegenerative diseases, the total daily dose is usually lower, typically in the range of about 0.5 to about 2 mg. Due to individual differences and additional drug treatment, patients must be titrated to achieve an effective dose.

[0010] Risperidone is metabolized to 9-hydroxyrisperidone, which has pharmacological properties and potency similar to those of the parent drug, risperidone, but a longer elimination half-life. Risperidone is distributed to and eliminated from brain tissue more rapidly than its metabolite, 9-hydroxyrisperidone.

[0011] Isoquinoline polymorphisms play a unique role in the metabolism of risperidone. Depending on the metabolic rate, humans can be classified as poor, intermediate, or extensive metabolizers. The metabolic rate is defined as the ratio of the urinary recovery rate of isoquinoline to the urinary recovery rate of its 4-hydroxyisoquinoline metabolite within 8 hours after oral ingestion of 10 mg of isoquinoline. In Oriental populations, extensive and poor metabolizers are quite rare, allowing phenotyping of over 99% of the population. However, in Caucasians, only about 90% of the population is phenotyped as extensive or intermediate metabolizers. Approximately 10% of the population is a poor metabolizer and has insufficient isoquinol hydroxylase content. The duration of action and peak plasma levels of the active agents (risperidone and 9-hydroxyrisperidone) are highly dependent on the isoquinoline metabolic rate of risperidone-treated human subjects. More specifically, when the total daily dose is administered in a single dose, a high instantaneous peak level of risperidone may be achieved in poor metabolizers. This may cause undesirable side effects, such as extrapyramidal syndrome (EPS) and hypotension (due to adrenergic effects). Generally, the rapid distribution of risperidone in plasma and brain tissues suggests that the drug should be administered at a continuous, controlled rate to better divide the dose regularly and avoid the possibility of excessively high peak levels (and side effects), while maintaining a clinically effective drug level. If risperidone can be administered transdermally, a rate-controlled transdermal delivery system clearly provides a practical solution to the above problem. It is desirable that the transdermal delivery system be able to deliver the drug at a substantially constant rate for at least about 24 hours, while minimizing the amount of unused and depleted drug in the system. Considering the pharmacological properties of risperidone, it is impossible to continuously deliver a therapeutic amount of risperidone from a transdermal delivery system that controls the drug's permeability primarily through skin permeability. To deliver a drug, it is necessary to develop a transdermal delivery system that controls the permeation rate of the drug, which itself controls the maximum rate at which the drug is delivered through the skin.

[0012] CN 101366705B and US8431152B1 describe the preparation of patch formulations by dissolving a predetermined dose of risperidone in an organic solvent, but do not intend to contain risperidone dispersed in a matrix in crystalline form. CN 101366705B does not disclose that the patch can be continuously administered at a constant rate for at least 3 days (72 hours) at a therapeutically effective dose, nor does it disclose the inclusion of risperidone dispersed in a matrix in crystalline form. Example 4 and Figure 6 of the patent show that there is no linear relationship between the cumulative release rate and the increasing dose of risperidone. According to a paper published by Chen Xiaojin, inventor of the patent, entitled "Research on Risperidone Transdermal Delivery Systems," oleic acid is not the most preferred permeation enhancer for risperidone patches (see the last line on page 29), and laurocapram, dodecanol, and propylene glycol are preferred permeation enhancers, although laurocapram has questionable pharmacological activity or its safety is questionable. Dodecanol is a skin irritant. Propylene glycol is a solvent for dissolving risperidone.

[0013] Therefore, there is a desperate need for a transdermal delivery system for risperidone or a pharmaceutically acceptable salt thereof that provides sustained delivery of therapeutically effective blood drug concentrations for a period of 24 hours to 14 days, thereby improving patient compliance and providing long-term, effective treatment for patients with schizophrenia. Summary of the Invention

[0014] The present inventors have discovered that when administering a transdermal delivery system containing risperidone, it is difficult to deliver risperidone to a patient's body at a substantially constant rate over a period of 24 hours to 14 days to maintain a therapeutically effective blood concentration of the drug in the body, let alone to release the drug to the patient at a controlled rate.

[0015] The present inventors have unexpectedly discovered that both lauryl lactate and long-chain aliphatic alcohols are effective skin penetration enhancers for risperidone. They have no pharmacological activity and are not skin irritating. The present inventors have also unexpectedly discovered that microcrystalline risperidone dissolved without the use of a solvent can provide sustained transdermal delivery at a constant rate for a long period of time. A transdermal delivery system containing a combination of risperidone crystalline Form A and a skin penetration enhancer (preferably a long-chain aliphatic alcohol such as lauryl lactate or oleyl alcohol) has excellent stability and can continuously deliver the drug in a controlled manner at a constant rate for sustained periods of 3, 7, 10, and 14 days, with the transdermal dose of risperidone maintained at 65% or more of the maximum transdermal dose between 3 and 7 days after administration. The system continuously delivers risperidone to the skin, and the skin penetration enhancer allows the drug to penetrate the skin and enter the blood circulation at a therapeutically effective dose.

[0016] The present invention further discovered that by controlling the dose of the skin permeation enhancer and risperidone crystalline form A, skin throughput can be improved, which helps to achieve the above technical effects.

[0017] The present invention further discovered that the matrix layer of the risperidone delivery system of the present invention contains undissolved risperidone crystalline Form A, which can improve skin throughput and help achieve the above technical effects. The present invention also discovered that by adjusting the amounts of the pressure-sensitive adhesive and the cohesion promoter relative to the total weight of the matrix layer, the adhesiveness of the transdermal delivery system can be improved and its skin tolerance can be improved.

[0018] The permeation enhancer accelerates the drug release from the transdermal delivery system, which is counter to the objective of sustained release. The inventors further discovered that certain matrix combinations can provide a risperidone transdermal delivery system that exists in both crystalline and amorphous states, which is advantageous for sustained delivery of risperidone at a constant rate.

[0019] Therefore, an object of the present invention is to provide a matrix-type risperidone transdermal administration system that can continuously deliver risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration at a constant rate for a period of 24 hours to 14 days.

[0020] Another object of the present invention is to provide a reservoir-type risperidone transdermal administration system that can continuously deliver risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

[0021] Another object of the present invention is to provide a method for preparing a matrix-type risperidone transdermal delivery system, which is capable of continuously delivering risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

[0022] Another object of the present invention is to provide a use of a therapeutically effective amount of a risperidone transdermal delivery system in the manufacture of a medicament for treating or preventing schizophrenia, mania and dementia, which comprises administering a therapeutically effective amount of a stable risperidone transdermal delivery system to a subject in need thereof.

[0023] Another object of the present invention is to provide a use of a therapeutically effective amount of a risperidone transdermal delivery system in the manufacture of a medicament for treating or preventing positive or negative symptoms of schizophrenia, which comprises administering a therapeutically effective amount of a stable risperidone transdermal delivery system to a subject in need thereof.

[0024] Another object of the present invention is to provide a use of a therapeutically effective amount of a stable risperidone transdermal delivery system in the manufacture of a medicament for treating or preventing hallucinations, delusions, and emotional withdrawal and blunted affect symptoms of schizophrenia, which comprises administering a therapeutically effective amount of a stable risperidone transdermal delivery system to a subject in need thereof.

[0025] Another object of the present invention is to provide a method for treating or preventing schizophrenia, mania, and dementia, which comprises administering to a subject in need thereof a therapeutically effective amount of a stable risperidone transdermal delivery system.

[0026] Another object of the present invention is to provide a method for treating or preventing positive or negative symptoms of schizophrenia, which comprises administering to a subject in need thereof a therapeutically effective amount of a stable risperidone transdermal delivery system.

[0027] Another object of the present invention is to provide a method for treating or preventing hallucinations, delusions, and emotional withdrawal and blunted affect symptoms of schizophrenia, which comprises administering to a subject in need thereof a therapeutically effective amount of a stable risperidone transdermal delivery system. [Brief explanation of the drawings]

[0028] [Figure 1] 1 is a schematic diagram of a backing layer, a matrix layer, and a release layer in a three-layer matrix-type transdermal delivery system according to the present invention. [Figure 2] 1 is a schematic diagram of a backing layer, a matrix layer, a skin contact adhesive layer, and a release layer in a four-layer matrix-type transdermal delivery system according to the present invention. [Figure 3] 1 is a schematic diagram of a backing layer, a matrix layer, a semipermeable membrane or woven fabric layer, a skin contact adhesive layer, and a release layer in a five-layer matrix-type transdermal delivery system according to the present invention. [Figure 4A] FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 4B] FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 4C] FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 4D] FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 4E]FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 4F] FIG. 1 is a schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films. [Figure 5] FIG. 1 is a graph showing the results of skin throughput tests for Comparative Examples 1 to 6. [Figure 6] FIG. 1 shows the results of skin throughput tests in Examples 1 to 3. [Figure 7] FIG. 10 shows the results of the skin throughput test in Example 4. [Figure 8] FIG. 1 shows XRPD spectroscopy of risperidone crystalline form A. [Figure 9] FIG. 1 shows XRPD spectroscopy of risperidone transdermal patch crystalline formulation. [Figure 10] FIG. 1 shows the results of the skin throughput test in Examples 5 and 8. [Figure 11] FIG. 1 shows the results of the skin throughput test in Examples 9 and 12. [Figure 12] FIG. 1 shows the results of skin throughput tests for Examples 26 to 33 and Comparative Example 7. [Figure 13] Schematic diagram of a matrix-type transdermal delivery system using overlapping adhesive films, where the separating layer and drug matrix layer / skin adhesive layer are cut into small pieces. [Figure 14] FIG. 1 is a schematic diagram of the separation layer and drug matrix layer when not cut into small pieces. [Figure 15] This is a schematic diagram of the separation layer and drug matrix layer being divided into four 12.5 cm2 pieces, where there is one connection point between each piece, and the intersecting black lines are the cut separation layer and drug matrix layer. [Figure 16] Schematic diagram of the separation layer and drug matrix layer being divided into four 12.5 cm2 pieces, where there are two connection points between each piece, and the intersecting black lines are the cut separation layer and drug matrix layer. [Figure 17]Schematic diagram of the separation layer and drug matrix layer being divided into four 12.5 cm2 pieces, where there are no connections between each piece and the intersecting black lines are the cut separation layer and drug matrix layer. [Figure 18] FIG. 18 shows the piece of FIG. 17 without connection points, and when the inner patch (separation layer and matrix layer) moves forward, the four parts of the inner patch are separated from each other and arranged in a disorderly manner. [Figure 19] FIG. 17 shows a piece containing two connection points, as shown in FIG. 16. When the inner patch (separation layer and matrix layer) moves forward, the four pieces of the inner patch are connected in an orderly manner. [Figure 20] FIG. 1 shows the results of the skin throughput test of Examples 42 to 45. DETAILED DESCRIPTION OF THE INVENTION

[0029] In one aspect, the present invention provides a risperidone transdermal delivery system, the system comprising: 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) a release layer.

[0030] In some embodiments, in the risperidone transdermal administration system, the risperidone crystalline form is crystalline form A, preferably micronized risperidone crystalline form A.

[0031] In some embodiments, the skin penetration enhancer is C1-C 30 selected from fatty acids, fatty acid esters, fatty alcohols, or one or more thereof; Preferably, the fatty acid is C 12 ~C 22 unsaturated fatty acids, more preferably oleic acid; Preferably, the fatty acid ester is a C1-C 30Fatty acids and C1-C 30 is selected from esters formed by bonding with alcohols, more preferably lauryl lactate, Preferably, the fatty alcohol is C 13 ~C 30 It is selected from alkenyl alcohols, more preferably oleyl alcohol.

[0032] In some embodiments, in the risperidone transdermal administration system, the matrix layer comprises the following components, based on the total weight of the matrix layer: 1) The total dose of risperidone is 9.5 to 15%, preferably 9.5 to 15% or 10 to 12%; 2) The dosage of the skin penetration enhancer is 1% to 50%, preferably 2 to 30%, 8.5 to 30%, 8.5 to 25%, or 8.5 to 15%, and more preferably C1 to C2 30 The dosage of fatty acid is 8.5-15%, the dosage of fatty acid ester is 1-10%, the dosage of fatty alcohol is 1-15%, and most preferably, the dosage of oleic acid is 8.5-15%, and the dosage of lauryl lactate is 1-10%, 1-6%, or 3-5%, and C 13 ~C 30 The dosage of the alkenyl alcohol is 1-15%, 5-15%, or 8-15%; 3) The dosage of the pressure-sensitive adhesive is 50-82%, preferably 50-80% or 55-80%; The dosage of each component in the matrix layer totals 100%.

[0033] In some embodiments, in the risperidone transdermal delivery system, the matrix layer comprises the following components, based on the total weight of the matrix layer: 1) The total dose of risperidone is 9.5 to 15%, preferably 9.5 to 15% or 10 to 12%; 2) The dosage of the skin penetration enhancer is 1% to 50%, preferably 2 to 30%, 8.5 to 30%, 8.5 to 25%, or 8.5 to 15%, and more preferably C1 to C2 30The dosage of fatty acid is 8.5-15%, the dosage of fatty acid ester is 1-10%, the dosage of fatty alcohol is 1-15%, and most preferably, the dosage of oleic acid is 8.5-15%, and the dosage of lauryl lactate is 1-10%, 1-6%, or 3-5%, and C 13 ~C 30 The dosage of the alkenyl alcohol is 1-15%, 5-15%, or 8-15%; 3) The dosage of the pressure-sensitive adhesive is 50-82%, preferably 50-80% or 55-80%; 4) The dosage of the antioxidant is 0% to 1%, preferably 0.05% to 0.5% or 0.1% to 0.3%; 5) The dosage of the aggregation promoter is 0 to 30%, preferably 1 to 5%; 6) The dosage of thickener is 0-40%; 7) The dosage of plasticizer is 0-40%; 8) Additional permeation enhancers are 0-10%; The dosage of each component in the matrix layer totals 100%.

[0034] The additional permeation enhancer refers to a permeation enhancer different from 2).

[0035] In some embodiments, the pressure sensitive adhesive is selected from one or more of an acrylic adhesive, a silicone adhesive, an acrylic-silicone copolymer adhesive, a polybutene adhesive, a styrene-isoprene-butene copolymer, and a styrene-butadiene-styrene copolymer.

[0036] In some embodiments, the coagulation promoter is selected from crospovidone, Eudragit E, Eudragit EPO, Eudragit S, Eudragit R, Plastoid B, and mixtures thereof. In some embodiments, the coagulation promoter is povidone K90, Eudragit EPO, povidone K90 and Eudragit EPO, crospovidone CL-M and Eudragit EPO, povidone K90, crospovidone CL-M and Eudragit EPO, povidone K90 and Plastoid B, crospovidone CL-M and Plastoid B, povidone K90 and crospovidone CL-M, with the preferred combination being povidone K90 and Eudragit EPO.

[0037] In some embodiments, the antioxidant is selected from tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate dihydrate, dibutylhydroxytoluene (BHT), and preferably α-tocopherol (i.e., vitamin E) or a combination of α-tocopherol and dibutylhydroxytoluene (BHT). In some embodiments, the additional chelating agent as a synergistic antioxidant is selected from citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA.

[0038] In some embodiments, the thickening agent is selected from polybutenes, terpenes, and mixtures thereof.

[0039] In some embodiments, the plasticizer is selected from mineral oil, silicone oil, triethyl citrate, and mixtures thereof.

[0040] In some embodiments, in the risperidone transdermal delivery system, the dosage of the matrix layer is 30 g / m 2 ~700g / m 2In some embodiments, the dosage of the matrix layer is 30 GSM to 700 GSM, 50 GSM to 700 GSM, 30 GSM to 100 GSM, 40 GSM to 150 GSM, 75 GSM to 150 GSM, 150 GSM to 300 GSM, or 350 GSM to 700 GSM. Specific dosages of the matrix layer are selected from 30 GSM, 50 GSM, 55 GSM, 75 GSM, 100 GSM, 125 GSM, 150 GSM, 175 GSM, or 200 GSM.

[0041] In some embodiments, during the manufacturing process of the risperidone transdermal delivery system, risperidone is added as micronized risperidone crystalline Form A, and preferably the particle size of the micronized risperidone is 20 μm or less. In some embodiments, 90% or more of the particles have an average diameter of 20 μm or less, more preferably 0.5 nm to 20 μm, and particularly preferably 0.5 nm to 15 μm.

[0042] In some embodiments, a solubilizing agent or solvent is further used in the preparation of the matrix layer of the risperidone transdermal delivery system. The solubilizing agent or solvent has the effect of reducing adhesion (i.e., is an adhesion-reducing agent). The solubilizing agent or solvent is selected from C1-C6 alkyl alcohols, n-heptane, ethyl acetate, toluene, and mixtures thereof, and is preferably ethanol, isopropyl alcohol, n-heptane, or ethyl acetate.

[0043] In some embodiments, a skin contact adhesive layer is added to the matrix layer (FIG. 2). 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) a skin contact adhesive layer; and 4) a release layer.

[0044] In some embodiments, a rate-controlling film layer (film or woven fabric as in FIG. 3) is added between the drug matrix reservoir layer and the skin-contacting adhesive layer, and the risperidone transdermal delivery system comprises: 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) a semipermeable membrane or woven fabric layer; 4) a skin contact adhesive layer; and 5) a release layer.

[0045] In some embodiments, the skin contact adhesive layer comprises a pressure sensitive adhesive, optional risperidone, and optional other excipients selected from one or more of a cohesion promoter, an antioxidant, an agent to prevent skin irritation, a thickener, a plasticizer, a solubilizer, a solvent, and a desiccant.

[0046] In some embodiments, the risperidone transdermal delivery system comprises: 1) a backing layer; 2) an overlap adhesive film layer, preferably wherein the overlap adhesive film layer material is selected from one or more of siloxane, polyisobutylene, or styrene-isoprene-styrene copolymer, and preferably wherein the dosage of the overlap adhesive film layer is 50-110 GSM; 3) a separation layer; 4) a matrix layer comprising risperidone dispersed in a crystalline and amorphous state in the matrix layer, a skin permeation enhancer, and a pressure-sensitive adhesive; 5) a release layer.

[0047] In some embodiments, the overlapping adhesive film layer of the risperidone transdermal delivery system comprises an adhesive, wherein the overlapping adhesive film layer adhesive is the same as or different from the drug matrix layer adhesive. Preferably, the solubility of the drug in the overlapping adhesive film layer adhesive is the same as or lower than the solubility of the drug in the matrix layer adhesive. More preferably, the solubility of the drug in the overlapping adhesive film layer adhesive is lower than the solubility of the drug in the matrix layer adhesive.

[0048] In some embodiments, the overlapping adhesive film may be one layer, two layers, or multiple layers. Preferably, a first overlapping adhesive film layer close to the backing layer can prevent other overlapping adhesive film layers further from the backing layer from migrating to the backing layer or to the side of the backing layer away from the skin.

[0049] In some embodiments, the adhesive of the first overlapping adhesive film layer is selected from Duro-Tak 387-2516, Duro-Tak 387-2287, Duro-Tak 387-4287, Duro-Tak 87-2051, Duro-Tak 87-2052, Duro-Tak 87-2054, Duro-Tak 87-2852, or mixtures thereof. In some embodiments, the adhesive of the second overlapping adhesive film layer is selected from polyisobutylene, styrene-isoprene-styrene copolymer, dimethylsiloxane, or mixtures thereof.

[0050] In some embodiments, the risperidone transdermal administration system comprising overlapping adhesive film layers comprises, in order from the backing layer to the release layer, a backing layer, one or more overlapping adhesive film layers, a separation layer, a matrix layer, and a release layer (as shown in FIG. 4A), wherein the backing layer, the one or more overlapping adhesive film layers, and the release layer extend circumferentially beyond the separation layer and matrix layer, and upon administration, the release layer is removed and the matrix layer that contacts the skin is sealed to the skin by the one or more overlapping adhesive film layers.

[0051] In some embodiments, in a risperidone transdermal delivery system comprising overlapping adhesive film layers, the overlapping adhesive film is one layer (as shown in Figures 4A, 4C, and 4F), and includes, in order from the backing layer to the release layer: i. a backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, and a release layer, the backing layer, the overlapping adhesive film layer, and the release layer extending circumferentially beyond the separation layer and the matrix layer, preferably having the structure shown in FIG. 4A; or ii. a backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, a skin adhesive layer, and a release layer, wherein the backing layer, the overlapping adhesive film layer, and the release layer circumferentially extend beyond the separation layer, the matrix layer, and the skin adhesive layer, preferably having a structure as shown in FIG. 4C; or iii. A backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, a semipermeable film layer, a skin adhesive layer, and a release layer, wherein the backing layer, the overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, preferably in the structure shown in Figure 4F.

[0052] In some embodiments, in a risperidone transdermal delivery system comprising overlapping adhesive film layers, the overlapping adhesive film is two-layered (as shown in Figures 4B, 4D, 4E, and 13), and upon administration, the release layer is removed and the skin-contacting matrix layer is sealed to the skin with a second overlapping adhesive film layer, where, from the backing layer to the release layer, in order: i. a backing layer, a first overlapping adhesive film layer, a second overlapping adhesive film layer, a separation layer, a matrix layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, the second overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer and the matrix layer, preferably in the structure shown in FIG. 4B; or ii. a backing layer, a first overlapping adhesive film layer, a separation layer, a matrix layer, a skin adhesive layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer, the matrix layer, and the skin adhesive layer, and the second overlapping adhesive film layer is filled between the first overlapping adhesive film layer and the release layer, preferably as shown in FIG. 4D; or iii. A backing layer, a first overlapping adhesive film layer, a separation layer, a matrix layer, a semipermeable film layer, a skin adhesive layer, a second overlapping adhesive film layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, the second overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, and the second overlapping adhesive film layer extends toward the first overlapping adhesive film layer and encases the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, preferably having a structure as shown in Figure 4E.

[0053] In some embodiments, the dosage of the first overlap adhesive film layer is 25-60 GSM and the dosage of the second overlap adhesive film layer is 25-60 GSM. Preferably, the dosage of the first overlap adhesive film layer is 50-60 GSM and the dosage of the second overlap adhesive film layer is 50-60 GSM. In some specific embodiments, the dosage of the first overlap adhesive film layer is 25, 50, 55, or 60 GSM and the dosage of the second overlap adhesive film layer is 25, 50, 55, or 60 GSM.

[0054] In some embodiments, the backing layer is made of a polymeric elastic film, a polymeric woven fabric, a bidirectional or multidirectional elastic nonwoven fabric, a stretchable polymeric film, a stretchable woven fabric, or a stretchable nonwoven fabric. In some embodiments, the backing layer is selected from polyester, polyethylene, polypropylene, polyvinyl chloride, polyethylene vinyl acetate, polyurethane, preferably KOB051 and KOB053.

[0055] In some embodiments, the separating layer is selected from a flexibly blocked single-layer or multi-layer polymer film. The separating layer polymer is selected from polyolefin, polyester, polyethylene, polyvinylidene chloride, or polyurethane. Preferably, the separating layer further comprises an aluminum film.

[0056] In some embodiments, the separation layer includes a plurality of small pieces that are partially connected to one another, and the matrix layer includes a plurality of small pieces that are all connected or partially connected. Preferably, the plurality of separation layer small pieces that are connected to one another in the separation layer are symmetrical or asymmetrical, the same or different. The plurality of small pieces that are connected to one another in the matrix layer are selected from symmetrical or asymmetrical, the same or different. More preferably, the connection points of some of the separation layer and some of the matrix layer are all aligned or partially aligned.

[0057] In some embodiments, there are one or more connection points between adjacent pieces in the separation layer or matrix layer, preferably 1, 2, 3, 4, or 5 connection points, and the length of each connection point is independently selected from the range of 0.5 to 3 mm.

[0058] In some embodiments, the stacked separation layer pieces and matrix layer pieces have the same shape, and the number of pieces in each transdermal delivery system unit is selected from 1 to 10.

[0059] In some embodiments, the area of ​​each piece is between 1 and 25 cm 2 and preferably 1 cm 2 , 4cm 2 , 6cm 2 , 8cm 2 , 9cm 2 , 10cm 2 , 12.5cm 2 , 16cm 2 , 25cm 2 is.

[0060] In some embodiments, the weight of the matrix layer is between 30 GSM and 700 GSM, between 50 GSM and 700 GSM, between 30 GSM and 100 GSM, between 40 GSM and 150 GSM, between 150 GSM and 300 GSM, or between 350 GSM and 700 GSM.

[0061] In another aspect, the present invention provides a method for preparing a stable matrix-type risperidone transdermal delivery system (shown in FIG. 1), the method comprising: Step 1, combining a skin penetration enhancer with optional cohesion enhancers, antioxidants, skin irritation inhibitors, thickeners, plasticizers, solubilizers, solvents, and drying agents to obtain Blend 1; Step 2: mixing Blend 1 with a pressure sensitive adhesive to obtain Blend 2; Step 3, adding micronized risperidone crystalline Form A or a pharmaceutically acceptable salt thereof to Blend 2 from Step 2 and stirring until the risperidone or a pharmaceutically acceptable salt thereof is uniformly suspended to obtain a drug wet mixture; Step 4: applying the drug wet mixture to a release layer; Step 5: drying to remove the solvent and solubilizer to obtain a release layer / drug matrix layer laminate material; and step 6 of laminating the release layer / drug matrix layer laminate material onto a backing layer to form a release layer / drug matrix layer / backing layer composite film.

[0062] In some embodiments, the present invention provides a method for a matrix-type risperidone transdermal delivery system (shown in FIG. 2), the method comprising: Step 1 of producing the release layer / matrix layer / backing layer composite film according to the above-mentioned Steps 1 to 6; Step 2: preparing a solution or suspension of a skin contact adhesive layer comprising a pressure-sensitive adhesive, optionally risperidone crystalline Form A or a pharmaceutically acceptable salt thereof, and optionally other excipients, applying the solution or suspension to a release layer, and drying the solution or suspension to form a release layer / skin contact adhesive layer laminate material; and step 3 of removing the release layer from the release layer / matrix layer / backing layer composite film, and laminating the adhesive surface layer of the release layer / skin-contact adhesive layer described in step 1 onto the matrix layer to form a release layer / skin-contact adhesive layer / matrix layer / backing layer composite film.

[0063] In some embodiments, the present invention provides a method for a matrix-type risperidone transdermal delivery system (shown in FIG. 3), the method comprising: Step 1 of producing the release layer / matrix layer / backing layer composite film according to the above-mentioned Steps 1 to 6 of the claim; Step 2: preparing a solution or suspension of a skin contact adhesive layer containing a pressure-sensitive adhesive, optionally risperidone crystalline form A or a pharmaceutically acceptable salt thereof, and optionally other excipients, applying the solution or suspension to a release layer and drying the release layer / skin contact adhesive layer laminate material, and laminating the adhesive surface layer to a semipermeable membrane or a woven fabric layer; and step 3 of removing the release layer from the release layer / matrix layer / backing layer composite film and laminating the semipermeable membrane or woven fabric layer side onto the matrix layer to form a release layer / skin-contact adhesive layer / semipermeable membrane or woven fabric layer / matrix layer / backing layer composite film.

[0064] In some embodiments, the present invention provides a risperidone transdermal administration system (shown in FIG. 4A), Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then combining it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: producing the release layer / drug matrix layer laminate material according to Steps 1 to 5 of claim 32, and laminating the release layer / drug matrix layer laminate material on a separation layer to form a release layer / drug matrix layer / separation layer film; Step C: removing the release film of the backing layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / drug matrix layer / separation layer film described in Step B on the overlapping adhesive film; Step D: removing the release film from the drug matrix layer and applying an extra-large release film to the drug matrix layer and the overlapping adhesive film layer; Step E: Die-cutting the final patch so that the overlapping adhesive film layer extends beyond the separating layer and drug adhesive layer in each direction.

[0065] In some embodiments, the present invention provides a risperidone transdermal administration system (shown in FIG. 4C), Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then combining it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: preparing a release layer / skin contact adhesive layer / drug matrix layer / separation layer composite film; Step C: removing the release film of the separation layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / skin contact adhesive layer / matrix layer / separation layer composite film formed in Step B on the overlapping adhesive film; Step D: removing the release film from the skin contact adhesive layer and applying an extra-large release film to the skin contact adhesive layer and the overlapping adhesive film layer; Step E: Die-cutting the final patch so that the overlapping adhesive film layer extends beyond the separation layer, matrix layer, and skin adhesive layer in each direction, preferably forming the structure depicted in Figure 4C.

[0066] In some embodiments, the present invention provides a risperidone transdermal administration system (shown in FIG. 4F), Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then combining it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: preparing the release layer / skin contact adhesive layer / semipermeable membrane or woven fabric layer / drug matrix layer / separation layer composite membrane; Step C: removing the release film of the backing layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / skin contact adhesive layer / semipermeable membrane or woven fabric layer / drug matrix layer / separation layer composite membrane described in Step B on the overlapping adhesive film; Step D: removing the release film from the skin contact adhesive layer and applying an extra-large release film to the skin contact adhesive layer and the overlapping adhesive film layer; Step E: Die-cutting the final patch, and extending the backing layer, overlapping adhesive film layer, and release layer circumferentially beyond the separation layer, matrix layer, semipermeable membrane or woven fabric layer, and skin adhesive layer, preferably to form the structure depicted in FIG. 4F.

[0067] In some embodiments, the present invention provides a risperidone transdermal administration system (shown in FIGS. 4B, 4D, and 4E), Step A: the first overlapping adhesive film layer pressure-sensitive adhesive is applied to a release film, dried, and then combined with a backing layer to obtain a backing layer / first overlapping adhesive film / release film composite film; the second overlapping adhesive film layer pressure-sensitive adhesive is applied to a release film, dried, and then combined with the first overlapping adhesive film layer from which the release film has been removed to obtain a backing layer / first overlapping adhesive film / second overlapping adhesive film / release film composite film; Step B: preparing a release layer / drug matrix layer / separation layer membrane (FIG. 4B), a release layer / skin adhesive layer / drug matrix layer / separation layer membrane (FIG. 4D), or a release layer / skin adhesive layer / semipermeable woven fabric layer / drug matrix layer / separation layer membrane (FIG. 4E); Step C: removing the release film of the backing layer / first overlapping adhesive film / second overlapping adhesive film / release film composite film described in Step A, and applying the separation layer described in Step B to the second overlapping adhesive film layer; Step D: removing the release film remaining from step C and applying a super-large release film to the side away from the backing layer; Step E: Die-cutting the final patch so that the second overlapping adhesive film layer extends over the separation layer, drug matrix layer, and optional skin adhesive layer and semipermeable membrane fabric layer in each direction, preferably to obtain the structure shown in Figures 4B, 4D, and 4E.

[0068] In some embodiments, the composite membrane prepared in step B above is cut into multiple partially connected pieces to obtain a structure of pieces (shown in Figures 13, 15-19), and in step C, the structure improves the alignment order (shown in Figures 18-19) when the composite membrane prepared in step B is moved.

[0069] In some embodiments, the drug wet mixture for preparing the matrix layer contains undissolved risperidone crystalline Form A.

[0070] In some embodiments, the solvent in step 1 or step B is selected from C1-C6 alkyl alcohol, n-heptane, ethyl acetate, toluene, and mixtures thereof, preferably ethanol, isopropyl alcohol, n-heptane, or ethyl acetate.

[0071] In some embodiments, the risperidone transdermal delivery system is packaged in a heat-sealed pouch.

[0072] In another aspect, the present invention provides the use of a therapeutically effective amount of a risperidone transdermal delivery system in the manufacture of a medicament for treating or preventing schizophrenia, mania, and dementia.

[0073] In another aspect, the present invention provides the use of a risperidone transdermal delivery system in the manufacture of a medicament for treating or preventing positive or negative symptoms of schizophrenia, in some embodiments, the positive or negative symptoms of schizophrenia including hallucinations, delusions, and emotional withdrawal and blunted affect.

[0074] In another aspect, the present invention provides a method for treating or preventing schizophrenia, mania, and dementia, comprising administering to a subject in need thereof a therapeutically effective amount of a risperidone transdermal delivery system.

[0075] In another aspect, the present invention provides a method for treating or preventing positive or negative symptoms of schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a risperidone transdermal delivery system, in some embodiments, the positive or negative symptoms of schizophrenia include hallucinations, delusions, and emotional withdrawal and blunted affect.

[0076] In some embodiments, the risperidone transdermal delivery system is administered once every 1, 3, 7, 10, or 14 days.

[0077] In some embodiments, the risperidone transdermal delivery system continuously delivers risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

[0078] In some embodiments, the risperidone transdermal delivery system continuously delivers risperidone into the patient's body at a substantially constant rate for a period of 24 hours to 14 days, preferably 24 hours to 7 days.

[0079] In some embodiments, after administration of the risperidone transdermal delivery system, the maximum transdermal dose of risperidone occurs within 24 to 36 hours, and 3 to 7 days after administration, the transdermal dose of risperidone is maintained at 65% or more of the maximum transdermal dose, preferably 65% ​​to 90%, and more preferably 75% to 85% of the maximum transdermal dose of risperidone.

[0080] In some embodiments, for patches that can be worn for 24 hours to 3 days, the matrix layer weight is between 30 GSM (grams per square meter) and 100 GSM, for patches that can be worn for 7 days, the matrix layer weight is between 40 GSM and 150 GSM, and for patches that can be worn for 14 days, the matrix layer weight is between 50 GSM and 700 GSM.

[0081] definition As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the scope of sound medical judgment, may be applied to contact a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, and the like, and that have a reasonable benefit / risk ratio and are effective for their intended use.

[0082] "Pharmaceutically acceptable salts" according to the present invention include inorganic and organic acid addition salts, which may be prepared in situ during the final isolation and purification process of the compound, or by separately reacting the purified compound (e.g., risperidone) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of inorganic acid addition salts include, but are not limited to, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, etc. Examples of organic acid addition salts include saturated or unsaturated C1-C 30The salts of fatty acids include, but are not limited to, mono- or dicarboxylates. Non-limiting examples include formate, glyoxylate, oxalate, acetate, glycolate, acrylate, pyruvate, malonate, propionate, 3-hydroxypropionate, lactate, glycerate, fumarate, maleate, oxaloacetate, crotonate, acetoacetate, 2-oxobutyrate, methylmalonate, succinate, malate, L-tartrate, DL-tartrate, mesotartrate, dihydroxytartrate, butyrate, isobutyrate, hydroxybutyrate, levofloxacin ... Phosphate, sorbate, itaconate, mesaconate, ketoglutarate, glutarate, succinate, methylsuccinate, valerate, isovalerate, pivalate, cis aconitate, trans aconitate, ascorbate, citrate, isocitrate, adipate, caproate, benzoate, salicylate, gentisate, protocatechuate, gallate, cyclohexanecarboxylate, pimelate, benzoate, chlorobenzoate, phthalate , isophthalate, terephthalate, terephthalate, phenylacetate, toluate, o-toluate, m-toluate, p-toluate, dinitrobenzoate, benzenesulfonate, toluenesulfonate, citrate, methanesulfonate, oleate, toluenesulfonate, methanesulfonate naphthoate, gluceptate, lacturonate, dodecanesulfonate and isethionate, mandelate, homogentisate, suberate, caprylate The term "cocoa salt" includes, but is not limited to, caprate, laurate, palmitate, stearate, isostearate, oleate, elaidate, polyacid salts, erucate, nervonate, ximenynate, octadecatrienoate, linoleate, alpha-linolenate, gamma-linolenate, octadecatrienoate, stearate, meadate, eicosadienoate, eicosatrienoate, dihomo-gamma-linolenate, arachidonate, docosadienoate, and the like, and combinations thereof.

[0083] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder; (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0084] As used herein, the term "about" refers to plus or minus 10% of the indicated number. For example, "about 10%" can represent a range of 9% to 11%, and "about 1" can represent 0.9 to 1.1.

[0085] As used herein, the terms "optional," "optional," or "optionally" include both optional and non-optional. For example, "optional risperidone Form A" refers to both the use of risperidone Form A and the absence of risperidone Form A, and "optional other excipients" refers to both the use of other excipients and the absence of other excipients.

[0086] As used herein, the term "treatment" refers to clinical intervention in an attempt to alter the natural course of the individual being treated and may be performed prophylactically or during the course of a clinical condition. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or ameliorating the disease state, and achieving remission or improved prognosis.

[0087] As used herein, the term "risperidone crystalline form A" is described in WO0212200A1, and its XRPD spectrum has characteristic peaks at 2θ values ​​of 14.2±0.2°, 21.3±0.2°, and further at 2θ values ​​of 10.6±0.2°, 11.4±0.2°, 16.4±0.2°, 18.9±0.2°, 19.9±0.2°, 22.5±0.2°, 23.3±0.2°, 25.4±0.2°, 27.6±0.2°, and 29.0±0.2°. Risperidone crystalline form A used in the present invention has an XRPD spectrum as shown in Figure 8.

[0088] As used herein, the term "micronized" refers to particles having a particle size of 20 μm or less. In some embodiments, 90% or more of the particles have an average diameter of 20 μm or less, more preferably 0.5 nm to 20 μm, and especially preferably 0.5 nm to 15 μm.

[0089] As used herein, the terms "backing layer" (FIGS. 1, 2, 3) and separation layer (FIGS. 4A-4F) refer to the upper surface of the transdermal patch and provide flexibility to the patch as a primary structural element. Preferably, the backing layer is substantially impermeable to the pharmaceutical composition to be transdermally administered. The backing layer is preferably made of a sheet or film of a flexible, elastic material. The backing layer is preferably air-impermeable. The backing layer used in the patch of the present invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and adheres closely 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 / vapor transmission. Preferably, the backing layer of the matrix-type transdermal delivery system (FIGS. 1-4) is occlusive. Preferably, the backing layer comprises a synthetic polymer, such as polyolefin, polyester, polyethylene, polyvinylidene chloride, polypropylene, polyethylene vinyl acetate, and polyurethane. Preferably, the backing layer has a thickness of about 0.5 mils to about 5 mils, more preferably about 1 mil to about 3 mils. Preferably, the oxygen transport rate is about 2 cc / m / 24 hr to about 100 cc / m / 24 hr, more preferably about 70 g / m / 24 hr to about 90 g / m / 24 hr. Preferably, the MVTR is about 0.1 g / m / 24 hr to about 50 g / m / 24 hr, more preferably 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 having a thickness of about 2.0 mils (commercially available, e.g., Scotchpak 9733, Scotchpak 9735, and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul, Minn.). Scotchpak 9733 is a translucent, laminated, heat-sealable sheet made of polyester and medium-density polyethylene / ethylene vinyl acetate heat-sealable layers, and can be used in the matrix-type transdermal delivery systems shown in Figures 1-3 and 4A-4F.More preferably, the backing layer comprises a laminate material including an aluminum foil layer between polymer film layers, such as Scotchpak 9738 and Scotchpak 1109. When the patch is attached to the skin, the aluminum layer can prevent light from contacting the photosensitive risperidone.

[0090] As used herein, the term "separation layer" may be used to separate the overlapping adhesive film layer and drug-containing matrix layer of the patches of Figures 4A-4F. The separation layer is preferably a polyester nonwoven fabric layer. Specific separation layers may be selected from Scotchpak 1109, Scotchpak 9738, Scotchpak 9733, and Scotchpak 9754.

[0091] As used herein, the term "composite film" refers to a composite having a multilayer structure. For example, in this specification, a "release layer / drug matrix layer / backing layer composite film" and a "backing layer / first overlapping adhesive film / second overlapping adhesive film / release film composite film" each have a multilayer composite structure. Unless otherwise specified, in this specification, different layers in a composite film are separated by " / ".

[0092] As used herein, the term "matrix layer" includes risperidone, a skin permeation enhancer, a pressure sensitive adhesive, and optional other excipients dispersed in the matrix layer in a crystalline and amorphous state.

[0093] The matrix layer may further comprise one or more other pharmaceutically acceptable excipients, non-limiting examples of which include, but are not limited to, cohesion promoters, antioxidants, skin irritation inhibitors, thickeners, and plasticizers.

[0094] Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate dihydrate, dibutylhydroxytoluene (BHT), and chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA. Preferably, the antioxidant is α-tocopherol (i.e., vitamin E) or a combination of α-tocopherol and dibutylhydroxytoluene (BHT).

[0095] Pressure sensitive adhesives include, but are not limited to, acrylic adhesives, silicone adhesives, acrylic-silicone copolymer adhesives, polybutene adhesives, styrene-isoprene-butene copolymers, styrene-butadiene-styrene copolymers, or combinations of two or more adhesives. Examples of acrylic adhesives include Duro-Tak® 387-2516, Duro-Tak® 387-4280, Duro-Tak® 387-2287, Duro-Tak® 387-2510, Duro-Tak® 87-2196, Duro-Tak® 387-2051, Duro-Tak® 387-2052, Duro-Tak® 387-2054, Duro-Tak® 87-2194, Duro-Tak® 87-235A, Duro-Tak® 87-900A, Duro-Tak® 87-9301, Duro-Tak® 87- 4098, GEFVA GMS® 788, GEFVA GMS® 9073, Duro-Tak® 387-2353, Duro-Tak® 87-2074, Duro-Tak® 87-2852, Duro-Tak® 87-2054, GELVA®-73 Tak® 80-1196, Duro-Tak® 87-2070, Duro-Tak® 87-2979, Duro-Tak® 87-2888 and Duro-Tak® 87-2296.DuPont (Midland, MI) silicones BIO-PSA® 7-4401, BIO-PSA® 7-4402, BIO-PSA® 7-4501, BIO-PSA® 7-4502, BIO-PSA® 7-4601, BIO-PSA® 7-4602, SRS7-4502, SRS7-4501, SRS7-4502, SRS7-4602, BIO-PSA® 7-4101, BIO-PSA® 7-4102, BIO-PSA® 7-4103, BIO-PSA® 7-4201, BIO-PSA® 7-4202, BIO-PSA® BIO-PSA® 7-4203, BIO-PSA® 7-4301, BIO-PSA® 7-4302, BIO-PSA® 7-4302, BIO-PSA® 7-6101, BIO-PSA® 7-6102, BIO-PSA® 7-6201, BIO-PSA® 7-6301, and BIO-PSA® 7-6302. Examples of polybutene adhesives include combinations of two or more low molecular weight polyisobutylenes (Oppanol B10, Oppanol B11, Oppanol B12 from BASF), medium molecular weight polyisobutylenes (Oppanol B50, Oppanol B80, Oppanol N80), and high molecular weight polyisobutylenes (Oppanol B100, Oppanol B150, Oppanol N100, Oppanol N150). An example of a styrene-isoprene-butene copolymer is D1161 (Kraton).

[0096] Preferably, the pressure-sensitive adhesive is an acrylic adhesive, more preferably a hydroxyethyl functional acrylic copolymeric adhesive, such as Duro-Tak 387-2516, Duro-Tak 387-4280, 387-2287, or Duro-Tak 387-2510. The amount of adhesive is 50-82% based on the total weight of the matrix layer, preferably 50-80% or 55-80%. Preferably, the pressure-sensitive adhesive is a pressure-sensitive adhesive solution, and the solvent is a poor solvent for risperidone. Examples of the solvent include n-heptane and ethyl acetate. Because n-heptane is a poor solvent for risperidone, most of the risperidone Form A does not dissolve in the pressure-sensitive adhesive solution and remains in the pressure-sensitive adhesive blend as the original polymorph of the crystals. When the solvent is removed during the coating and drying process, risperidone remains in the dried drug matrix layer as the original stable polymorph A. Non-limiting examples of thickeners include polybutene terpenes and mixtures thereof. The amount of thickener present in the matrix layer is about 0% to about 30% by weight of the adhesive material, preferably about 0% to about 25%.

[0097] Non-limiting examples of cohesion enhancers include soluble polyvinylpyrrolidone (also known as povidone), insoluble crospovidone, Eudragit E, Eudragit EPO, Eudragit S, Eudragit R, Plastoid B, and mixtures thereof. The matrix layer of the present invention contains a liquid skin penetration enhancer, which causes cold flow around the patch, resulting in the appearance of a black ring on the skin while wearing the patch, or the transfer of adhesive to the skin when the patch is removed. The cohesion enhancer increases the cohesion of the matrix layer, reducing cold flow and the appearance of a black ring on the skin or the transfer of adhesive to the skin. One example of a soluble povidone is povidone K90, and one example of an insoluble crospovidone is CL-M. The present inventors have surprisingly discovered that povidone K90 is an excellent cohesion enhancer. Preferably, the coagulation promoter is a combination of povidone K90, Eudragit EPO, povidone K90 and Eudragit EPO, crospovidone CL-M and Eudragit EPO, povidone K90, crospovidone CL-M and Eudragit EPO, povidone K90 and Plastoid B, crospovidone CL-M and Plastoid B, povidone K90 and crospovidone CL-M, and a preferred combination is one of povidone K90 and Eudragit EPO.

[0098] Skin penetration enhancers are C1 to C 30 In some embodiments, fatty acids include, but are not limited to, C 7-30 fatty acids, C 7-22 fatty acids, C 12-22 The C1 to C6 fatty acids may be used. 30Fatty acids include saturated or unsaturated 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, mesotartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, levulinic acid, sorbic acid, itaconic acid, mesaconic 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, caproic acid, benzoic acid, salicylic acid, gentisic acid, proton Examples of suitable oleic acids include catechuic 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, caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, polycarboxylic acid, erucic acid, nervonic acid, ximenynic acid, octadecatrienoic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, octadecatrienoic acid, stearic acid, mead acid, eicosadienoic acid, eicosatrienoic acid, dihomo-γ-linolenic acid, arachidonic acid, docosadienoic acid, and combinations thereof. Preferred are oleic acid, isostearic acid, and stearic acid.

[0099] The skin penetration enhancer further comprises a fatty alcohol. The fatty alcohol may comprise one or more saturated, monounsaturated, or polyunsaturated C 7-30 Alkyl group or C 3-30 Alkenyl alcohols, preferably containing one or more saturated, monounsaturated or polyunsaturated C 13-30 Alkyl group or C 13-30Alkenyl alcohols may include, but are not limited to, one or more of tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmityl alcohol, heptadecanol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, nonadecanol, arachidonoyl alcohol, octyldodecanol, behenyl alcohol, sinapyl alcohol, lignocerol, and lignocerol. Saturated fatty alcohol permeation enhancers may include, but are not limited to, one or more of myristyl alcohol, isomyristyl alcohol, antiisomyristyl alcohol, cetyl alcohol, isohexadecanol, antiisohexadecanol, stearyl alcohol, isostearyl alcohol, and antiisostearyl alcohol. In some embodiments, the fatty alcohol is myristyl alcohol.

[0100] The skin penetration enhancer further comprises a fatty acid ester. The fatty acid ester may be any of C1 to C6 30 Fatty acids and C1-C 30 It refers to an ester formed by the binding of alcohol. Non-limiting examples include lauryl lactate, myristyl lactate, cetyl lactate, palmityl lactate, Ceraphyl 31, ethyl laurate, methyl laurate, isopropyl myristate, isopropyl palmitate, diisoadipic acid, medium-chain triglycerides, and diethyl sebacate.

[0101] The skin penetration enhancer further comprises a surfactant, such as one or more of glycerides (monoglycerides, diglycerides, triglycerides), polyoxylstearyl esters, a mixture of octatriacontatetraene ester-4 phosphate ester with ethylene glycol palmitate stearate and diethylene glycol palmitate stearate, a mixture of polyglycerol-3 diisostearate ester with PEG-6 stearate, ethylene glycol palmitate stearate and PEG-32 stearate, oleoyl polyoxy-6 glyceride, lauroyl polyoxy-6 glyceride, capryloyl polyoxy-8 glyceride, and propylene glycol monocaprylate. Cholesterol, propylene glycol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, polyglyceryl-3 dioleate, a mixture of PEG-6 stearate and PEG-32 stearate, lecithin, cetyl alcohol, cholesterol, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, triethanolamine stearate, polyoxyethylene fatty alcohol ethers, glyceryl monostearate, sorbitan monolaurate, lanolin alcohol and ethoxylated lanolin alcohol, sorbitan fatty acid esters, sucrose distearate, Span 20, Span 40, Span 80, Tween 20, Tween 40, Tween 80, pentadecanolide, glyceryl monolactate, glyceryl monostearate, glyceryl monooleate, or combinations thereof.

[0102] According to one preferred embodiment of the present invention, the weight percent content of the skin permeation enhancer is 1%-50% of the drug reservoir layer, preferably 2-30%.

[0103] Optional non-limiting solubilizers or solvents include C1-C6 alkyl alcohols, n-heptane, ethyl acetate, toluene, or a combination or more of two. The solubilizer or solvent also reduces the viscosity of the drug-adhesive suspension, allowing it to be applied as a uniform film.

[0104] As used herein, the term "semipermeable membrane or woven fabric layer" refers to a membrane that encases a liquid or semi-solid matrix material within a matrix drug layer, and its function is to control the diffusion of risperidone from the liquid or semi-solid matrix drug layer to the skin-contact adhesive layer. 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 copolymer membranes 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. The semipermeable membrane or woven fabric layer and backing layer may be sealed together around their peripheries.

[0105] Suitable semipermeable membranes include continuous and microporous membranes and can be made of braided or non-braided materials. Semipermeable membranes are preferably made of flexible polymeric materials commonly used by those skilled in the art. Polymeric membranes that can be used to make the semipermeable film layer include, but are not limited to, low-density polyethylene, high-density polyethylene, ethyl-vinyl acetate copolymer, polypropylene, and suitable polymers thereof. In one embodiment, the semipermeable film layer is made of a microporous membrane made of an ethylene-vinyl acetate copolymer containing about 0.5 to about 28 wt.% vinyl acetate. Suitable braided materials include Saatifil PES, e.g., PES 105 / 52 available from Saatitech, Inc. A suitable nonwoven fabric is Sontara from DuPont Nonwovens Sontara Technologies. In a preferred embodiment, the semipermeable film 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™). The thickness of the semipermeable film layer may typically be from about 10 um to about 100 um, and preferably from about 15 um to about 50 um.

[0106] As used herein, the term "skin contact adhesive layer" serves to adhere the risperidone transdermal delivery system to the skin surface. A protective release layer may also be used to control the rate of delivery of risperidone to the skin after removal. The skin contact adhesive layer comprises a pressure-sensitive adhesive, optional risperidone, and optional other excipients selected from cohesion promoters, antioxidants, skin irritation prevention agents, thickeners, plasticizers, solubilizers, and solvents. The pressure sensitive adhesive may comprise one or more of an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a siloxane adhesive, an acrylic-co-polysiloxane copolymer adhesive, and the acrylic adhesive may be one or more of 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 GMS 9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industry Co., Ltd.), the polyisobutylene adhesive is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppanol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene H1900 from Ineos with a mineral oil thickener, and the siloxane adhesive is DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400 and 7-4500, 7-4600 Bio-PSA The acrylic-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA 7-6100, 7-6200, and 7-6300. The combination of an acrylic adhesive with a silicone adhesive and the combination of polyisobutylene with styrene-isoprene-styrene are also good adhesive choices.

[0107] As used herein, the term "overlapping adhesive film" refers to a patch comprising a backing layer made of an elastic material, an overlapping adhesive film, a separation layer, a matrix layer, and a release layer (as shown in Figures 4A-4F and 13) that adheres more firmly to the skin than a patch comprising a backing layer, a drug matrix layer, and a release layer (as shown in Figure 1). The overlapping adhesive film may be one-layer, two-layer, or multi-layer, and a two-layer overlapping adhesive film transdermal delivery system is shown in Figures 4B, 4D, and 4E. Overlapping adhesive film layer 1 can prevent overlapping adhesive film layer 2 from migrating to the side of the backing layer away from the skin. The overlapping adhesive film comprises an adhesive, examples of which include acrylate esters such as Duro-Tak 387-2516, Duro-Tak 387-2287, Duro-Tak 387-4287, Duro-Tak 87-2051, Duro-Tak 87-2052, and Duro-Tak 87-2054, siloxanes, polyisobutylenes, styrene-isoprene-styrene copolymers, or a combination of two or more adhesives. The present inventors have discovered that when the overlapping adhesive film is one or two acrylate esters, a significant amount of nonvolatile risperidone migrates from the drug-containing matrix layer to the overlapping adhesive film layer, whereas when the overlapping adhesive film layer connected to the separating layer is siloxane, polyisobutylene, or styrene-isoprene-styrene copolymer, only a small amount of nonvolatile risperidone migrates from the drug-containing matrix layer to the overlapping adhesive film layer.

[0108] As used herein, the term "release layer" includes, but is not limited to, silicone coated polyester release liners available from many suppliers, nitrogen-containing polymer coated polyester release liners from 3M, and fluorosilicone coated polyester release liners.

[0109] The present invention has the following advantages and technical effects.

[0110] The prior art does not disclose a transdermal administration system that can continuously release a drug containing risperidone or a pharmaceutically acceptable salt thereof to a patient in a controlled manner at a constant rate, nor does it disclose a method for continuously delivering risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

[0111] 1. The present invention provides risperidone crystalline Form A or a pharmaceutically acceptable salt thereof in combination with a skin penetration enhancer, thereby providing it with good stability and enabling the sustained delivery of risperidone or a pharmaceutically acceptable salt thereof through the skin and into the blood circulation. Surprisingly, the transdermal administration system of the present invention can enable the sustained delivery of risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

[0112] 2. The present invention can improve the skin throughput by controlling the ratio of the skin permeation enhancer and risperidone crystalline form A, thereby helping to achieve the above technical effects.

[0113] 3. The present invention includes undissolved risperidone crystalline form A in the matrix layer of the risperidone administration system, which can improve skin throughput, thereby helping to achieve the above technical effects.

[0114] 4. The present invention improves the adhesiveness of the transdermal administration system and improves its skin tolerance by adjusting the amounts of the pressure-sensitive adhesive and cohesion promoter relative to the total weight of the matrix layer.

[0115] Therefore, the present invention provides a stable risperidone transdermal delivery system that can continuously release a drug to a patient in a rate-controlled manner and continuously deliver risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration at a constant rate for a period of 24 hours to 14 days. The risperidone transdermal delivery system of the present invention is stable in nature, safe and non-irritating, has good adhesion and cohesion to the skin, and is well tolerated by the skin.

[0116] 5. The present invention enhances the skin adhesion of the patch by using overlapping adhesive film layers.

[0117] 6. The present invention significantly reduces the migration of non-volatile drug molecules from the drug-containing layer to the overlapping adhesive film layer by using an adhesive for the overlapping adhesive film that is different from that used for the central drug-containing layer (i.e., matrix layer).

[0118] 7. The present invention provides a separating layer and a drug-containing layer having a thickness of 2 to 20 cm. 2 The drug-containing layer was cut into small pieces to enhance the skin adhesion of the drug-containing layer.

[0119] 8. The pieces of the separation layer and drug-containing layer of the present invention are partially connected to each other, which makes the die-cutting process easier than if they were not partially connected. Pieces that are not partially connected will be disordered during the die-cutting process. Pieces of the separated drug layer that are partially connected will be neat during the die-cutting process.

[0120] MODE FOR CARRYING OUT THE INVENTION In order to clarify the objectives, technical solutions, and advantages of the embodiments of the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiment is not all embodiments, but one modular embodiment of the present invention. Elements and features described in one embodiment of the present invention can be combined with elements and features shown in one or more other embodiments. It should be noted that, for the sake of clarity, the description omits the expression and description of components and processes known to those skilled in the art that are not related to the present invention. All other embodiments obtained based on the embodiments of the present invention without the need for creative efforts by those skilled in the art are within the scope of protection of the present invention.

[0121] In vitro skin throughput experiments: In vitro permeation studies were performed using a statically modified vertical Franz cell. The receiving cell had a volume of 7 ml and was filled with a buffer solution at pH 7.0, resulting in an effective skin permeation rate of 0.61 cm. 2 The cadaver skin was attached to the receiving cell with the dermis layer facing the receiving cell. The matrix layer was placed on the stratum corneum side of the cadaver skin. An O-ring was placed on top of the skin. The donor cell was fixed on top of the receiving cell. The Franz cell was placed in an incubator at 32°C on a magnetic stir plate. At each preset time point, 2 ml of solution was withdrawn, the remaining solution was discarded, and new receiving solution was replenished. The receiving solution was immediately analyzed for risperidone content by HPLC.

[0122] Comparative Examples 1 to 6: K90, oleic acid, EPO, DL-α-tocopherol, 0.002% ascorbyl palmitate NF, 0.1% butylhydroxytoluene, and risperidone were dissolved in ethanol. Crospovidone was added and mixed for 24 hours. Duro-Tak 387-2516 was added and mixed uniformly. The wet blend was applied to a release film, dried, and laminated to a backing layer, Scotchpak 1109. Comparative Examples 5 and 6 were prepared in a manner similar to Comparative Example 1. In vitro skin throughput tests were conducted, and the results are shown in Table 1 and Figure 5. In vitro skin throughput was low. From Comparative Example 1 to Comparative Example 3, at 3% risperidone, increasing the oleic acid content from 10% to 12% to 17% decreased in vitro skin throughput. This is because increasing the solubilizer oleic acid reduces the drug concentration in the oleic acid and leads to unsaturation. Similar trends are observed in Comparative Examples 4 to 6.

[0123] [Table 1]

[0124] Examples 1 to 3 Examples 1 to 3 were prepared in a manner similar to Comparative Example 1. The dissolved drug recrystallized after the solvent was removed. When the solubilizer oleic acid was fixed at 10%, the risperidone concentration increased from 4.1772% to 4.9964%-5.7904%. An in vitro skin throughput test was conducted, and the results are shown in Table 2 and Figure 6. The in vitro skin throughput increased. This was due to the increased drug concentration in oleic acid. However, because the initial drug saturation was not high, the drug became subsaturated after 80 hours, resulting in a decrease in skin throughput after 80 hours.

[0125] [Table 2]

[0126] Example 4: Example 4 was prepared in a manner similar to Comparative Example 1. The dissolved drug recrystallized after the solvent was removed. An in vitro skin throughput test was conducted, and the results are shown in Table 3. The in vitro skin throughput was high and did not decrease within 168 hours, which is due to the high saturation of the 7.5% concentration.

[0127] [Table 3]

[0128] Examples 5 to 8 K90, oleic acid, EPO, DL-α-tocopherol, 0.002% ascorbyl palmitate NF, and 0.1% butylhydroxytoluene were dissolved in isopropyl alcohol. The solution was mixed for 24 hours. Duro-Tak 387-2516 was added and mixed uniformly. Micronized risperidone crystalline Form A (Figure 8, XRPD of API crystals) was added to form a uniform suspension, containing undissolved risperidone crystals. The wet blend was applied to a release film, dried, and laminated to a Scotchpak 1109 backing film. Four laminated materials with different coating weights (90 gsm, 180 gsm, 290 gsm, and 400 gsm) were produced. Microscopic analysis revealed that the laminated materials were saturated with risperidone crystals. XRPD results (Figure 9) indicated that the risperidone crystals were Form A. As shown in Table 4 and Figure 10, the throughput remains constant within 248 hours (10.5 days) with a coating weight of 90 gsm. When the coating weight is increased to 180 gsm, 290 gsm, and 400 gsm, respectively, the throughput remains nearly constant within 336 hours (14 days).

[0129] [Table 4]

[0130] Examples 9 to 12 K 90, oleic acid, EPO, DL-α-tocopherol, 0.002% ascorbyl palmitate NF, and 0.1% butylhydroxytoluene were dissolved in isopropyl alcohol. The solution was mixed for 24 hours. Duro-Tak 387-2287 was added and mixed uniformly. Micronized risperidone Form A was added to form a uniform suspension, with undissolved risperidone crystals suspended within. The wet blend was applied to a release film, dried, and laminated to a Scotchpak 1109 backing film. Four laminated materials with different coating weights (90 gsm, 180 gsm, 290 gsm, and 400 gsm) were produced. Microscopic analysis revealed that the laminated plates were saturated with crystals. XRPD results indicated that the crystals were Form A. As shown in Table 4 and Figure 11, throughput remained constant within 272 hours (11.5 days) at a coating weight of 100 gsm. When the coating weight is increased to 200 gsm, 300 gsm and 400 gsm respectively, the throughput remains nearly constant within 336 hours (14 days).

[0131] [Table 5]

[0132] Physical properties and skin adhesion - finger stickiness results The patch was placed on a work surface with the adhesive layer facing up. The index finger pressed the adhesive for 5 seconds, then lifted it while grasping a portion of the patch with the fingers of another hand. The thumb was used to observe and touch the front of the index finger to determine whether the finger was sticky. If any adhesive was transferred to the index finger after the patch adhesive layer was lifted from the adhesive layer, the finger was sticky. The softer the adhesive, the weaker the rheological cohesion, and the more adhesive would be expected to transfer from the patch adhesive to the finger. Adhesive transfer to the skin can reduce skin adhesion and increase the black ring around the patch.

[0133] The results are shown in Table 6, where the commercially available patch was used as the standard for finger tack, with a rating of 10. No adhesive transferred to the fingers. In Example 13, Formulation 13 had a finger tack of 15, with adhesive transferring to 40% of the contacted fingers. In Examples 14-23, different levels of crospovidone CL-M, povidone K90, and Eudragit EPO were used to obtain formulations with finger tack ranging from 1 to 15 and no adhesive transferred to the contacted fingers; Formulation 22 was excluded due to insufficient Eudragit content.

[0134] [Table 6]

[0135] Patch Wear Test One healthy volunteer participated in the patch wear study. The skin of both thighs was cleaned with a wet tissue and then wiped with a dry tissue. In each study, one or more patches were applied to the left and right thighs. After application, the patch was pressed with the palm of the hand for 30 seconds. The start date and time of the experiment were recorded. The adhesion score was recorded. The results are shown in Table 7. Adhesion was scored using a five-point scale from 0 to 4.

[0136] The skin adhesion scores of the patch study are recorded in Table 6. Most formulations had an adhesion score of 2 and no cold flow black ring. The data showed that by adjusting the amount of cohesion promoter, the cold flow black ring could be adjusted to zero. However, the adhesion could not meet the requirements.

[0137] [Table 7]

[0138] Examples 24-25 Each ingredient was weighed according to Table 8. K90, isostearic acid or stearic acid, EPO, DL-α-tocopherol, and 0.1% butylhydroxytoluene were dissolved in isopropyl alcohol. The solution was mixed for 24 hours. Duro-Tak 387-2287 was added and mixed uniformly. Micronized risperidone Form A was added to form a uniform suspension, with undissolved risperidone crystals suspended in it. The wet blend was applied to a release film, dried, and laminated to a backing film, Scotchpak 9738.

[0139] [Table 8]

[0140] Example 26: Matrix-type transdermal delivery system using overlapping adhesive films Duro-Tak 387-2516 (10% w / w) and Duro-Tak 387-2287 (90% w / w) were mixed uniformly and then coated onto a release film. After drying (40°C for 4 minutes, 85°C for 4 minutes), the mixture was combined with a separating layer polyester fabric KOB053 to produce a backing layer / overlap adhesive film / release film composite with a coating thickness of 110 gsm. The release film layer of the backing layer / overlap adhesive film / release film composite was removed, and the 10 cm 2 The separation layer of the drug patch was placed on the overlapping adhesive film. 2 The release film was removed from the drug adhesive layer (drug matrix layer), and extra-large release films were applied to the drug adhesive layer and the overlapping adhesive film layer. The final patch was die-cut so that the overlapping adhesive film layer exceeded the separating layer and drug adhesive layer by 10 millimeters in each direction.

[0141] Comparative Example 7 Comparative Formula 7 patches were prepared according to Example 4 of Patent CN 101366705B. As shown in Table 9 and Figure 12, the skin throughput of Comparative Formula 7 rapidly decreased after 48 hours, and the skin throughput from 24 to 168 hours was not constant but constantly decreased. The skin throughput at 168 hours was 61% lower than the maximum skin throughput.

[0142] Examples 26 to 33 Lauryl lactate, oleyl alcohol, EPO, DL-α-tocopherol, 0.002% ascorbyl palmitate NF, and 0.1% butylhydroxytoluene were dissolved in isopropyl alcohol. The solution was mixed for 24 hours. Duro-Tak 387-2287 was added and mixed uniformly. Micronized risperidone Form A was added to form a uniform suspension, containing undissolved risperidone crystals. The wet blend was applied to a release film, dried, and laminated to a backing layer film, Scotchpak 1109, to produce five laminated materials with a coating weight of 150 gsm. Microscopic analysis revealed that the laminated plates were saturated with crystals. As shown in Table 9 and Figure 12, not only was the skin throughput substantially constant from 24 hours to 168 hours, but the transdermal dose at 168 hours maintained greater than 70% of the maximum transdermal dose of risperidone.

[0143] Table 9. Skin throughput in Examples 26 to 33 and Comparative Example 7 Average skin density of 3 donors

[0144] [Table 9-1]

[0145] [Table 9-2]

[0146] Example 34: Matrix-type transdermal delivery system using overlapping adhesive films Duro-Tak 387-2051 and Duro-Tak 387-2054 were mixed uniformly and then applied to a release film. After drying (40°C for 4 minutes, 85°C for 4 minutes), the mixture was combined with the backing layer KOB053 to produce a backing layer / overlapping adhesive film / release film composite. The release film layer of the backing layer / overlapping adhesive film / release film composite was removed, and the 10 cm 2 The separation layer of the drug patch was placed on the overlapping adhesive film. 2 The release film was removed from the drug adhesive layer (drug matrix layer), and extra-large release films were applied to the drug adhesive layer and the overlapping adhesive film layer. The final patch was die-cut so that the overlapping adhesive film layer exceeded the separating layer and drug adhesive layer by 10 millimeters in each direction.

[0147] Example 35: Matrix-type transdermal delivery system using overlapping adhesive films The matrix-type transdermal delivery system of Example 35 was prepared in a manner similar to that of Example 34. The backing layer KOB053 / (Duro-Tak 387-2054+Duro-Tak 387-2051) in Example 34 was replaced with the backing layer KOB053 / (Duro-Tak 387-2516+Duro-Tak 387-2287).

[0148] Example 36: Matrix-type transdermal delivery system using overlapping adhesive films Duro-Tak 387-2516 (10% w / w) and Duro-Tak 387-2287 (90% w / w) were mixed uniformly and then coated onto a release film. After drying (40°C for 4 minutes, 85°C for 4 minutes), the mixture was combined with a backing layer KOB053. A polyisobutylene adhesive layer was coated onto the Duro-Tak 387-2516 and Duro-Tak 387-2287 mixed adhesive layer. A backing layer / overlapping adhesive film / release film composite was produced. The release film layer of the backing layer / overlapping adhesive film / release film composite was removed, and the 10 cm 2The separation layer of the drug patch was placed on the overlapping adhesive film. 2 The release film was removed from the drug adhesive layer (drug matrix layer), and extra-large release films were applied to the drug adhesive layer and the overlapping adhesive film layer. The final patch was die-cut so that the overlapping adhesive film layer exceeded the separating layer and drug adhesive layer by 10 millimeters in each direction.

[0149] Example 37: Matrix-type transdermal delivery system using overlapping adhesive films The matrix-type transdermal delivery system of Example 37 was prepared in a manner similar to that of Example 36. The backing layer KOB( / Duro-Tak 387-2516+Duro-Tak 387-2287) / PIB in Example 36 was replaced with the backing layer KOB053 / (Duro-Tak 387-2516+Duro-Tak 387-2287) / Bio-PSA 7-4301.

[0150] Example 38: Matrix-type transdermal delivery system using overlapping adhesive films The matrix-type transdermal delivery system of Example 38 was prepared in a manner similar to that of Example 36. The backing layer KOB( / Duro-Tak 387-2516+Duro-Tak 387-2287) / PIB in Example 36 was replaced with the backing layer KOB053 / (387-2516+387-2287) / SIS.

[0151] The test results for Examples 34 to 38 for migration of the non-volatile component risperidone from the central drug-containing layer to the overlapping adhesive film layer are summarized in Table 10.

[0152] Example 34: As shown in Table 10, when the overlapping adhesive film layer adhesive was a mixture of two acrylate adhesives (Duro-Tak 387-2054, Duro-Tak 387-2051), a significant amount of non-volatile risperidone migrated from the central drug-containing layer to the overlapping adhesive film layer.

[0153] Example 35: As shown in Table 10, even when the overlapping adhesive film layer adhesive was a mixture of two other acrylate adhesives (Duro-Tak 387-2516, Duro-Tak 387-2287), a significant amount of non-volatile risperidone migrated from the central drug-containing layer to the overlapping adhesive film layer.

[0154] Examples 36, 37, and 38: Surprisingly, when the overlapping adhesive film layer in contact with the central backing layer was siloxane Bio-PSA 7-4301, styrene-isoprene-styrene, or polyisobutylene, very small amounts of non-volatile risperidone migrated from the central drug-containing layer to the overlapping adhesive coating layer.

[0155] [Table 10]

[0156] Comparative Example 8 The separating layer and the drug matrix layer did not have multiple small pieces.

[0157] As shown in FIG. 14, the transdermal patch is: (a) an 82 cm 2 backing layer and (b) 82 cm 2 overlapping adhesive layer and (c) 50cm 2 and (d) 50 cm 2 and (e) a release film. The separation layer and drug matrix layer were not cut into multiple small pieces. Fifteen volunteers completed the seven-day wear period, and on the seventh day, the adhesion score of the overlapping layer edge was 0.1, while the adhesion score of the inner patch was 1.

[0158] Example 39: Multiple pieces of the separation layer and drug matrix layer have one connection point Example 39 is shown in Figure 15 and is a transdermal patch comprising: (a) an 82 cm 2 backing layer and (b) 82 cm 2 overlapping adhesive layer and (c) 50cm 2and (d) 50 cm 2 and (e) a release film. The separation layer and drug matrix layer were half-cut into four small pieces, each with one connection point. After seven days of wear, the adhesion score of the overlapping layer edge was 0.1, while the adhesion score of the inner patch was 0.3.

[0159] Example 40: Multiple pieces of the separation layer and drug matrix layer have two connection points As shown in FIG. 16, the transdermal patch is: (a) an 82 cm 2 backing layer and (b) 82 cm 2 overlapping adhesive layer and (c) 50cm 2 and (d) 50 cm 2 and (e) a release film. The separation layer and drug matrix layer were half-cut into four small pieces, each of which had two connection points. After seven days of wear, the adhesion score of the overlapping layer edges was 0.1, while the adhesion score of the inner patch was 0.3.

[0160] Comparative Example 9: Small pieces without connection points were arranged in an irregular order during transfer. As shown in Figure 18, the separation layer and drug matrix layer were half-cut into four 12.5 cm pieces using a die-cutting machine. There were no connection points (gray) between the pieces, and the intersecting black lines represent the cut separation layer and drug matrix layer. When the inner patch (separation layer and matrix layer) moved forward, the four parts of the inner patch were separated from each other and arranged in an irregular order.

[0161] Example 41: Pieces with two connection points were aligned in an orderly fashion during movement. As shown in Figure 19, the separation layer and drug matrix layer were cut into four 12.5 cm pieces using a die-cutting machine. 2The inner patch was cut into small pieces. There were connection points (gray) between the small pieces, and the intersecting black lines were the cut separation layer and drug matrix layer. When the inner patch (separation layer and matrix layer) moved forward, the four parts of the inner patch were connected in an orderly manner.

[0162] Examples 42 to 45 Skin Throughput Test of Patches The transdermal patches of Examples 42 to 45 have the structure shown in Figure 4B, where the drug matrix is ​​prepared according to Formulations 42 to 45 in Table 11, the risperidone is micronized risperidone crystalline Form A, the first overlapping adhesive film is a 55 GSM acrylate ester adhesive Duro-Tak 87-2054, the second overlapping adhesive film is a 55 GSM polyisobutylene, the separating layer is Scotchpak 1109, and the backing layer is KOB053. The die-cut matrix layer and separating layer have connection points as shown in Figures 16 and 19.

[0163] [Table 11]

Claims

1. 1. A risperidone transdermal delivery system comprising: 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) A risperidone transdermal delivery system comprising a release layer.

2. 2. The risperidone transdermal administration system of claim 1, wherein the risperidone crystalline form is crystalline form A, preferably micronized risperidone crystalline form A.

3. The skin penetration enhancer is C １ ~C ３０ selected from fatty acids, fatty acid esters, fatty alcohols, or one or more thereof; Preferably, the fatty acid is C １２ ~C ２２ unsaturated fatty acids, more preferably oleic acid; Preferably, the fatty acid ester is C １ ~C ３０ Fatty acids and C １ ~C ３０ is selected from esters formed by bonding with alcohols, more preferably lauryl lactate, Preferably, the fatty alcohol is C １３ ~C ３０ The risperidone transdermal administration system according to claim 1 or 2, wherein the alcohol is selected from alkenyl alcohols, more preferably oleyl alcohol.

4. The matrix layer comprises the following components, based on the total weight of the matrix layer: 1) the total dose of risperidone is 9.5-15%, preferably 9.5-15% or 10-12%; 2) The dosage of the skin penetration enhancer is 1% to 50%, preferably 2 to 30%, 8.5 to 30%, 8.5 to 25%, 8.5 to 15%, more preferably C １ ~C ３０ The dosage of fatty acid is 8.5-15%, the dosage of fatty acid ester is 1-10%, the dosage of fatty alcohol is 1-15%, and most preferably the dosage of oleic acid is 8.5-15%, the dosage of lauryl lactate is 1-10%, 1-6% or 3-5%, and C １３ ~C ３０ the dosage of alkenyl alcohol is 1-15%, 5-15%, or 8-15%; 3) The dosage of the pressure sensitive adhesive is 50-82%, preferably 50-80% or 55-80%; The risperidone transdermal administration system according to any one of claims 1 to 3, wherein the dosage of each component in the matrix layer totals 100%.

5. The matrix layer comprises the following components, based on the total weight of the matrix layer: 1) the total dose of risperidone is 9.5-15%, preferably 9.5-15% or 10-12%; 2) The dosage of the skin penetration enhancer is 1% to 50%, preferably 2 to 30%, 8.5 to 30%, 8.5 to 25%, 8.5 to 15%, more preferably C １ ~C ３０ The dosage of fatty acid is 8.5-15%, the dosage of fatty acid ester is 1-10%, the dosage of fatty alcohol is 1-15%, and most preferably the dosage of oleic acid is 8.5-15%, the dosage of lauryl lactate is 1-10%, 1-6% or 3-5%, and C １３ ~C ３０ the dosage of alkenyl alcohol is 1-15%, 5-15%, or 8-15%; 3) The dosage of the pressure sensitive adhesive is 50-82%, preferably 50-80% or 55-80%; 4) The dosage of antioxidant is 0% to 1%, preferably 0.05% to 0.5% or 0.1% to 0.3%; 5) The dosage of the aggregation promoter is 0-30%, preferably 1-5%; 6) The dosage of the thickener is 0-40%; 7) The dosage of plasticizer is 0-40%; 8) the additional permeation enhancer is 0-10%; The risperidone transdermal administration system according to any one of claims 1 to 4, wherein the dosage of each component in the matrix layer totals 100%.

6. The risperidone transdermal administration system of claim 5, wherein the pressure-sensitive adhesive is selected from one or more of an acrylic adhesive, a silicone adhesive, an acrylic-silicone copolymer adhesive, a polybutene adhesive, a styrene-isoprene-butene copolymer, and a styrene-butadiene-styrene copolymer.

7. 6. The risperidone transdermal administration system of claim 5, wherein the coagulation promoter is selected from crospovidone, Eudragit E, Eudragit EPO, Eudragit S, Eudragit R, Plastoid B, and mixtures thereof.

8. The risperidone transdermal administration system according to claim 5, wherein the coagulation promoter is a combination of povidone K90, Eudragit EPO, povidone K90 and Eudragit EPO, crospovidone CL-M and Eudragit EPO, povidone K90, crospovidone CL-M and Eudragit EPO, povidone K90 and Plastoid B, crospovidone CL-M and Plastoid B, or povidone K90 and crospovidone CL-M, with the preferred combination being povidone K90 and Eudragit EPO.

9. The risperidone transdermal administration system according to any one of claims 5 to 8, wherein the antioxidant is selected from one or more of tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate dihydrate, dibutylhydroxytoluene (BHT), and preferably the further chelating agent as a synergistic antioxidant is selected from citric acid, tartaric acid, calcium disodium edetate, disodium edetate and EDTA.

10. The risperidone transdermal administration system according to any one of claims 5 to 9, wherein the thickener is selected from polybutene, terpene and mixtures thereof.

11. The risperidone transdermal administration system according to any one of claims 5 to 10, wherein the plasticizer is selected from mineral oil, silicone oil, triethyl citrate, and mixtures thereof.

12. The dosage of the matrix layer is 30 g / m ２ ~700g / m ２ The risperidone transdermal administration system according to any one of claims 1 to 11, wherein

13. The risperidone transdermal administration system according to any one of claims 1 to 12, wherein risperidone is added as micronized risperidone crystalline form A in the manufacturing process, and preferably the particle size of the micronized risperidone is 20 μm or less.

14. The matrix layer is further prepared using a solubilizer or solvent, which may be selected from the group consisting of C １ ~C ６ The risperidone transdermal administration system according to any one of claims 1 to 13, wherein the solubilizer or solvent is selected from alkyl alcohols, n-heptane, ethyl acetate, toluene and mixtures thereof, and the solubilizer or solvent is preferably ethanol, isopropyl alcohol, n-heptane or ethyl acetate.

15. 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) a skin contact adhesive layer; and 4) A release layer. The risperidone transdermal administration system according to any one of claims 1 to 14.

16. 1) a backing layer; 2) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure-sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 3) a semipermeable membrane or woven fabric layer; 4) a skin contact adhesive layer; 5) A release layer. The risperidone transdermal administration system according to any one of claims 1 to 14.

17. 18. The risperidone transdermal administration system of claim 16 or 17, wherein the skin contact adhesive layer comprises a pressure-sensitive adhesive, optional risperidone, and optional other excipients, wherein the other excipients are selected from one or more of cohesion promoters, antioxidants, skin irritation inhibitors, thickeners, plasticizers, solubilizers, solvents, and desiccants.

18. 1) a backing layer; 2) an overlapping adhesive film layer, wherein the preferred overlapping adhesive film layer material is selected from one or more of siloxane, polyisobutylene, or styrene-isoprene-styrene copolymer, and preferably the overlapping adhesive film layer has a dosage of 50 to 110 GSM; 3) a separation layer; 4) a matrix layer comprising risperidone, a skin permeation enhancer, and a pressure sensitive adhesive dispersed in the matrix layer in a crystalline and amorphous state; 5) A release layer. The risperidone transdermal administration system according to any one of claims 1 to 14.

19. The risperidone transdermal administration system of claim 18, wherein the overlapping adhesive film layer comprises an adhesive, and the adhesive of the overlapping adhesive film layer is the same as or different from the adhesive of the drug matrix layer, and preferably the solubility of the drug in the overlapping adhesive film layer adhesive is the same as or lower than the solubility of the drug in the matrix layer adhesive, and more preferably the solubility of the drug in the overlapping adhesive film layer adhesive is lower than the solubility of the drug in the matrix layer adhesive.

20. The risperidone transdermal administration system of claim 18 or 19, wherein the overlapping adhesive film may be one layer, two layers or multiple layers, and preferably the first overlapping adhesive film layer close to the backing layer can prevent other overlapping adhesive film layers away from the backing layer from migrating to the backing layer or the side of the backing layer away from the skin.

21. 21. The risperidone transdermal administration system of claim 20, wherein the adhesive of the first overlapping adhesive film layer is selected from Duro-Tak 387-2516, Duro-Tak 387-2287, Duro-Tak 387-4287, Duro-Tak 87-2051, Duro-Tak 87-2052, Duro-Tak 87-2054, Duro-Tak 87-2852, or a mixture thereof, and the adhesive of the second overlapping adhesive film layer is selected from polyisobutylene, styrene-isoprene-styrene copolymer, dimethylsiloxane, or a mixture thereof.

22. 22. The risperidone transdermal administration system according to any one of claims 18 to 21, comprising, from the backing layer to the release layer, a backing layer, one or more overlapping adhesive film layers, a separation layer, a matrix layer, and a release layer in that order, the backing layer, the one or more overlapping adhesive film layers, and the release layer extend circumferentially beyond the separation layer and matrix layer, and upon administration, the release layer is removed, and the matrix layer that contacts the skin is sealed to the skin by the one or more overlapping adhesive film layers.

23. The overlapping adhesive film is one layer, and includes, in order from the backing layer to the release layer: i. a backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, and a release layer, wherein the backing layer, the overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer and the matrix layer, preferably having the structure shown in FIG. 4A; or ii. a backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, a skin adhesive layer, and a release layer, wherein the backing layer, the overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer, the matrix layer, and the skin adhesive layer, preferably having the structure shown in FIG. 4C; or iii. The risperidone transdermal administration system of claim 22, comprising a backing layer, an overlapping adhesive film layer, a separation layer, a matrix layer, a semipermeable film layer, a skin adhesive layer, and a release layer, wherein the backing layer, the overlapping adhesive film layer, and the release layer circumferentially extend beyond the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, preferably having a structure as shown in Figure 4F.

24. The overlapping adhesive film is two-layered, and upon administration, the release layer is removed and the skin-contacting matrix layer is sealed to the skin with a second overlapping adhesive film layer, where, from the backing layer to the release layer, in order: i. a backing layer, a first overlapping adhesive film layer, a second overlapping adhesive film layer, a separation layer, a matrix layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, the second overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer and the matrix layer, preferably in the structure shown in FIG. 4B; or ii. A backing layer, a first overlapping adhesive film layer, a separation layer, a matrix layer, a skin adhesive layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, and the release layer extend circumferentially beyond the separation layer, the matrix layer, and the skin adhesive layer, and the second overlapping adhesive film layer is filled between the first overlapping adhesive film layer and the release layer, preferably having the structure shown in Figure 4D; or a backing layer, a first overlapping adhesive film layer, a separation layer, a matrix layer, a semipermeable film layer, a skin adhesive layer, a second overlapping adhesive film layer, and a release layer, wherein the backing layer, the first overlapping adhesive film layer, the second overlapping adhesive film layer, and the release layer circumferentially extend beyond the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, and the second overlapping adhesive film layer extends toward the first overlapping adhesive film layer and encases the separation layer, the matrix layer, the semipermeable film layer, and the skin adhesive layer, preferably having the structure shown in Figure 4E; The risperidone transdermal administration system of claim 22, wherein the dosage of the first overlapping adhesive film layer is preferably 25-60 GSM and the dosage of the second overlapping adhesive film layer is preferably 25-60 GSM.

25. The risperidone transdermal administration system according to any one of claims 18 to 24, wherein the backing layer is made of a polymeric elastic film, a polymeric woven fabric, a bidirectional or multidirectional elastic nonwoven fabric, a stretchable polymeric film, a stretchable woven fabric, or a stretchable nonwoven fabric.

26. 26. The risperidone transdermal administration system of claim 25, wherein the backing layer is selected from polyester, polyethylene, polypropylene, polyvinyl chloride, polyethylene vinyl acetate, polyurethane, preferably KOB051 and KOB053.

27. The risperidone transdermal administration system according to any one of claims 18 to 26, wherein the separating layer is selected from a flexible blocked single-layer or multi-layer polymer film, the polymer being selected from polyolefin, polyester, polyethylene, polyvinylidene chloride or polyurethane, and preferably the separating layer further comprises an aluminum membrane.

28. the separation layer includes a plurality of small pieces that are partially connected to each other, and the matrix layer includes a plurality of small pieces that are all connected or partially connected; A risperidone transdermal administration system according to any one of claims 18 to 27, wherein preferably, the multiple separation layer pieces connected to each other in the separation layer are symmetrical or asymmetrical, the same or different, and the multiple separation layer pieces connected to each other in the matrix layer are selected from symmetrical or asymmetrical, the same or different, and more preferably, the connection points of some of the separation layers and the connection points of some of the matrix layers are all aligned or partially aligned.

29. The risperidone transdermal administration system of claim 28, wherein there are one or more connection points between adjacent small pieces, preferably 1, 2, 3, 4 or 5 connection points, and the length of each connection point is independently selected from the range of 0.5 to 3 mm.

30. The separating layer pieces and the matrix layer pieces stacked one above the other have the same shape, the number of pieces in each transdermal administration system unit is selected from 1 to 10, and the area of ​​each piece is 1 to 25 cm ２ and preferably 1 cm ２ , 4 cm ２ , 6 cm ２ , 8 cm ２ , 9 cm ２ , 10 cm ２ , 12.5 cm ２ , 16cm ２ , 25cm ２ 30. The risperidone transdermal administration system of claim 28 or 29, wherein

31. 31. The risperidone transdermal administration system of claim 1, wherein the matrix layer has a weight of 30 GSM to 700 GSM, 50 GSM to 700 GSM, 30 GSM to 100 GSM, 40 GSM to 150 GSM, 75 GSM to 150 GSM, 150 GSM to 300 GSM, or 350 GSM to 700 GSM.

32. A method for producing the stable matrix-type risperidone transdermal administration system according to any one of claims 1 to 14, comprising the steps of: Step 1: mixing a skin penetration enhancer with optional cohesion enhancers, antioxidants, skin irritation inhibitors, thickeners, plasticizers, solubilizers, solvents, and drying agents to obtain Blend 1; Step 2: mixing Blend 1 with a pressure sensitive adhesive to obtain Blend 2; Step 3, adding micronized risperidone crystalline Form A or a pharmaceutically acceptable salt thereof to Blend 2 from Step 2 and stirring until the risperidone or a pharmaceutically acceptable salt thereof is uniformly suspended to obtain a drug wet mixture; Step 4: applying the drug wet mixture to a release layer; Step 5: drying to remove the solvent and solubilizer to obtain a release layer / drug matrix layer laminate material; and step 6. laminating the release layer / drug matrix layer laminate material to a backing layer to form a release layer / drug matrix layer / backing layer composite film.

33. Step 1 of producing the release layer / matrix layer / backing layer composite film according to Steps 1 to 6 of the method of claim 32; Step 2: preparing a solution or suspension of a skin contact adhesive layer containing a pressure-sensitive adhesive, optionally risperidone crystalline Form A or a pharmaceutically acceptable salt thereof, and optionally other excipients, applying the solution or suspension to a release layer, and drying the solution or suspension to form a release layer / skin contact adhesive layer laminate material; 3. The method of claim 32, further comprising: removing the release layer from the release layer / matrix layer / backing layer composite film; and laminating the adhesive surface layer of the release layer / skin contact adhesive layer described in step 1 onto the matrix layer to form a release layer / skin contact adhesive layer / matrix layer / backing layer composite film.

34. Step 1 of producing the release layer / matrix layer / backing layer composite film according to Steps 1 to 6 of the method of claim 32; Step 2: preparing a solution or suspension of a skin contact adhesive layer containing a pressure-sensitive adhesive, optionally risperidone crystalline form A or a pharmaceutically acceptable salt thereof, and optionally other excipients, applying the solution or suspension to a release layer, and drying the solution to form a release layer / skin contact adhesive layer laminate material, and laminating the adhesive surface layer to a semipermeable membrane or a woven fabric layer; 3. The method of claim 32, comprising step 3 of removing the release layer from the release layer / matrix layer / backing layer composite membrane and laminating the semipermeable membrane or woven fabric layer side to the matrix layer to form a release layer / skin contact adhesive layer / semipermeable membrane or woven fabric layer / matrix layer / backing layer composite membrane.

35. A method for producing the risperidone transdermal administration system according to any one of claims 18 to 23 or 25 to 31, comprising: Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then compounding it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: preparing the release layer / drug matrix layer laminate material according to Steps 1 to 5 of claim 32, and laminating the release layer / drug matrix layer laminate material onto a separation layer to form a release layer / drug matrix layer / separation layer film; Step C: removing the release film of the backing layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / drug matrix layer / separation layer film described in Step B on the overlapping adhesive film; Step D: removing the release film from the drug matrix layer and applying an extra-large release film to the drug matrix layer and the overlapping adhesive film layer; Step E: die-cutting the final patch so that the overlapping adhesive film layer extends beyond the separation layer and drug adhesive layer in each direction.

36. 24. A method for producing the risperidone transdermal administration system of claim 23, comprising: Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then compounding it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: preparing a release layer / skin contact adhesive layer / drug matrix layer / separation layer composite film; Step C: removing the release film of the separation layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / skin contact adhesive layer / matrix layer / separation layer composite film formed in Step B on the overlapping adhesive film; Step D: removing the release film from the skin contact adhesive layer and applying an extra-large release film to the skin contact adhesive layer and the overlapping adhesive film layer; Step E: die-cutting the final patch so that the overlapping adhesive film layer extends beyond the separation layer, matrix layer, and skin adhesive layer in each direction, preferably forming the structure depicted in Figure 4C.

37. 24. A method for producing the risperidone transdermal administration system of claim 23, comprising: Step A: applying the overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then compounding it with a backing layer to obtain a backing layer / overlapping adhesive film / release film composite; Step B: preparing the release layer / skin contact adhesive layer / semipermeable membrane or woven fabric layer / drug matrix layer / separation layer composite membrane; Step C: removing the release film of the backing layer / overlapping adhesive film / release film composite described in Step A, and placing the separation layer of the release layer / skin contact adhesive layer / semipermeable membrane or woven fabric layer / drug matrix layer / separation layer composite membrane described in Step B on the overlapping adhesive film; Step D: removing the release film from the skin contact adhesive layer and applying an extra-large release film to the skin contact adhesive layer and the overlapping adhesive film layer; Step E: die-cutting the final patch, and the backing layer, overlapping adhesive film layer, and release layer circumferentially extending beyond the separation layer, matrix layer, semipermeable membrane or woven fabric layer, and skin adhesive layer, preferably forming the structure described in Figure 4F.

38. 25. A method for producing the risperidone transdermal administration system of claim 24, comprising: Step A: applying the first overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then compounding it with a backing layer to obtain a backing layer / first overlapping adhesive film / release film composite film; applying the second overlapping adhesive film layer pressure-sensitive adhesive to a release film, drying it, and then compounding it with the first overlapping adhesive film layer from which the release film has been removed to obtain a backing layer / first overlapping adhesive film / second overlapping adhesive film / release film composite film; Step B: preparing a release layer / drug matrix layer / separating layer membrane, a release layer / skin adhesive layer / drug matrix layer / separating layer membrane, or a release layer / skin adhesive layer / semipermeable woven fabric layer / drug matrix layer / separating layer membrane; Step C: removing the release film of the backing layer / first overlapping adhesive film / second overlapping adhesive film / release film composite film described in step A, and applying the separation layer described in step B to the second overlapping adhesive film layer; Step D: removing the release film remaining from step C and applying a super-large release film to the side away from the backing layer; Step E: Die-cutting the final patch so that the second overlapping adhesive film layer extends over the separation layer, drug matrix layer, and optional skin adhesive layer and semipermeable membrane fabric layer in each direction, preferably to obtain the structure of Figures 4B, 4D, and 4E.

39. A method for producing the risperidone transdermal administration system according to any one of claims 28 to 32, comprising: A method for manufacturing a composite membrane according to claim 35-38, comprising cutting the composite membrane produced in step B into a plurality of partially connected small pieces to obtain a structure of small pieces according to claim 28-31, and in step C, the structure improves the alignment order when the composite membrane of step B is moved.

40. The method of any one of claims 32 to 39, wherein the drug wet mixture for preparing the matrix layer contains undissolved risperidone crystalline form A.

41. The solvent in step 1 or step B is C １ ~C ６ 41. The method according to any one of claims 32 to 40, wherein the solvent is selected from alkyl alcohols, n-heptane, ethyl acetate, toluene and mixtures thereof, preferably ethanol, isopropyl alcohol, n-heptane or ethyl acetate.

42. 42. Use of a therapeutically effective amount of the risperidone transdermal administration system according to any one of claims 1 to 41 in the manufacture of a medicament for treating or preventing schizophrenia, mania and dementia.

43. 42. Use of a therapeutically effective amount of the risperidone transdermal administration system according to any one of claims 1 to 41 in the manufacture of a medicament for treating or preventing positive or negative symptoms of schizophrenia.

44. 44. The use of claim 43, wherein the positive or negative symptoms of schizophrenia include hallucinations, delusions, and emotional withdrawal and bluntedness.

45. 42. A method for treating or preventing schizophrenia, mania, and dementia, comprising administering to a subject in need thereof a therapeutically effective amount of the risperidone transdermal delivery system of any one of claims 1 to 41.

46. 42. A method for treating or preventing positive or negative symptoms of schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of the risperidone transdermal delivery system of any one of claims 1 to 41.

47. 47. The method of claim 46, wherein the positive or negative symptoms of schizophrenia include hallucinations, delusions, and emotional withdrawal and bluntedness.

48. The use of any one of claims 42 to 44 or the method of any one of claims 45 to 47, wherein the risperidone transdermal delivery system is administered once every 1 day, 3 days, 7 days, 10 days or 14 days.

49. The use of any one of claims 42 to 44 or the method of any one of claims 45 to 47, wherein the risperidone transdermal delivery system continuously delivers risperidone or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for a period of 24 hours to 14 days.

50. The use of any one of claims 42 to 44 or the method of any one of claims 45 to 47, wherein the risperidone transdermal administration system continuously delivers risperidone to the patient's body at a substantially constant rate for a period of 24 hours to 14 days, preferably 24 hours to 7 days.

51. The use or method according to claim 50, wherein the maximum transdermal amount of risperidone is reached within 24 to 36 hours after administration of the risperidone transdermal delivery system, and the transdermal amount of risperidone is maintained at 65% or more of the maximum transdermal amount, preferably 65% ​​to 90%, and more preferably 75% to 85% of the maximum transdermal amount of risperidone, 3 to 7 days after administration.

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