WO2023134641A1

WO2023134641A1 - Olanzapine transdermal administration system, and preparation method therefor and use thereof

Info

Publication number: WO2023134641A1
Application number: PCT/CN2023/071410
Authority: WO
Inventors: 唐俭生
Original assignee: 新领医药技术(深圳)有限公司
Priority date: 2022-01-12
Filing date: 2023-01-09
Publication date: 2023-07-20
Also published as: CN116829131B; CN116829131A

Abstract

The present invention relates to an olanzapine transdermal administration system, and a preparation method therefor and the use thereof. Olanzapine or a pharmaceutically acceptable salt thereof in the transdermal administration system is dispersed in an amorphous state in a matrix layer, which can realize stable drug release.

Description

Olanzapine transdermal drug delivery system and its preparation method and use

technical field

The invention relates to a transdermal drug delivery system. More specifically, the present invention relates to a transdermal drug delivery system comprising olanzapine or a pharmaceutically acceptable salt thereof, a preparation method and use thereof.

Background technique

The transdermal drug delivery route is a drug delivery route superior to the oral drug delivery route, which keeps the drug concentration in the blood at a constant level by continuously delivering the drug to the blood system throughout the body. The transdermal route of administration not only reduces the fluctuation of the drug concentration in the blood between peaks and valleys, but also avoids the first-pass effect. In addition, since the transdermal route of administration avoids the direct contact of the drug and the excipients with the gastrointestinal system, it significantly reduces or eliminates side effects such as nausea and vomiting often associated with the oral route of administration. Another advantage of the transdermal route of delivery is that it is not affected by diet. Administration can be easily terminated by removing the transdermal patch from the skin if necessary. Furthermore, transdermal patches improve patient compliance by reducing the frequency of dosing. This is especially important for elderly patients and pediatric patients.

Common dosage forms for the transdermal route of administration include transdermal patch formulations. Currently common transdermal drug delivery patch preparations include but are not limited to drug reservoir type patches and matrix type patches. A drug reservoir type patch preparation is a patch preparation that contains a drug in a reservoir having a drug-permeable substrate surface, and a matrix type patch preparation is a patch preparation that dissolves or disperses a drug in a polymer matrix layer. Both types of designs typically also include a backing layer and a release liner layer that is removed prior to use. In addition, patches typically also contain a penetration enhancer and an adhesive layer.

In recent years, the advantages of transdermal drug delivery have enabled many drugs to be effectively administered through the transdermal route. These advances include the development of many physical methods to increase skin permeability and facilitate transdermal drug delivery, eg. Using iontophoresis, electroporation, ultrasound, or microneedling. However, there are still limited drugs that can be effectively and safely administered continuously through the skin for 7 days or more without causing skin adhesion, skin irritation, or sensitization.

Olanzapine is a novel antagonist of dopamine at D-1 and D-2 receptors, in addition to having antimuscarinic and anticholinergic properties at the 5HT-2 receptor site and noradrenergic alpha receptors and Antagonist activity (Moore et al., J. Pharmacol. Exp. Ther. 262(2):545-551 (1992)). The drug has relaxant, anxiolytic and antiemetic properties and is useful in the treatment of schizophrenia, acute mania and mild anxiety states, particularly in the treatment of schizophrenia, as described in the aforementioned Charrabarti et al. patent.

Early treatment of schizophrenia usually includes the antipsychotics haloperidol, clozapine, and flusimapine (7-fluoro-2-methyl-10-(4-methyl-1-piperazinyl)- 4H-thieno[2,3-b][1,5]-benzodiazepine

). However, as explained in US Patent No. 5,229,382 to Chakrabarti et al., these drugs are problematic in a number of ways. Haloperidol was found to cause a high incidence of extrapyramidal symptoms such as parkinsonism, acute dystonic responses, akathisia, tardive dyskinesia, and tardive dystonia. Although clozapine is said to be largely free of such extrapyramidal symptoms, it was found to cause agranulocytosis in some patients, a condition that reduces white blood cell counts to potentially life-threatening levels. Flumazepine was found to lead to further problems leading to termination of clinical trials prior to commercialization, mainly related to high levels of certain enzymes such as creatinine phosphokinase, serum glutamate oxalate aminotransferase, and serum glutamate pyruvate aminotransferase unacceptable. A related drug, chlorpromazine, was also found to cause a number of problems.

Olanzapine has been developed as a very effective drug in the treatment of psychosis, acute mania and mild anxiety states. Olanzapine has been found to be a very safe and effective antipsychotic that does not appear to cause additional pyramidal symptoms, agranulocytosis, or unacceptably high enzyme levels. Olanzapine has been shown to be more effective than clozapine in blocking studies of 5HT2 and dopamine-D2 (Fuller et al., Chem. Pathol. Pharmac. Res. Commun. 77: 1187-1193 (1992)). In addition, olanzapine was discovered in a phase II clinical trial and concluded that it was effective in the treatment of positive and negative symptoms of schizophrenia and was well tolerated (PV Tran et al. Neuropsychpharmacology pl. 10(3):267S, suppl ., pt.2 (1994)).

Currently, olanzapine is mainly administered orally or by injection. While the drug is an extremely effective antipsychotic, drug noncompliance is a serious problem and is believed to account for about one-third of all short-term hospitalization costs. Long-acting olanzapine injection has the problem of drug overdose, so the drug needs to be administered in hospitals with emergency departments. After the dose is injected, the patient must stay in the hospital and be monitored for 3 hours. Injections have a black box on the label. Transdermal administration of olanzapine, as disclosed and claimed herein, is accomplished by providing a time period useful for administering the drug over a period of about three to seven to ten to fourteen days, and possibly up to twenty-one days. Significantly improved patient compliance due to advanced delivery systems.

Transdermal olanzapine has many other advantages. Oral olanzapine has gastrointestinal side effects (dry mouth up to 32%, constipation up to 11%, dyspepsia, abdominal pain, diarrhea, dyspepsia, increased salivation, nausea, vomiting) and other side effects. Transdermal administration provides steady-state drug concentrations in plasma, avoiding the large fluctuations between peaks and troughs associated with oral medications; this often results in greatly reduced gastrointestinal and other side effects. Continuous transdermal administration of olanzapine provides sustained blood levels; the transdermal patch is easily removed if any side effects do occur; and the likelihood of patient acceptance is significantly improved. The transdermal patch can be used at home, and the caregiver or patient does not need to go to the hospital or any medical center to receive a dose of olanzapine injection.

US 5891461 discloses a transdermal olanzapine patch, which comprises at least one of olanzapine base and pharmaceutically acceptable acid addition salts and C2-C6 alkanediol and fatty ester in a pharmaceutical preparation , at least one of fatty acids and fatty alcohols. These are small molecule skin penetration enhancers. Large amounts of small molecule skin penetration enhancers can lead to poor skin adhesion and high skin irritation of the patch. In addition, because small molecule skin penetration enhancers co-penetrate the skin, the transdermal release rate of olanzapine decreases rapidly, so the high sustained transdermal release rate of olanzapine cannot be sustained.

U.S. Patent Publication 2007/0148218A1 discloses an olanzapine matrix-type transdermal delivery system comprising a backing layer, a matrix layer containing olanzapine, an adhesive, and a plurality of one or more small molecule skin-permeable Accelerator. The use of large amounts of small molecule skin penetration enhancers often results in poor adhesive cohesion of the matrix layer and skin irritation.

WO2020/131915A1 discloses combination therapy of PARP inhibitors and olanzapine for the treatment of nausea and vomiting. Olanzapine is given orally or transdermally. WO2021/146309A1 discloses a transdermal composition for reducing chemotherapy-induced nausea and vomiting, comprising (i) a pressure-sensitive adhesive; (ii) a fatty acid ester; (iii) olanzapine; (iv) and Oleic acid. It discloses another composition for transdermal delivery comprising: (i) a pressure sensitive adhesive; (ii) as an option only, a polyvinylpyrrolidone, ethylcellulose or silicon dioxide; ( iii) isopropyl palmitate; (iv) olanzapine; (v) oleic acid. Again, the use of large amounts of small molecular weight molecules such as fatty acid esters and oleic acid makes the composition less adherent to the skin.

Contents of the invention

An object of the present invention is to provide a matrix type olanzapine transdermal drug delivery system that can continuously deliver olanzapine or a pharmaceutically acceptable salt thereof at a therapeutically effective amount of blood drug concentration for a prolonged period of time .

An object of the present invention is to provide a matrix type olanzapine transdermal drug delivery system, which can have good skin adhesive properties during the period of sustained delivery of olanzapine or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a matrix type olanzapine transdermal drug delivery system that is non-irritating and/or irritating to the skin during the period of sustained delivery of olanzapine or a pharmaceutically acceptable salt thereof. sensitivity.

Another object of the present invention is to provide a method for the preparation of a matrix type olanzapine transdermal drug delivery system that can continuously deliver a therapeutically effective amount of olanzapine or its Pharmaceutically acceptable salt, and non-irritating and sensitizing to the skin.

Another object of the present invention is to provide a method of treating or preventing positive and negative symptoms of schizophrenia, which comprises administering a therapeutically effective amount of a matrix type olanzapine transdermal drug delivery system to a subject in need thereof.

Another object of the present invention is to provide a method of treating or preventing psychosis, acute mania and mild anxiety states, comprising administering a therapeutically effective amount of a matrix type olanzapine transdermal drug delivery system to a subject in need thereof .

Another object of the present invention is to provide a therapeutically effective amount of matrix-type olanzapine transdermal drug delivery system in the preparation of medicaments for treating or preventing positive and negative symptoms of schizophrenia.

Another object of the present invention is to provide a therapeutically effective amount of matrix-type olanzapine transdermal drug delivery system used in the preparation of drugs for the treatment or prevention of psychosis, acute mania and mild anxiety state.

Another object of the present invention is to provide a method of reducing or eliminating chemotherapy and PARP inhibitor (PARPi) induced emesis and nausea comprising administering to a subject in need thereof a therapeutically effective amount of stromal type olanzapine transdermally drug delivery system.

In one embodiment of the present invention, a kind of olanzapine transdermal delivery system is provided, has the three-layer structure as shown in Figure 1, and it comprises:

1) backing layer;

2) a matrix layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, a _C2 to _C30 saturated or unsaturated fatty acid and a pressure-sensitive adhesive agent; and

3) Release layer.

In a further embodiment, the polymeric skin penetration enhancer is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, plastone K29/32 , Copovidone VA64, Crospovidone CL-M, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose Acetate Succinate, Hydroxypropylmethylcellulose Phthalate , hydroxypropyl betad, α, β, λ cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or one or more of carrageenan.

In a further embodiment, the matrix layer comprises the following components relative to the total weight of the matrix layer:

1) The dosage of olanzapine or its pharmaceutically acceptable salt is 3-30%;

2) The dosage of the polymer skin penetration enhancer is 1.5-90%;

3) The amount of _C2 to _C30 saturated or unsaturated fatty acid is 3-30%;

4) The consumption of pressure-sensitive adhesive is 30-90%;

The amount of each component in the matrix layer is 100% in total.

In a further embodiment, the matrix layer also includes a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following:

1) Carbohydrate polymers, preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylbeta De, α, β, λ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;

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

3) Polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone, preferably povidone K30, povidone K90, plastone K29/32, copovidone VA64, or crospovidone CL-M.

In a further embodiment, the pressure sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives One or more of adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives;

1) The acrylic adhesive is selected from Henkel's Duro-Tak adhesive 387-2051, 387-2054, 387-2353, 87-235A, 87-2852, 87-2074, 87-2677, 387-2516, 387-2287, 387-4287, 387-2510, crosslinked 387-2510, 87-900A, 87-9301, 87-4098, 87-2194, Gelva GMS788, Gelva GMS 9073, Gelva 737, Gelva 2655, Polythick 410- SA (Sanyo Chemical Industry Co., Ltd.);

2) The polyisobutylene binder is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene H1900 from Ineos and mineral oil tackifier agent;

3) The silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400 and 7-4500,7-4600Bio-PSA SR7-4400, SRS7-4500, SRS7 -4600;

4) the acrylic acid-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA 7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, The solvent is selected from one or more of n-heptane, ethyl acetate and toluene or hot melt.

In a further embodiment, the content of olanzapine or a pharmaceutically acceptable salt thereof is 5% to 20%, preferably 5% to 15%, or 5% to 12% of the total weight of the stroma layer.

In a further embodiment, the content of the soluble polymer skin penetration enhancer is 5 to 40% of the total weight of the matrix layer, preferably 5-30%, 5-24, 10-20%, 12.5-20%.

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

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

In a further embodiment, the matrix layer further comprises one or more of small molecule skin penetration enhancers, antioxidants, and anti-skin irritation agents.

In a further embodiment, the small molecule skin penetration enhancer includes one or more of _C2 to _C30 saturated or unsaturated fatty acids, surfactants, and lauroazepine.

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

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

In another embodiment, an olanzapine transdermal drug delivery system is provided, which has a four-layer structure as shown in Figure 2, comprising:

1) backing layer;

2) a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, _C2 to _C30 saturated or unsaturated fatty acids and pressure-sensitive adhesive;

3) skin contact adhesive layer; and

4) Release layer.

In further embodiments, the skin contact adhesive layer includes, but is not limited to, acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer One or more of material adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives.

In another embodiment, an olanzapine transdermal drug delivery system is provided, which has a five-layer structure as shown in Figure 3, comprising:

1) backing layer;

2) a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, _C2 to _C30 saturated or unsaturated fatty acids and pressure-sensitive Adhesive

3) semi-permeable membrane or woven fabric layer;

4) skin contact adhesive layer; and

5) Release layer.

In further embodiments, the semi-permeable membrane comprises a continuous membrane or a microporous membrane.

In a further embodiment, the thickness of the semi-permeable membrane or woven fabric layer is from about 10 um to about 100 um, preferably from about 15 μm to about 50 μm.

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

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

In any olanzapine transdermal drug delivery system, the matrix layer does not contain nonanol, isopropyl myristate, isopropyl palmitate or lauryl lactate.

In any olanzapine transdermal drug delivery system, the solvent is selected from one or more of dimethylacetamide or dimethyl sulfoxide in the preparation process; ethanol, isopropanol or Other solvents act as co-solvents.

In another embodiment, there is provided a method for preparing the olanzapine transdermal drug delivery system, comprising the following steps:

Step 1. Dissolving olanzapine or a pharmaceutically acceptable salt thereof in a solvent as premix A;

Step 2. Mixing the pressure-sensitive adhesive solution with the insoluble polymer skin penetration enhancer, and optional small molecule skin penetration enhancer, surfactant, and antioxidant for 0.1 to 24 hours to obtain a premix B;

Step 3. adding premix A to premix B to obtain a drug wet mixture, in which olanzapine or a pharmaceutically acceptable salt thereof is dispersed in an amorphous state;

Step 4. Coating the drug wet mixture on the release layer;

Step 5. Drying to remove the solvent to obtain a release layer/substrate layer laminate;

Step 6. Laminate the substrate layer to the backing layer.

Step 1. Dissolving the polymer penetration enhancer in a solvent, the solvent includes but not limited to dimethylacetamide, dimethyl sulfoxide or a mixed solvent; optionally add a small molecule skin penetration enhancer, surface active agents and antioxidants, mixed for 0.1 hour to 24 hours;

Step 2. Add olanzapine or its pharmaceutically acceptable acid addition salt, mix and dissolve until olanzapine or its pharmaceutically acceptable salt is dispersed in an amorphous state;

Step 3. Add the pressure sensitive adhesive and mix well to obtain the drug wet mixture;

Step 4. Coating the drug wet mixture on the release layer;

Step 6. Laminate the substrate layer to the backing layer.

In another embodiment, there is provided a method for preparing the olanzapine transdermal drug delivery system, when there is a skin contact adhesive component, comprising the following steps:

Step 1. Prepare a release layer/matrix layer laminate according to any of the aforementioned steps 1 to 5, as a drug reservoir;

Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates;

Step 3. Laminate the adhesive side of the skin contact adhesive layer/release layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.

In another embodiment, there is provided a method for preparing the olanzapine transdermal drug delivery system, when having a semipermeable membrane or a woven fabric layer, comprising the following steps:

Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates with an adhesive face layer laminated to a semi-permeable membrane or woven fabric layer;

Step 3. Laminate the semipermeable membrane or woven fabric layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.

In another embodiment, there is provided a therapeutically effective amount of olanzapine transdermal drug delivery system prepared for the treatment or prevention of positive and negative symptoms of schizophrenia, or reducing chemotherapy-related and PARP inhibitor (PARPi)-induced The frequency and intensity of nausea and vomiting of the drug used in the drug.

In a further embodiment, said positive and negative symptoms of schizophrenia include psychosis, acute mania, and a mild anxiety state.

In another embodiment, there is provided a method of treating or preventing positive and negative symptoms of schizophrenia or reducing the frequency and intensity of chemotherapy-related and PARP inhibitor (PARPi)-induced nausea and vomiting comprising administering A subject in need thereof is administered a therapeutically effective amount of the olanzapine transdermal delivery system.

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

In a further embodiment, the olanzapine transdermal drug delivery system delivers about 1 mg to about 18 mg of olanzapine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject per day, preferably About 2 mg to about 12 mg of olanzapine base, or a pharmaceutically acceptable salt thereof, is delivered to the blood circulatory system of the subject.

Surprisingly, the olanzapine transdermal drug delivery system of the present invention can continuously deliver olanzapine or a pharmaceutically acceptable salt thereof with high skin flux for about 1 day, about 3 days, about 7 days, about 10 days , about 14 days, about 21 days, about 28 days or longer.

In addition, the olanzapine transdermal drug delivery system of the present invention has long-lasting and good skin adhesion properties during the continuous delivery of olanzapine or a pharmaceutically acceptable salt thereof.

Moreover, the olanzapine transdermal drug delivery system of the present invention has no irritation and sensitization to the skin during the continuous delivery of the olanzapine or a pharmaceutically acceptable salt thereof.

Description of drawings

Fig. 1 shows a schematic diagram of the three-layer matrix type transdermal drug delivery system of the present invention.

Fig. 2 shows a schematic diagram of the four-layer matrix type transdermal drug delivery system of the present invention.

Fig. 3 shows a schematic diagram of the five-layer matrix type transdermal drug delivery system of the present invention.

Fig. 4 shows the measurement curves of the skin flux of the transdermal drug delivery systems described in Examples 1, 8 and Comparative Example 1.

FIG. 5 shows the measurement curves of the skin flux of the transdermal drug delivery systems described in Examples 21, 22 and Comparative Examples 2, 3, 4, and 5.

FIG. 6 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example 24.

FIG. 7 shows the measurement curves of the skin flux of the transdermal drug delivery systems described in Example 25 and Comparative Example 6. FIG.

Fig. 8 shows the skin flux of the transdermal drug delivery system described in embodiment 26 (100GSM), embodiment 26 (200GSM), embodiment 26 (300GSM), embodiment 26 (400GSM), embodiment 27 (400GSM) measurement curve.

Fig. 9 shows measurement curves of the skin flux of the transdermal drug delivery systems described in Example 28 and Comparative Example 7.

FIG. 10 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example 29.

Fig. 11 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples 30-33 and Comparative Examples 8-11.

Detailed ways

definition

As used herein, the term "pharmaceutically acceptable salt" means a salt suitable for use in contact with a subject (eg, a human subject) without undue toxicity, irritation, allergic response, etc., within reasonable medical judgment, with reasonable benefit/risk ratio and are those salts that are effective for their intended use.

The "pharmaceutically acceptable salt" mentioned in the present invention includes inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final isolation and purification of the compound, or can be prepared by adding the free base form of the purified compound (eg olanzapine) are prepared separately by reacting 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, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates , pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, etc. Examples of organic acid addition salts include saturated or unsaturated C1 to C30 fatty acid salts, including but not limited to monocarboxylates or dicarboxylates. Non-limiting examples include formate, glyoxylate, oxalate, acetate, glycolate, acrylate, pyruvate, malonate, propionate, 3-hydroxypropionate, milk Glycerate, Fumarate, Maleate, Oxaloacetate, Crotonate, Acetoacetate, 2-Oxobutyrate, Methylmalonate, Succinate , malate, L-tartrate, DL-tartrate, meso-tartrate, dihydroxytartrate, butyrate, isobutyrate, hydroxybutyrate, levulinate, sorbate, coating Conate, mesaconate, ketoglutarate, glutarate, succinate, methylsuccinate, valerate, isovalerate, pivalate, cis-aconitate , trans-aconitate, ascorbate, citrate, isocitrate, adipate, caproate, benzoate, salicylate, gentisate, protocatechuate, Gallate, Cyclohexanecarboxylate, Pimelate, Benzoate, Chlorobenzoate, Phthalate, Isophthalate, Terephthalate, Terephthalate Diformate, phenylacetate, toluate, o-toluate, m-toluate, p-toluate, dinitrobenzoate, benzenesulfonate, toluenesulfonate , citrate, mesylate oleate, tosylate, mesylate naphthoate, glucoheptonate, lactobionate, laurylsulfonate and isethionate, Mandelate, Homogentisate, Suberate, Caprylate, Caprate, Laurate, Palmitate, Stearate, Isostearate, Oleate, Elaidate, Gondolate, Erucate, Neurate, and Simeonate, Hexadecatrienoate, Linoleate, Alpha-Linolenate, Gamma-Linolenate, Calendula, Hard Fatty acid salt, mead salt, eicosadienoate, eicosatrienoate, dihomo-γ-linolenate, arachidonic acid salt, docosadienoate, etc. and their combinations.

As used herein, the term "therapeutically effective amount" means an amount of a compound or molecule of the invention which, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) attenuates, Ameliorate or eliminate one or more symptoms of a particular disease, disorder or condition, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder or condition described herein.

As used herein, the term "about" refers to plus or minus 10% of the indicated figure. For example, "about 10%" can mean a range of 9% to 11%, and "about 1" can mean 0.9-1.1.

As used herein, the term "treatment" refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, prevention of occurrence or recurrence of disease, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of disease, prevention of metastasis, reduction of the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

As used herein, the term " _C2 to _C30 fatty acid" includes saturated or unsaturated _C2 to _C30 fatty acid fatty acids, including but not limited to monocarboxylic or dicarboxylic acids. Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxalic acid, Acetoacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid Acid, hydroxybutyric acid, levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitic acid Acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, heptanoic acid Diacid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic 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, Argondoic Acid, Erucic Acid, Neural Acid, and Simene Acid , hexadecatrienoic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, calendulaic acid, stearic acid, meadic acid, eicosadienoic acid, eicosatrienoic acid, two Homo-gamma-linolenic acid, arachidonic acid, docosadienoic acid, and combinations thereof. Preferred is oleic acid, isostearic acid, or stearic acid.

As used herein, the term "backing layer" serves as the upper surface of the transdermal patch and as the main structural element provides flexibility to the patch. Preferably, the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions. The backing layer is preferably made of a sheet or film of flexible elastic material. The backing layer is preferably air impermeable. The backing layer used in the patch of the invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement. The non-occlusive backing layer allows the area to breathe (ie facilitates water vapor transmission from the skin surface), while the occlusive backing layer reduces air/vapor penetration. Preferably, the backing layer of the matrix-type transdermal delivery system (Figs. 1-3) is closed. Preferably, the backing layer comprises synthetic polymers such as polyolefins, polyesters, polyethylenes, polyvinylidene chlorides and polyurethanes. Preferably, the thickness of the backing layer is from about 0.5 mil to about 5 mils; more preferably, the thickness of the backing layer is from about 1 mil to about 3 mils. Preferably, the oxygen delivery rate is from about 2 cc/m/24hr to about 100 cc/m/24hr. Preferably, the MVTR is from about 0.1 g/m/24hr to about 50 g/m/24hr, more preferably, the MVTR is from about 0.3 g/m/24hr to about 30 g/m/24hr. In a preferred embodiment, the backing layer is an occlusive polyester film layer about 2.0 mil thick (commercially available, such as Scotchpak 9733, Scotchpak 9735 and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul Minn.). Scotchpak 9733 consists of polyester and MDPE/ethylene vinyl acetate heat seal layers, the laminate is translucent, conformable, hermetic and heat sealable. It can be used in the matrix type transdermal drug delivery system shown in Figures 1-3. More preferably, the backing layer comprises a laminate comprising a layer of aluminum foil between layers of polymer film, such as Scotchpak 9738 and Scotchpak 1109. When the patch is on the skin, the aluminum layer prevents light from coming into contact with the photosensitive olanzapine.

As used herein, the term "matrix layer" comprises olanzapine or a pharmaceutically acceptable salt thereof, a polymeric skin penetration enhancer, and optionally a small molecule skin penetration enhancer, a pressure sensitive adhesive and other additives.

In addition, the matrix layer may also contain one or more other pharmaceutically acceptable additives. Non-limiting examples of additives include antioxidants, anti-skin irritants, cohesion promoting additives, plasticizers, tackifiers, and the like.

Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, Sodium formaldehyde sulfoxylate, chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA. Preferably, the antioxidant is alpha-tocopherol, vitamin E. The content of α-tocopherol is 0.05 to 0.5%, preferably 0.1 to 0.2%, of the total weight of the adhesive layer.

Non-limiting examples of plasticizers include mineral oil, silicone oil, triethyl citrate, and mixtures thereof. The amount of plasticizer present in the adhesive layer is from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material, most preferably From about 0% to about 30%. About 20% by weight of binder material.

Non-limiting examples of tackifiers include silicone oils, mineral oils, polybutenes, terpenes, and mixtures thereof. The tackifier is present in the adhesive layer in an amount from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material.

As used herein, the term "semi-permeable membrane or woven fabric layer" is used to contain a liquid or semi-solid matrix material within the matrix drug layer, which functions to control olanzapine or a pharmaceutically acceptable salt thereof from liquid Or the diffusion of the semisolid matrix drug layer to the skin contact adhesive layer. The semi-permeable membrane or woven fabric layer and the backing layer can be sealed together around the peripheral edge.

Semipermeable membranes include, but are not limited to, ethylene-co-vinyl acetate copolymer membranes, polyethylene polymer membranes, polypropylene polymer membranes. Non-limiting examples of ethylene-co-vinyl acetate copolymers include 3M Cotran 9702, Cotran 9712, Contan 9716, and Contran 9728. Non-limiting examples of polyethylene polymer films include Solupore. Non-limiting examples of polypropylene polymer films include Celgard 2400.

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

The thickness of the semi-permeable membrane layer may generally be about 10 um to about 100 um, preferably about 15 μm to about 50 μm.

As used herein, the term "skin contact adhesive layer" serves to adhere the olanzapine transdermal delivery system to the skin surface. It can also be used to control the rate of delivery of olanzapine to the skin after the protective release layer is removed.

As used herein, the term "release liner" includes, but is not limited to, silicon-coated polyester release liners, fluoropolymer-coated polyester release liners from 3M, and fluorosilicone-coated polyester release liners available from a number of suppliers Isolation liner.

As used herein, the term "GSM" refers to the number of grams of solid matrix layer contained in a transdermal system per square meter, and the specific unit is "grams per square meter" or (g/m ² ).

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiment is a module embodiment of the present invention, rather than Full examples. Elements and features described in one embodiment of the present invention may be combined with elements and features shown in one or more other embodiments. It should be noted that representation and description of components and processes that are not related to the present invention and that are known to those of ordinary skill in the art are omitted from the description for the purpose of clarity. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Anti-crystallization stability test

Table 1. Olanzapine Anti-Crystallization Stability

Comparative example 1

Olanzapine (1.5 g) and dimethylacetamide (2.5 g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution. Add Duro-Tak 387-2516 (17.71 g), mix to form a homogeneous suspension, and degas to remove air bubbles. Dry coat at 100 gsm to a siliconized polyester release liner in a forced air oven at 50C for 5 minutes, then in a forced air oven at 120C for 15 minutes to remove solvent. One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109. The three-ply laminates were die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. Microscopic analysis was performed on day 7 after patch fabrication. From the crystal observation results in Table 1, it can be seen that many crystals were observed under 100 times magnification on the 7th day and 28th day of the transparent Scotchpak 9733 backing patch. Since Comparative Formulation 1 in Comparative Example 1 contained no crystallization inhibitor, the dissolved olanzapine crystallized rapidly.

Embodiment 1 (prescription 1)

Povidone K30 (0.45g), olanzapine (0.90g) and dimethylacetamide (2.25g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution. Add Duro-Tak 387-2516 (15.94g), mix to form a homogeneous suspension, and degas to remove air bubbles. Dry coat at 100 gsm to a siliconized polyester release liner in a 50C forced air oven for 5 minutes then in a 120C forced air oven for 15 minutes to remove solvent. One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109. The three-ply laminates were die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. The crystal observation results are shown in Table 1. After 18 days, no olanzapine crystals were observed under a transmitted light microscope at 100 times magnification (Table 1). Formulation 1 in Example 1 contained povidone K30 as a crystallization inhibitor, so no crystals formed on storage.

Embodiment 2 to embodiment 5 (prescription 2 to prescription 5)

Olanzapine (1.02g), lactic acid (0.512g) and dimethylacetamide (2.508g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution. Add Crospovidone CL-M (1.04 g) and mix well. Add lauryl lactate (1.51 g) and Duro-Tak 387-2516 (12.74 g), mix to form a homogeneous suspension, and degas to remove air bubbles. Dry coat at 100 gsm to a siliconized polyester release liner in a 50C forced air oven for 5 minutes then in a 120C forced air oven for 15 minutes to remove solvent. One part of the dried two-ply laminate was laminated adhesive side to clear backing film ScotchPak 9733 and the other part was laminated to aluminized backing film Scotchpak 1109. The three-ply laminates were die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. From the crystallization observation results in Table 1, it can be seen that after the transparent Scotchpak 9733 backing patch was stored at room temperature for 10 days and 31 days or at 40°C for 31 days, no olanzapine was observed with a transmitted light microscope at a magnification of 100 times crystals. This is due to the presence of the crystallization inhibitor crospovidone CLM and the solubilizer lactic acid. Crospovidone also improves the physical properties and skin adhesion of formulations containing liquid lactic acid or other liquid excipients, as described in the Skin Adhesion, Finger Pressure, and Physical Properties section.

Prescriptions 3 to 5 in Examples 3 to 5 were prepared similarly. It can be seen from Table 1 that due to the presence of the crystallization inhibitor crospovidone CLM and the solubilizer lactic acid, no crystals were formed after 31 days at room temperature and 40°C.

Embodiment 6 (prescription 6) and embodiment 7 (prescription 7)

Formulations 6 and 7 contained crystallization inhibitor povidone K30 and silicone binders Bio-PSA 4202 and 7-4302, and no olanzapine crystals were observed after 31 days.

Embodiment 8 (prescription 8) and embodiment 9 (prescription 9)

As can be seen from Table 1, prescription 9 in embodiment 9 contains 22% crystallization inhibitor crospovidone CLM (22%) than prescription 8 in embodiment 8 contains more crospovidone CLM (15%), preparation 9 was more stable to crystallization than formulation 8 at day 26, as no crystals were observed in formulation 9 but a small amount of crystals were observed in formulation 8 at day 26.

Embodiment 10 (prescription 10) to embodiment 12 (prescription 12)

Because Formulation 10 contained the very hydrophobic silicone binder Bio-PSA 7-4302, 15% crospovidone CL-M was not sufficient to inhibit olanzapine crystallization, but it Duro-Tak 387-2516 is more formulated to inhibit crystallization.

Embodiment 13 (prescription 13) to embodiment 17 (prescription 17)

Examples 13 through 17 further demonstrate that formulations containing the acrylic binder Duro-Tak 387-2516 are more stable to olanzapine crystallization as the CLM of crospovidone is increased.

Embodiment 18 (prescription 18) to embodiment 20 (prescription 20)

When the adhesive was changed from the hydroxyethyl-functional acrylic adhesive Duro-Tak 387-2516 to the carboxyl-functional acrylic adhesive Duro-Tak 387-2504, even at 10% crospovidone CL-M, the patch Olanzapine crystals also did not form after 3 months at room temperature and 40C.

Embodiment 22 (prescription 22) to embodiment 24 (prescription 24)

For formulations 22 to 24 containing a liquid solubilizer (lactic acid or oleic acid) and a crystallization inhibitor (micronized solid powder crospovidone CL-M) partially dissolving olanzapine, no crystals were observed after 48 days at room temperature. This means that crospovidone CL-M improves the stability against olanzapine crystallization. As described in the Skin Adhesion, Finger Adhesion and Physical Properties sections, Crospovidone CL-M also improved the physical properties and skin adhesion of formulations containing liquid solubilizers.

Embodiment 25 (prescription 25)

Add Eudragit E100 (6g), oleic acid (4g) and dimethylacetamide (16g), DL-α tocopherol (0.12g), ascorbyl palmitate NF (0.04g), sodium metabisulfite (0.002g) into glass jars. Mix and heat at 50°C to dissolve and form a clear solution. Duro-Tak 387-2516 (54 g) was added and mixed for 24 hours to a homogeneous suspension. Olanzapine (4 g) was added and after mixing for 2 hours, degassed to remove air bubbles. Dry coat at 100 gsm to a siliconized polyester release liner in a forced air oven at 50C for 4 minutes followed by a forced air oven at 90C for 6 minutes to remove solvent. Laminate adhesive side to clear backing film ScotchPak 9733. The three-layer laminate was die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies. Pouch patches are stored at room temperature. As can be seen from the crystallization observation results in Table 1, due to the presence of both oleic acid and Eudragit E100, no crystallization was formed after 32 days at room temperature. Eudragit E100 also improves the physical properties and skin adhesion of the formulation, as described in the Skin Adhesion, Finger Adhesion and Physical Properties sections.

Comparative example 2 (comparison prescription 2) and comparative example 3 (comparison prescription 2)

Comparative Formulation 2 and Comparative Formulation 3 contained liquid lactic acid and oleic acid in the absence of povidone, crospovidone CLM or Eudragit E100. Although no crystals formed after 48 days at room temperature, their physical properties and skin adhesion were unacceptable, as described in the Skin Adhesion, Fingertip, and Physical Properties sections.

Comparative example 4 (comparative prescription 4)

In order to prepare comparative prescription 4, the mixed solution, olanzapine solution, and excipient solution were prepared according to Table 2-1, Table 2-2, and Table 2-3, respectively. Wet formulation formulations were then prepared in accordance with Tables 2-4. The final dry formulation composition formulations are shown in Tables 2-5.

Table 2-1. Mixed solvents

成分Element	克gram
丙酮acetone	19.01919.019
甲醇Methanol	4.764.76
三氟乙酸Trifluoroacetate	0.290.29
总和sum	24.06224.062

Table 2-2. Olanzapine solution

成分Element	克gram	w/w％w/w%
混合溶剂mixed solvent	21.0621.06	96.2896.28
奥氮平Olanzapine	0.810.81	3.723.72
总和sum	21.8821.88	100.00100.00

Table 2-3. Excipient solution

成分Element	克gram	w/w％w/w%
油酸Oleic acid	2.682.68	57.1357.13
肉豆蔻酸异丙酯Isopropyl myristate	1.351.35	28.7928.79
奥氮平Olanzapine	0.660.66	14.0814.08
总和sum	4.694.69	100.00100.00

Table 2-4. Wet Recipe

Table 2-5. Dry Recipe

Embodiment 26 (prescription 26):

Premix A: Povidone K90 (6g), Eudragit E100 (6g), oleic acid (6g) and dimethylacetamide (24g), DL-α tocopherol (0.09g), ascorbyl palmitate NF (0.0006g), sodium metabisulfite (0.0005g) were added to a glass jar. Mix to dissolve and form a clear solution. Mix at room temperature for 24 hours to a homogeneous solution. Olanzapine (5.5 g) was added and mixed for 1 hour to form a solution.

Solution B: Weigh the prescribed amount of adhesive Dura-Tak387-2287 (64.9g) into a glass bottle. DL-alpha tocopherol (0.0825 g), ascorbyl palmitate NF (0.0006 g), sodium metabisulfite (0.0004 g), and hydroxybutyltoluene (0.0275 g) were added to a glass jar. Mix at room temperature for 24 hours.

Add 48g of premix solution A to solution B and mix homogeneously for 7 minutes. Dry coat at 50 gsm to a siliconized polyester release liner in a forced air oven at 50C for 4 minutes followed by a forced air oven at 90C for 6 minutes to remove solvent. Laminate adhesive side to clear backing film ScotchPak 9733. The three-layer laminate was die-cut into 10 cm2 patches and each patch was heat-sealed in an aluminized bag for stability studies.

Example 27 was prepared using a similar method. At the time of writing this formulation did not form crystals. Povidone and Eudragit E100 effectively inhibited olanzapine crystal formation for 49 days at room temperature and 40 days at a storage temperature of 40 °C.

Embodiment 28 (implementing prescription 28) and comparative example 7 (comparing prescription 7):

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

In another coat, a wet coat was dried at 50°C for 5 minutes and at 90°C for 3.5 minutes. GC analysis found 2.70% residual DMSO. Microscopic analysis of the patches revealed the formation of numerous olanzapine crystals on day 1.

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

Comparative example 7 (comparative prescription 7):

Olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) were added to a glass jar. Mix to dissolve and form a clear solution. Add Dura-Tak 87-900A (52.06g). well mixed. After degassing, it was coated on a release liner with a target dry thickness of about 130 GSM. Dry at 37.8°C for 60 minutes. Apply a backing film on top of the adhesive. The release liner was found to be peelable. GC found residual DMSO at 7.25%.

In another coat, a wet coat was dried at 50°C for 5 minutes and at 90°C for 3.5 minutes. GC found 3.52% residual DMSO. Microscopic analysis of the patches revealed the formation of numerous olanzapine crystals on day 1. Microscopic analysis of the patches revealed the formation of numerous olanzapine crystals on day 1.

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

Embodiment 29 (prescription 29):

Premix A: Povidone K90 (5.5g), oleic acid (8.25g) and dimethylacetamide (22g), D-alpha tocopherol (0.2063g), ascorbyl palmitate NF (0.0413g) , a 10% aqueous solution of sodium metabisulfite (0.0062 g) and hydroxybutyltoluene (0.2063 gram) were added to a glass jar. Mix and heat at 50°C to dissolve and form a clear solution. Mix at room temperature for 24 hours to a homogeneous solution. Olanzapine (5.5 g) was added and mixed for 1 hour to form a solution.

Solution B: Weigh the adhesive Dura-Tak 387-2510 (64.3814g) containing 0.56% polybutyl titanate into a glass bottle. D-alpha tocopherol (0.05 g), ascorbyl palmitate NF (0.01 g), 10% sodium metabisulfite (0.0015 g), and hydroxybutyl toluene (0.05 g) were added to a glass jar and mixed for 24 hours.

Add 30.33g of premix solution A into solution B, and mix homogeneously for 7 minutes. Dry coat at 50 gsm to a siliconized polyester release liner in a forced air oven at 50C for 4 minutes followed by a forced air oven at 90C for 6 minutes to remove solvent. Laminate adhesive side to clear backing film ScotchPak 9733.

In vitro skin flux assay

In vitro permeation testing using vertical statically modified Franz cells. The receiving pool has a volume of 7ml and is filled with a pH 6.5 buffer solution with an effective skin permeability of 0.61cm2. Mount the human cadaver skin on the receiving pool with the dermis side facing the receiving pool. The stroma layer was placed on the stratum corneum side of human cadaver skin. Place the O-ring on top of the skin. . Fix the donor cell on top of the receiver cell. Place the Franz cell in a 32oC incubator on a magnetic stir plate. Take 2ml of the solution at each prearranged time point, pour off the remaining solution, and replenish with new receiving solution. The receiving solution was immediately analyzed by HPLC for the amount of olanzapine.

Olanzapine dissolved in Crospovidone CL-M crystallized after formulation due to the absence of crystallization inhibitors Povidone K30, Povidone K90. As shown in Table 3 (Figure 4), the in vitro skin flux of the crystalline formulation (Comparative Formulation 1 in Comparative Example 1) decreased rapidly from the 48 hour time point to the 168 hour time point. From the 48 hour time point to the 168 hour time point, the in vitro skin flux of the two non-crystalline formulations (Formulation 2 and Formulation 8) was still much higher than that of the comparative formulation 1.

Table 3. skin permeation flux (ug/cm2/hr): embodiment 1, embodiment 8 and comparative example 1

The in vitro skin flux of amorphous formulation 22 containing 15% by weight of crospovidone CL-M was higher than that of comparative formulation 2 without crospovidone CL-M or povidone K30 (Table 4, Figure 5). As will be described in the Skin Adhesion, Finger Test and Physical Properties section, Comparative Formulation 2 observed some adhesive transfer to the finger in the finger test (Comparative Example 12, Table 11), its physical properties and skin adhesion is unacceptable. Crospovidone CL-M not only increased skin flux but also improved the physical properties and skin adhesion of Formulation 22 by increasing adhesive matrix cohesion and thus reducing adhesive transfer to the skin.

Formulation 23 containing 15% by weight crospovidone CL-M had higher in vitro skin flux than comparative formulation 3 and comparative formulation 5 without crospovidone CL-M or povidone K30 (Table 4, Figure 5) . Physical properties of Comparative Formulation 3 and Comparative Formulation 5 as will be described in the Skin Adhesion, Finger Test and Physical Properties sections (there was some adhesive transfer to the finger in the finger test, see Comparative Example 13, Table 11) Adhesion to skin is unacceptable. Crospovidone CL-M not only increased skin flux but also improved the physical properties and skin adhesion of Formulation 23 by increasing adhesive matrix cohesion and thus reducing adhesive transfer to the skin.

Although the in vitro skin flux of US20070148218A1 Example 1 was good due to the presence of skin penetration enhancers, as shown in Table 11 of the present application, excessive adhesive transfer to the finger was observed and formed in the finger test The adhesive flowed (Comparative Example 15, Table 11), so the physical properties of the examples in 20070148218A1 were not acceptable.

Comparative Example 4: 4.6% fatty ester (lauryl lactate) was added to Formulation 23 to obtain Comparative Formulation 4. Compared to Example 23, the average skin flux of Comparative Example 4 was low, indicating that the addition of liquid lauryl lactate reduced the average skin flux (Table 4, Figure 5). The addition of liquid lauryl lactate also reduced the integrity of the adhesive matrix. Therefore, there was some adhesive transfer to the finger in the finger test (Comparative Example 14, Table 11).

Table 4. Skin permeation flux (g/cm ² /hr): Examples 22-23, Comparative Examples 2-5

Table 5 (Figure 6) shows that the in vitro skin flux of amorphous formulation 24 containing 9.3% oleic acid and 15% Eudragit was high from the 24 hour time point to the 168 hour time point. As shown in Table 11, there was no adhesive transfer to the finger in the finger test of Formulation 24 (Example 38, Table 11).

Table 5. Skin permeation flux (μg/cm ² /hr): Example 24

The average epidermal flux of Comparative Example 6 is similar to that of Example 25, and the results are shown in Table 6 (Fig. 7). The fatty alcohol nonanol did not increase the skin penetration of olanzapine.

Table 6. Skin permeation flux (μg/cm ² /hr): Example 25 and Comparative Example 6

Example 26

The composition of prescription 26 of Example 26 is: 10% olanzapine, 10% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-α-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% coke Sodium Sulfite NF, 0.1% BHT, 59.5965% Dura-Tak 387-2287.

The formulation contained a polymer skin penetration enhancer (10% povidone K90) and 10% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1). The 7-day skin penetration rate of this formulation is higher (Table 7, Figure 8), and from 100GSM (grams per square meter), 200GSM, 300GSM, 400GSM, the skin penetration rate increases with the increase of matrix thickness (coating weight) . At the same time the polymeric skin penetration enhancer (10% Povidone K90) increased the cohesion of the adhesive, thereby reducing the transfer of the adhesive to the finger in the finger test (Example 39, Table 11).

Example 27

The composition of prescription 27 in Example 27 is: 10% olanzapine, 15% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-α-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.1% BHT, 54.5965 Dura-Tak 387-2287 (400GSM matrix layer).

The formulation contained a polymeric skin penetration enhancer (10% povidone K90) and 15% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1). Compared to Example 26, the 7-day skin penetration rate of this formulation was higher at 400GSM (Table 7, Figure 8). At the same time the polymer skin penetration enhancer (10% Povidone K90) increased the cohesion of the adhesive, thereby reducing the transfer of the adhesive to the finger in the finger test (Example 40, Table 11).

Table 7. Skin permeation flux (μg/cm ² /hr): Example 26, Example 27

Example 28 and Comparative Example 7

The composition of prescription 28 in Example 28 is: 9% olanzapine, 10% oleic acid, 16% DMSO (2.7% after drying), 65% Duro-Tak 87-900A (110GSM matrix layer).

The composition of the comparative prescription 7 of comparative example 7 is: 9% olanzapine, 10% oleic acid, 16% DMSO (3.5% after drying), 3.5% isopropyl palmitate, 3% myristyl alcohol, 3.5% GMO ( Glyceryl Monooleate), 55% Duro-Tak 87-900A (120GSM matrix layer).

The average epidermal flux of Comparative Example 7 is similar to that of Example 28, and the results are shown in Table 8 (Fig. 9). Isopropyl palmitate (fatty acid ester) and myristyl alcohol (fatty alcohol) did not increase the skin penetration of olanzapine and, on the contrary, decreased the integrity of the adhesive matrix. Therefore, there was some adhesive transfer to the finger in the finger test (Comparative Example 12, Table 11).

Example 28 and Comparative Formulation 7 did not contain the polymeric skin penetration enhancer povidone. Thus, both formulations formed olanzapine crystals on day 1. The skin flux of both formulations was much lower than that of formulations 26, 27 and 29 prepared according to preparation method 2 containing 10% povidone K90 and 10% oleic acid.

Table 8. Skin permeation flux (μg/cm ² /hr): Example 28 and Comparative Example 7

Example 29

The composition of prescription 29 in Example 29 is: 10% olanzapine, 15% oleic acid, 10% povidone K90, 0.5% DL-α tocopherol, 0.1% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.5% BHT, 63.8985% Duro-Tak 387-2510, 0.56% Polybutylate (600GSM matrix layer).

Formulation 29 of Example 29 contained a polymer skin penetration enhancer (10% povidone K90) and 10% to 20% oleic acid. This system was able to effectively inhibit the crystal formation of olanzapine (Table 1). The 14-day skin penetration rate of this formulation is very high (Table 9, Figure 10), and it is the first formulation among all drug transdermal systems whose skin flux can satisfy the drug effect for up to 14 days. At the same time the polymer skin penetration enhancer (10% povidone K90) increased the adhesive cohesion, thereby reducing the transfer of the adhesive to the finger in the finger test (Example 40, Table 11).

Table 9. Skin permeation flux (μg/cm ² /hr): Example 29

Example 30 and Comparative Example 8

The composition of prescription 30 in Example 30 is: 8% olanzapine, 16% oleic acid, 5% KollidonCL-M, 0.5% butylated hydroxytoluene, 70.5% Duro-Tak87-900A.

The composition of the comparative prescription 8 of embodiment 8 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% KollidonCL-M, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87-900A .

Example 30 (prescription 30) did not contain 10% isopropyl palmitate, and Comparative Example 8 (comparative prescription 8) contained 10% isopropyl palmitate. The skin flux of Example 30 was higher than that of Comparative Formulation 8 (Table 10, Figure 11). In the finger test, comparative formulation 8 transferred more adhesive to the finger than formulation 30 (Table 11).

Example 31 and Comparative Example 9

The composition of prescription 31 in Example 31 is: 8% olanzapine, 16% oleic acid, 15% KollidonCL-M, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak87-900A.

The composition of the comparative prescription 9 of embodiment 9 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% KollidonCL-M, 0.5% butyl hydroxytoluene, 50.5% Duro-Tak87-900A .

Example 31 (prescription 31) did not contain 10% isopropyl palmitate, and Comparative Example 9 (comparative prescription 9) contained 10% isopropyl palmitate. The skin flux of Example 31 was higher than that of Comparative Example 9 (Table 10, Figure 11). In the finger test, Comparative Formulation 9 transferred more adhesive to the finger than Formulation 31 (Table 11).

Example 32 and Comparative Example 10

The composition of prescription 32 in Example 32 is: 8% olanzapine, 16% oleic acid, 5% copovidone Kollidon64, 0.5% butylated hydroxytoluene, and 70.5% Duro-Tak87-900A.

The composition of the comparative prescription 10 of embodiment 10 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% copovidone Kollidon64, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87- 900A.

Example 32 (prescription 32) did not contain 10% isopropyl palmitate, and Comparative Example 10 (comparative prescription 10) contained 10% isopropyl palmitate. The skin flux of Example 32 was higher than that of Comparative Example 10 (Table 10, Figure 11). In the Finger Test, Comparative Formulation 10 transferred more adhesive to the finger than Formulation 20 (Table 11).

Example 33 and Comparative Example 11

The composition of prescription 33 in Example 33 is: 8% olanzapine, 16% oleic acid, 15% copovidone Kollidon64, 0.5% butylhydroxytoluene, 60.5% Duro-Tak87-900A.

The composition of the comparative formulation 11 of Example 11 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% copovidone Kollidon64, 0.5% 50.5% Duro-Tak87-900A.

Example 33 (prescription 33) did not contain 10% isopropyl palmitate, and Comparative Example 11 (comparative prescription 11) contained 10% isopropyl palmitate. The skin flux of Example 33 was higher than that of Comparative Example 11 (Table 10, Figure 11). In the finger test, Comparative Example 11 transferred more adhesive to the finger than Example 33 (Table 11).

Table 10. Skin permeation flux (ug/cm ² /hr): Examples 30-33, Comparative Examples 9-11

Physical Properties and Skin Adhesion - Finger Test

Place the patch on the work surface, adhesive side up. Press the adhesive with your index finger for 5 seconds, then lift while holding part of the patch with the fingers of your other hand. Look with your thumb and touch the front of your index finger to see if your finger is sticky. A finger is tacky if there is transfer of adhesive to the index finger when the finger is lifted from the patch adhesive layer. The softer the adhesive and the lower the rheological cohesion, the more adhesive transfer from the patch adhesive to the finger is expected and the lower the tack. Refer to Table 11 for the finger test results of each embodiment.

Examples 34 and 35:

As shown in Table 11, formulation 8 (Example 34) and formulation 9 (Example 35) contained 15% by weight and 22% by weight of crospovidone CL-M, respectively, and no adhesive transfer to the index finger was observed.

Examples 36-37 and Comparative Examples 12-13:

Formulation 22 (Example 36) and Formulation 23 (Example 37) containing 15% Crospovidone CL-M also had no adhesive transfer to the fingers. In contrast, Comparative Formulation 2 (Comparative Example 12) and Comparative Formulation 3 (Comparative Example 13) without Crospovidone CL-M, Povidone K30, or Eudragit E100 had adhesive transfer to the fingers.

Comparative example 14 (comparative prescription 4):

The 4.6% lauryl lactate of Comparative Formulation 4 (Comparative Example 14) increased adhesive transfer to the fingers relative to Example 37 (Formulation 23).

Comparative example 15 (comparative prescription 5):

Comparative formulation 5 (comparative example 15) not only contained very high content of liquid oleic acid (17.17%) and liquid isopropyl palmitate (8.59%), but also did not contain crospovidone CL-M, povidone K30 or EudragitE100, so severe adhesive transfer was observed in the finger test.

Embodiment 38 (prescription 24):

Formulation 24 contained the polymer Eudragit E100 and there was no adhesive transfer to the finger in the finger test.

Embodiment 39-40 (prescription 26-27):

These formulations contain polymeric penetration enhancers (povidone and Eudragit E100) that promote adhesive cohesion, excellent physical properties, and no adhesive transfer to the finger was observed in the finger test.

Embodiment 41 (prescription 28) and comparative example 16 (comparative prescription 7):

Example 41 contained no fatty acid esters or fatty alcohols, and despite adhesive transfer due to the presence of high amounts of DMSO, the liner was still peeled off cleanly. Comparative Example 16 contained fatty acid ester isopropyl ester and fatty alcohol myristyl alcohol, and in the finger test, the release liner could not be removed and a large amount of adhesive transfer to the finger was observed.

Embodiment 42 (prescription 29):

Formulation 29 in Example 42 contained a sufficient amount of polymeric cohesion promoter that no adhesive transfer to the finger was observed in the finger test.

Embodiment 43 (prescription 30) and comparative example 17 (comparison prescription 8):

Example 43 with 5% curing agent Kolliodn CL-M (i.e. crospovidone CL-M) had only a small amount of adhesive transfer to the finger, but Comparative Example 17 with 10% isopropyl palmitate had a lot of adhesion The solution is transferred to the fingers.

Embodiment 44 (prescription 31) and comparative example 18 (comparative prescription 8):

Example 44 containing 15% curing agent Kolliodn CL-M (i.e., crospovidone CL-M) did not observe adhesive transfer to the fingers, but Comparative Example 18 containing 10% isopropyl palmitate had a lot of stickiness. The mixture is transferred to the fingers.

Embodiment 45 (prescription 32) and comparative example 19 (comparative prescription 8):

Example 45 with 5% curing agent copovidone VA64 had only a small amount of adhesive transfer to the finger, but Comparative Example 19 with 10% isopropyl palmitate had a large amount of adhesive transfer to the finger.

Embodiment 46 (prescription 33) and comparative example 20 (comparative prescription 8):

Example 46 with 15% of the curing agent copovidone VA64 had no adhesive transfer to the fingers, but Comparative Example 20 with 10% isopropyl palmitate had significant adhesive transfer to the fingers.

Table 11. Summary of Finger Test Results

Placebo patch wear test

Placebo Patch Formulation 1 and Placebo Patch Formulation 2 described in Table 14 and Table 15 were prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain the olanzapine base . For placebo formulation 1, patches were prepared in two coating weights (454 GSM (grams per square meter of olanzapine)). One healthy volunteer participated in Placebo Wear Study #1 (Example 47). The skin on the left and right outer arms was cleaned with wet paper towels and dried with dry paper towels. The Formulation 1 patch was applied on the left upper outer arm. Apply the prescription 22 patch to the upper right outer arm. After the patches are applied, smooth them out to ensure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily. Adhesion was scored using a five-point scale from 0 to 4, as shown in Table 12. Primary skin irritation was scored using a 0-7 point scoring system as shown in Table 13.

The Skin Adhesion Score and Major Skin Irritation Score for Placebo Wear Study #1 (Example 47) are reported in Tables 16 and 17. Cohesion was low for both the placebo prescription 1 patch and the placebo prescription 2 patch because insufficient amounts of crospovidone CLM or povidone K30 were used to avoid the use of large amounts of liquid excipients (lactic acid and lauryl lactate). As a result, in the finger test, a large amount of adhesive was transferred to the index finger (Table 11). Due to the low cohesion of the adhesive layer, in the placebo wear study, the Placebo Prescription 1 patch was slippery and moved its position on the upper arm by itself after 28 hours of wearing, while the Placebo Prescription 2 patch had 80 % of the patch, lift after 12 hours of wearing.

Table 12. Skin Tackiness Score

Table 13. Skin Irritation Scores

皮肤外观skin appearance	得分Score
没有刺激的证据no evidence of irritation	00
几乎看不到的最小红斑barely visible minimal erythema	11
明显可见的红斑，轻微水肿或轻微丘疹Visible erythema, mild edema, or mild papules	22
红斑和丘疹erythema and papules	33
明确水肿 clear edema	44
红斑，浮肿和丘疹erythema, puffiness and papules	55
水疱疹 Herpes	66
贴剂范围有强烈的反应Patch range has a strong reaction	77

Table 14. Placebo patch prescription 1 (backing film is Scotchpak 9733)

成分Element	干,w/w％Dry, w/w%
交聚维酮CLMCrospovidone CLM	15.0015.00
乳酸lactic acid	3.003.00
乳酸月桂酯lauryl lactate	15.0015.00
聚丙烯酸Duro-Tak 87-2516Polyacrylic acid Duro-Tak 87-2516	67.0067.00
总和sum	100.00100.00

Table 15. Placebo patch prescription 2 (backing film is Scotchpak 9733)

成分Element	干,w/w％Dry, w/w%
交聚维酮CLMCrospovidone CLM	10.0010.00
乳酸lactic acid	5.005.00
乳酸月桂酯lauryl lactate	10.0010.00
聚丙烯酸Duro-Tak 87-2516Polyacrylic acid Duro-Tak 87-2516	75.0075.00
总和sum	100.00100.00

Table 16. Placebo Patch Wearing Test 1: Scoring of Placebo Patch Prescription 1 (454GSM Adhesive Layer Thickness)

*The test stopped due to automatic displacement due to slipping.

Table 17. Placebo Patch Wearing Experiment 1: Scoring of Placebo Patch Prescription 2 (426GSM Adhesive Layer Thickness)

*Because 80% of the patch peeled off the skin, the test was stopped.

Placebo patch wear test

Embodiment 47 (placebo prescription 3)

Placebo patch formulation 3 described in Table 18 was prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain olanzapine. For placebo formulation 3, patches were prepared in two coat weights, 200 GSM (grams per square meter) and 400 GSM. Nine healthy volunteers participated in Placebo Wear Study #1 (Example 47). Clean the outer skin of the upper arm with a damp paper towel and dry with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily.

The skin adhesion scores and major skin irritation scores for Placebo Wear Study #3 (Example 47) are reported in Tables 19 and 20. The 168-hour (7-day)-skin adhesion score for most volunteers was 0 (greater than 90% of the patch adhered to the skin) or 1 (75% to 89% of the patch adhered to the skin), with few Volunteers were able to wear the patch for 12 or 13 days. Major skin irritations in most volunteers were 0 (no irritation) or 1 (almost no irritation) within 168 hours (7 days).

Table 18. Placebo patch prescription 3 (backing film is Scotchpak 9733)

Table 21. Placebo patch prescription 4 (backing film is Scotchpak 9733)

Embodiment 48 (placebo patch prescription 4)

For placebo formulation 4, the coating weight of the patch was 400 GSM (grams per square meter). One healthy volunteer wore both patches in Placebo Wear Study #3 (Example 48). The skin of the upper left foreleg was cleaned with a wet paper towel and dried with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Adhesion and irritation scores (based on skin itching and skin appearance such as redness) were recorded daily.

The skin adhesion scores and major skin irritation scores for Placebo Wear Study 3 (Example 48) are reported in Tables 22 and 23. The 28-day skin adhesion score was 0 (greater than 90% patch adhered to the skin). Major skin irritation at 28 days was also 0 (no irritation). The formulation with 15% crospovidone CLM maintained good cohesion and provided excellent skin adhesion for up to 28 days despite the presence of high amounts of liquid oleic acid in the formulation.

Claims

A kind of olanzapine transdermal drug delivery system, it comprises:

1) backing layer;

2) a matrix layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, a C2 to C30 saturated or unsaturated fatty acid and a pressure sensitive adhesive mixture; and

3) Release layer.
The olanzapine transdermal drug delivery system according to claim 1, wherein the polymer skin penetration enhancer is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone Ketone K90, Plastone K29/32, Copovidone VA64, Crospovidone CL-M, Hydroxypropyl Methyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose Acetate Succinate, Ortho Hydroxypropylmethylcellulose phthalate, hydroxypropyl betadide, alpha, beta, lambda cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan One or more of vegetable gum.
According to the olanzapine transdermal drug delivery system according to claim 1 or 2, with respect to the gross weight of the matrix layer, the matrix layer comprises the following components:

1) The dosage of olanzapine or its pharmaceutically acceptable salt is 3-30%;

2) The dosage of the polymer skin penetration enhancer is 1.5-90%;

3) The amount of C2 to C30 saturated or unsaturated fatty acid is 3-30%;

4) The consumption of pressure-sensitive adhesive is 30-90%;

The amount of each component in the matrix layer is 100% in total.
According to the olanzapine transdermal drug delivery system according to any one of claims 1 to 3, the matrix layer also includes a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following:

1) Carbohydrate polymers, preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylbeta De, α, β, λ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;

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

3) Polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone, preferably povidone K30, povidone K90, plastone K29/32, copovidone VA64, or crospovidone CL-M.
Olanzapine transdermal drug delivery system according to any one of claims 1-4, wherein said pressure-sensitive adhesive is selected from acrylic adhesive, methacrylic adhesive, polyisobutylene adhesive, One or more of styrene-isoprene-styrene block copolymer adhesives, silicone adhesives, and acrylic-copolysiloxane copolymer adhesives;

1) The acrylic adhesive is selected from Henkel's Duro-Tak adhesive 387-2051, 387-2054, 387-2353, 87-235A, 87-2852, 87-2074, 87-2677, 387-2516, 387-2287, 387-4287, 387-2510, crosslinked 387-2510, 87-900A, 87-9301, 87-4098, 87-2194, Gelva GMS788, Gelva GMS 9073, Gelva 737, Gelva 2655, Polythick 410- SA (Sanyo Chemical Industry Co., Ltd.);

2) The polyisobutylene binder is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene H1900 from Ineos and mineral oil tackifier agent;

3) the silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400 and 7-4500,7-4600 Bio-PSA SR7-4400, SRS7-4500, SRS7-4600;

4) the acrylic acid-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA 7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, The solvent is selected from one or more of n-heptane, ethyl acetate and toluene or hot melt.
The olanzapine transdermal drug delivery system according to any one of claims 1-5, wherein the content of the olanzapine or a pharmaceutically acceptable salt thereof is 5% to 20% of the total weight of the matrix layer, preferably 5% to 15%, or 5% to 12%.
The olanzapine transdermal drug delivery system according to any one of claims 1-6, wherein the content of the soluble polymer skin penetration enhancer is 5 to 40% of the total weight of the matrix layer, preferably 5-30% , 5-24, 10-20%, 12.5-20%.
The olanzapine transdermal drug delivery system according to any one of claims 1-6, wherein the content of the insoluble polymer skin penetration enhancer is 5 to 60% of the total weight of the matrix layer, preferably 7.5-45% , 7.5-36, 15-36%.
The olanzapine scalp drug delivery system according to any one of claims 1-7, wherein the content of the pressure-sensitive adhesive is 40% to 80%, preferably 45% to 65%, of the total weight of the matrix layer.
The olanzapine transdermal drug delivery system according to any one of claims 1-8, wherein the matrix layer further comprises one or more of a small molecule skin penetration enhancer, an antioxidant, an anti-skin irritant kind.
The olanzapine transdermal drug delivery system according to claim 9, wherein the small molecule skin penetration enhancer includes one or more of C2 to C30 saturated or unsaturated fatty acids, surfactants, and lauroazepine.
The olanzapine transdermal delivery system according to any one of claims 1-10, wherein the C2 to C30 saturated or unsaturated fatty acid is selected from C2 to C20 saturated or unsaturated fatty acid, preferably oleic acid, isostearic acid one or more of stearic acid or stearic acid.
The olanzapine transdermal delivery system according to any one of claims 1-11, wherein the molar ratio of the C2 to C30 saturated or unsaturated fatty acid to olanzapine or a pharmaceutically acceptable salt thereof is 0.05 to 3.3, preferably 0.5 to 1.65.
According to the olanzapine transdermal drug delivery system described in any one of claims 1-12, comprising:

1) backing layer;

2) a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, C2 to C30 saturated or unsaturated fatty acids and pressure-sensitive adhesive;

3) skin contact adhesive layer; and

4) Release layer.
The olanzapine transdermal drug delivery system according to claim 13, wherein said skin contact adhesive layer includes but not limited to acrylic adhesive, methacrylic adhesive, polyisobutylene adhesive, styrene- One or more of isoprene-styrene block copolymer adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives.
The olanzapine transdermal drug delivery system according to any one of claims 1-12, comprising:

1) backing layer;

2) a matrix reservoir layer comprising olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer, C2 to C30 saturated or unsaturated fatty acids and pressure-sensitive Adhesive

3) semi-permeable membrane or woven fabric layer;

4) skin contact adhesive layer; and

5) Release layer.
The olanzapine transdermal drug delivery system according to claim 16, wherein said semipermeable membrane comprises a continuous membrane or a microporous membrane.
The olanzapine transdermal drug delivery system according to claim 16 or 17, wherein the semipermeable membrane or woven fabric layer has a thickness of about 10 um to about 100 um, preferably about 15 μm to about 50 μm.
According to the olanzapine transdermal drug delivery system according to any one of claims 1-18, the coating weight of the matrix layer is 100 to 1000g/m 2 , preferably 100, 200, 300, 400, 500, 600g /m 2 .
The olanzapine transdermal delivery system according to any one of claims 1-18, said olanzapine base or a pharmaceutically acceptable salt thereof is 7 days, 14 days, 21 or 28 days or longer Skin penetration over time of greater than or equal to 2 μg/ cm2 /hr, preferably greater than or equal to 3, 4, 5, 6, 7, 8, 9, or 10 μg/cm2/hr; or delivery of about 1 mg to about 18 mg of olanzapine per day Olanzapine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject, preferably about 2 mg to about 12 mg of olanzapine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject.
According to the olanzapine transdermal delivery system according to any one of claims 1-18, the matrix layer does not contain nonanol, isopropyl myristate, isopropyl palmitate or lauryl lactate.
According to the olanzapine transdermal delivery system described in any one of claims 1-18, it is characterized in that, in the preparation process, the solvent is selected from one of dimethylacetamide or dimethyl sulfoxide or more; ethanol, isopropanol or other solvents can be further selected as co-solvents.
A method for preparing the olanzapine transdermal drug delivery system described in any one of claims 1-13, comprising the following steps:

Step 1. Dissolving olanzapine or a pharmaceutically acceptable salt thereof in a solvent as premix A;

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

Step 3. adding premix A to premix B to obtain a drug wet mixture, in which olanzapine or a pharmaceutically acceptable salt thereof is dispersed in an amorphous state;

Step 4. coating the drug wet mixture on the release film;

Step 5. drying to remove the solvent to obtain a release film/substrate layer laminate;

Step 6. Laminate the substrate layer to the backing layer.
A method for preparing the olanzapine transdermal drug delivery system according to any one of claims 1-13, comprising:

Step 1. Dissolving the polymer penetration enhancer in a solvent, the solvent includes but not limited to dimethylacetamide, dimethyl sulfoxide or a mixed solvent; optionally add a small molecule skin penetration enhancer, surface active agents and antioxidants, mixed for 0.1 hour to 24 hours;

Step 2. Add olanzapine or its pharmaceutically acceptable acid addition salt, mix and dissolve until olanzapine or its pharmaceutically acceptable salt is dispersed in an amorphous state;

Step 3. Add the pressure sensitive adhesive and mix well to obtain the drug wet mixture;

Step 4. Coating the drug wet mixture on the release film;

Step 5. drying to remove the solvent to obtain a release film/substrate layer laminate;

Step 6. Laminate the substrate layer to the backing layer.
A method for preparing the olanzapine transdermal drug delivery system according to any one of claims 14-15, comprising:

Step 1. Prepare a backing layer/matrix layer laminate according to step 1 to step 5 described in claim 23 or 24, as a drug reservoir;

Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates;

Step 3. Laminate the adhesive side of the skin contact adhesive layer/release layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.
A method for preparing olanzapine transdermal drug delivery system according to any one of claims 16-18, comprising:

Step 1. preparing a backing layer/matrix reservoir layer laminate according to steps 1 to 5 of the method of claim 22 or 23;

Step 2. Prepare a skin contact adhesive layer solution or suspension comprising one or more adhesives and optionally skin penetration enhancers, antioxidants and other additives, apply to the release layer and dry to form Skin contact adhesive layer/release liner laminates with an adhesive face layer laminated to a semi-permeable membrane or woven fabric layer;

Step 3. Laminate the semipermeable membrane or woven fabric layer of the material prepared in step 2 to the matrix reservoir layer of the material prepared in step 1.
A therapeutically effective amount of the olanzapine transdermal delivery system according to any one of claims 1-25 is used in the preparation of positive and negative symptoms for the treatment or prevention of schizophrenia, or to reduce chemotherapy-related and PARP inhibitors (PARPi) The frequency and intensity of the drug's use of the drug caused by nausea and vomiting.
The described purposes of claim 26, wherein, the positive and negative symptom of described schizophrenia comprises psychosis, acute mania and mild anxiety state.
A method of treating or preventing positive and negative symptoms of schizophrenia or reducing the frequency and intensity of chemotherapy-related and PARP inhibitor (PARPi)-induced nausea and vomiting comprising administering to a subject in need thereof a therapeutically effective amount of the olanzapine transdermal drug delivery system according to any one of claims 1-25.
The method according to claim 28, wherein said positive and negative symptoms of schizophrenia include psychosis, acute mania, and hypoanxiety states.
The method according to claim 28 or 29, wherein the olanzapine transdermal drug delivery system is administered every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, every 28 days once.
The method according to claim 28 or 29, wherein the olanzapine transdermal delivery system delivers about 1 mg to about 18 mg of olanzapine or a pharmaceutically acceptable salt thereof to the blood circulation of the subject per day The system, preferably, delivers about 2 mg to about 12 mg of olanzapine base or a pharmaceutically acceptable salt thereof per day to the blood circulatory system of the subject.