WO2023134618A1

WO2023134618A1 - Transdermal patch for inhibiting drug crystallization, and preparation method therefor

Info

Publication number: WO2023134618A1
Application number: PCT/CN2023/071264
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: CN117157062A

Abstract

A transdermal drug delivery system for inhibiting drug crystallization, and a preparation method therefor and the use thereof. A drug or a pharmaceutically acceptable salt thereof in the drug delivery system is stably dispersed, in an amorphous state, in a matrix layer of a pressure-sensitive adhesive, so that the formation of drug crystallization can be inhibited, and stable release of the drug is realized.

Description

Transdermal patch for inhibiting drug crystallization and preparation method thereof

technical field

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

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.

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

It has recently been found that the systems described above unfortunately exhibit long-term stability problems. If drug crystals form in the self-adhesive matrix during long-term storage, crystal growth can lead to a reduced drug release rate, with the risk of eventually falling below the specified value. It is very difficult to stabilize the amorphous state of pharmaceutical substances in pharmaceutical dosage forms, including transdermal systems. Amorphous forms are only relatively stable and readily convert to crystals.

Contents of the invention

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

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

Another object of the present invention is to provide a matrix type drug transdermal drug delivery system which is not irritating and/or sensitizing to the skin during the period of sustained delivery of the drug or a pharmaceutically acceptable salt thereof.

One object of the present invention is to provide a method for preparing a matrix-type transdermal drug delivery system. The method heats a wet mixture of drug and pressure sensitive adhesive to above room temperature and then coats to produce an adhesive matrix patch free of drug crystals. If the wet mixture is not heated, the drug will form crystals from the matrix.

Another object of the present invention is to provide a method of treating or preventing a disease, which comprises administering a therapeutically effective amount of a matrix-type transdermal drug delivery system to a subject in need.

Another object of the present invention is to provide a therapeutically effective dose matrix-type transdermal drug delivery system used in the preparation of medicines for treating or preventing diseases.

Detailed description of the invention

In one class of embodiments of the present invention, a transdermal drug delivery system comprising:

1) backing layer;

2) a matrix layer comprising a drug or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting crystallization of the drug, and a pressure-sensitive adhesive;

3) Release layer.

In some embodiments, the stabilizer that inhibits drug crystallization is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer (preferably povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, copovidone VA64, crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL -SF), hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betad, alpha, β, λ cyclodextrin, one or more of chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or carrageenan. In the technical scheme of olanzapine, it is also called polymer skin penetration enhancer.

In some embodiments, the drug crystallization inhibiting stabilizer is selected from an insoluble drug crystallization inhibiting stabilizer, a soluble drug crystallization inhibiting stabilizer, or a combination thereof.

In some embodiments, the insoluble drug crystallization inhibiting stabilizer is selected from insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F , Crospovidone CL-SF.

In some embodiments, the drug crystallization-inhibiting stabilizer further comprises a soluble drug crystallization-inhibiting stabilizer on the basis of an insoluble drug crystallization-inhibiting stabilizer; preferred soluble drug crystallization-inhibiting stabilizers are selected from soluble povidone , more preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, and copovidone VA64.

In some embodiments, the matrix layer further includes other pharmaceutically acceptable excipients, and the other pharmaceutically acceptable excipients are preferably one or more of skin penetration enhancers, viscosity enhancers, and cohesion-promoting additives.

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

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

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

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

4) Tackifier 0-50%;

5) Skin penetration enhancer 0-30%;

6) Cohesion-promoting additive 0-20%;

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

In some embodiments, the matrix layer further comprises 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.

In some embodiments, the pressure sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, benzene One or more of ethylene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic acid-copolysiloxane copolymer adhesives;

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 and mineral oil tackifiers from Ineos ;

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 some embodiments, the transdermal drug delivery system according to any one of claims 1-9, wherein the content of the drug or a pharmaceutically acceptable salt thereof is 5% to 20% of the total weight of the matrix layer, Preferably 5% to 15%, or 5% to 12%, 7.5%.

In some embodiments, the content of the stabilizer for inhibiting drug crystallization is 6% to 40%, preferably 6% to 30%, 6% to 20%, 6.7%-20%, 6.70%, 8.2% of the total weight of the matrix layer. %, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.

In some embodiments, the content of the insoluble drug crystallization-inhibiting stabilizer is 5 to 40% of the total weight of the matrix layer, preferably 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35%, 40%, 45%; the preferred insoluble stabilizer for inhibiting drug crystallization is selected from insoluble crospovidone CL-M, crospovidone CL, crosslinked Povidone CL-F, crospovidone CL-SF.

In some embodiments, the content of the soluble stabilizer for inhibiting drug crystallization is 2 to 40% of the total weight of the matrix layer, preferably 2-30%, 5-30%, 5-24%, 10-20%, 12.5% -20%, 2.5%, 3.4%, 4%, 5%; preferred soluble stabilizers for drug crystallization are selected from soluble povidone, preferably povidone K30, povidone K90, povidone K12, povidone One or more of povidone K17, povidone K25, plastone K29/32, and copovidone VA64.

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

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

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

In some embodiments, nonanol, isopropyl myristate, isopropyl palmitate, or lauryl lactate are absent from the matrix layer.

In some embodiments, the drug is selected from the group consisting of Olanzapine, rotigotine, Donepezil, Almotriptan, Aripiprazole, Apixaban ( Apixaban), Asenapine, Baricigtinib, Bisoprolol, Blonanserin, Buprenorphine, Dextroamphetamine, Dextroamphetamine Dexmedetomidine, Eletriptan, Escitalopram, Frovatriptan, Granisetron, Indomethacin, Latex Lasmiditan, Meloxicam, Naratriptan, naproxen, Oxybutynin, Piroxicam, Pramipexole , rizatriptan, ropinirole, sumatriptan, tolubuterol, testosterone, and zolmitriptan, or their pharmaceutically acceptable of salt.

In another type of embodiment of the present invention, a method for preparing the aforementioned transdermal drug delivery system is provided, comprising the following steps:

Step 1. Dissolving the drug or its pharmaceutically acceptable salt in a solvent as premix A; preferably, the solvent includes but not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, One or more of dimethyl sulfoxide and ethyl acetate, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof.

Step 2. Mix the pressure-sensitive adhesive solution with the stabilizer for inhibiting drug crystallization to obtain premix B; the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizer for inhibiting drug crystallization, soluble stabilizer for inhibiting drug crystallization agent or combination thereof; mixing time is preferably from 0.1 hour to 24 hours.

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

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

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

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

In another type of embodiment of the present invention, a method for preparing the aforementioned transdermal drug delivery system is provided, comprising:

Step 1. Dissolve the stabilizer that inhibits drug crystallization in a solvent and mix well; preferably, the solvent includes but is not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, acetic acid One or more of ethyl esters, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof. The drug crystallization inhibiting stabilizer is selected from insoluble drug crystallization inhibiting stabilizers, soluble drug crystallization inhibiting stabilizers or combinations thereof. The mixing time is preferably from 0.1 hour to 24 hours. ;

Step 2. Add the drug or its pharmaceutically acceptable salt, mix and dissolve until dispersed in an amorphous state;

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

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

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

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

In some embodiments, step 3 is to add a pressure-sensitive adhesive heated to 30-65°C and mix uniformly to obtain a drug wet mixture; the heating temperature is preferably 35-45, 45-55°C.

In some embodiments, step 4 is coating the wet drug mixture on the release film at 30-65°C; the heating temperature is preferably 30-40, 35-45, 45-55°C.

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

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

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, which comprises olanzapine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a polymer skin penetration enhancer (ie, the aforementioned stabilizer for inhibiting drug crystallization), C ₂ to C ₃₀ Saturated or unsaturated fatty acids and pressure sensitive adhesives; and

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:

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, styrene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives;

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 and mineral oil tackifier from Ineos ;

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, styrene-butadiene-styrene block copolymer 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 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.

In a class of embodiments of the present invention, a rotigotine transdermal drug delivery system is provided, comprising:

1) backing layer;

2) a matrix layer comprising rotigotine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting drug crystallization, and a pressure-sensitive adhesive;

3) Release layer.

In some embodiments, the inhibitory drug crystallization comprises insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone Ketone CL-SF.

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

In some embodiments, the weight ratio of rotigotine to insoluble povidone is not higher than 9:40, preferably 9:1-9:24, 9:5-9:22.8, 9:5, 9:6.8, 9:8, 9:10, 9:12, 9:18, 9:20, 9:21, 9:22.8, 9:24.

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

In some embodiments, the stabilizer for inhibiting drug crystallization includes polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, and plastone K29/32, Copovidone VA64, Crospovidone CL-M, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose Acetate Succinate, Hydroxypropylmethylcellulose Phthalate , hydroxypropyl betad, α, β, λ cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or one or more of carrageenan.

In some embodiments, the matrix layer further contains other pharmaceutically acceptable excipients. Other pharmaceutically acceptable excipients can be selected from one or more of skin penetration enhancers, thickeners, and cohesion-promoting additives.

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

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

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

4) Tackifier 0-50%;

5) Skin penetration enhancer 0-30%;

6) Cohesion-promoting additive 0-20%;

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

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

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

In some embodiments, the content of rotigotine or a pharmaceutically acceptable salt thereof is 5% to 20%, preferably 5% to 15%, or 5% to 12% of the total weight of the matrix layer.

In some embodiments, the content of the stabilizer for inhibiting drug crystallization is 6% to 40%, preferably 6% to 30%, 6% to 20%, 6.7%-20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.

In some embodiments, the content of the pressure sensitive adhesive is 35% to 90%, preferably 40% to 90%, 70% to 90%, 65%, 70%, 75%, 80%, 90%.

In some embodiments, the tackifier is selected from silicone oils, mineral oils, polybutenes, terpenes, and mixtures thereof, preferably light mineral oils. In some embodiments, the amount of tackifier is 0-50%, preferably 0-30%, 0-28% of the total weight of the substrate layer.

In some embodiments, the weight ratio of rotigotine to the viscosity enhancer is 9:25-9:40, preferably 9:30-9:35.

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

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

In some embodiments, the rotigotine transdermal drug delivery system may further include structures such as a skin contact adhesive layer, a semipermeable membrane or an organic fabric layer.

In another type of embodiment of the present invention, a method for the aforementioned rotigotine transdermal drug delivery system is provided, comprising the following steps:

Step 1. Dissolving the stabilizer that inhibits drug crystallization in a solvent and mixing for 0.1 to 24 hours;

Step 2. Add rotigotine or a pharmaceutically acceptable salt thereof, mix and dissolve until rotigotine or a pharmaceutically acceptable salt thereof is dispersed in an amorphous state;

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

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

In some embodiments, the solvent in step 1 includes but not limited to one or more of toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, preferably toluene, ethanol, isopropanol propanol or its mixed solvents.

In some embodiments, step 2 includes the step of heating to 30-65°C to bring the drug into solution. The heating temperature in step 2 is preferably 30-35°C, 35-45°C, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C ℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, 50℃, 51℃, 52℃, 53℃, 54℃, 55℃.

In some embodiments, step 3 is to add a pressure sensitive adhesive heated to 30-65°C and mix well to obtain a drug wet mixture. The heating temperature in step 3 is preferably 30-35, 35-45, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.

In some embodiments, step 4 is to coat the wet drug mixture on the release film at a temperature of 35-65°C. The heating temperature in step 4 is preferably 30-35, 35-45, 45-55°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C ℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, 50℃, 51℃, 52℃, 53℃, 54℃, 55℃.

In another type of embodiment of the present invention, there is provided a therapeutically effective amount of the rotigotine transdermal drug delivery system according to the preparation of a medicament for treating or preventing a disease sensitive to the action of a dopamine receptor agonist. the use of.

In some embodiments, the disease is a disease sensitive to the effects of rotigotine.

In some embodiments, the disease is Parkinson's, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and loss of dopaminergic neurons.

In another class of embodiment of the present invention, there is provided a method for treating or preventing a disease sensitive to the action of a dopamine receptor agonist, which comprises administering to a subject in need a therapeutically effective amount of the aforementioned rotigol transdermal drug delivery system.

In some embodiments, the rotigotine transdermal delivery system is administered once every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, every 28 days.

In some embodiments, the rotigotine transdermal delivery system delivers about 1 mg to about 18 mg of rotigotine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject per day, preferably daily From about 2 mg to about 12 mg of rotigotine base or a pharmaceutically acceptable salt thereof is administered to the subject's blood circulatory system.

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 Prepared by separate reaction with a suitable organic or inorganic acid and isolation of 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 combinations thereof.

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 medium density polyethylene/ethylene vinyl acetate heat seal layers, the laminate is translucent, conformable, closed and heat sealable. It can be used in the matrix type transdermal drug delivery system shown in Figures 1-3. More preferably, the backing layer comprises a laminate comprising a layer of aluminum foil between polymeric film layers, such as Scotchpak 9738 and Scotchpak 1109. When the patch is on the skin, the aluminum layer prevents light from coming into contact with the photosensitizing medication.

As used herein, the term "insoluble crospovidone" is a high-molecular water-insoluble polymer obtained by cross-linking N-vinyl-2-pyrrolidone. It is a white or near-white powder, odorless and tasteless, and flows Good sex, insoluble in water and various solvents, also insoluble in strong acid or alkali. Non-limiting examples of "insoluble crospovidone" include CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.

Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, Sodium formaldehyde sulfoxylate, chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA. Preferably, the antioxidant is alpha-tocopherol (α-dl-tocopherol), ie 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.

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 the transition of the drug or its pharmaceutically acceptable salt from the liquid or semi-solid Diffusion of a solid matrix drug layer into a skin contact adhesive layer. The semi-permeable membrane or woven fabric layer and the backing layer can be sealed together around the peripheral edge.

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

Suitable semi-permeable membranes include continuous membranes and microporous membranes, which can be made of woven or non-woven materials. The semipermeable membrane is preferably made of flexible polymeric materials commonly used by those skilled in the art. Polymeric membranes that can be used to make the semipermeable membrane layer include, but are not limited to, those comprising low density polyethylene, high density polyethylene, ethyl vinyl acetate copolymer, polypropylene, and other suitable polymers. 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 transdermal drug delivery system to the skin surface. After removing the protective release layer, it can also be used to control the rate of drug delivery to the skin.

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 ).

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 system described in Examples A1, A8 and Comparative Example A1.

Fig. 5 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples A21, A22 and Comparative Examples A2, A3, A4, A5.

Figure 6 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example A24.

Fig. 7 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Example A25 and Comparative Example A6.

Fig. 8 shows the skin flux of the transdermal delivery system described in embodiment A26 (100GSM), embodiment A26 (200GSM), embodiment A26 (300GSM), embodiment A26 (400GSM), embodiment A27 (400GSM) measurement curve.

Fig. 9 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Example A28 and Comparative Example A7.

Figure 10 shows the measurement curve of the skin flux of the transdermal drug delivery system described in Example A29.

Fig. 11 shows the measurement curves of the skin flux of the transdermal drug delivery system described in Examples A30-A33 and Comparative Examples A8-A11.

Fig. 12 shows the measurement curves of the skin flux of the transdermal drug delivery systems of Examples C1-C2.

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 A1

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 crystallization observation results in Table 1, it can be seen that many crystals were observed under the magnification of 100 times on the 7th day and the 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 A1 (prescription A1)

Povidone K30 (0.45g), olanzapine (0.90g) and dimethylacetamide (2.25g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution. Add Duro-Tak 387-2516 (15.94g), mix to form a homogeneous suspension, and degas to remove air bubbles. 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 A1 contained povidone K30 as a crystallization inhibitor, so no crystals formed on storage.

Embodiment A2 to embodiment A5 (prescription A2 to prescription A5)

Olanzapine (1.02g), lactic acid (0.512g) and dimethylacetamide (2.508g) were added to a glass jar. Mix and heat at 85°C to dissolve and form a clear solution. 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.

Formulations A3 to A5 in Example A3 to Example A5 were prepared similarly. It can be seen from Table 1 that due to the presence of the crystallization inhibitor crospovidone CLM and the solubilizer lactic acid, no crystals were formed after 31 days at room temperature and 40°C.

Embodiment A6 (prescription A6) and embodiment A7 (prescription A7)

Formulation 6 and Formulation A7 contained crystallization inhibitor povidone K30 and silicone binders Bio-PSA 4202 and 7-4302, and no olanzapine crystals were observed after 31 days.

Embodiment A8 (prescription A8) and embodiment A9 (prescription A9)

As can be seen from Table 1, prescription A9 in embodiment A9 contains 22% crystallization inhibitor crospovidone CLM (22%) than prescription A8 in embodiment A8 contains more crospovidone CLM (15%), preparation 9 was more stable to crystallization than formulation 8 at day 26, as no crystals were observed in formulation 9 but a small amount of crystals were observed in formulation 8 at day 26.

Embodiment A10 (prescription A10) to embodiment A12 (prescription A12)

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 A 13 (prescription A 13) to embodiment A 17 (prescription A 17)

Examples A13 to A17 further demonstrate that formulations containing the acrylic binder Duro-Tak 387-2516 are more stable to olanzapine crystallization as the CLM of crospovidone is increased.

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

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 A 22 (prescription A 22) to embodiment A 24 (prescription A 24)

For formulations A 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 .It means that crospovidone CL-M improves the stability against crystallization of olanzapine. 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 A 25 (prescription A 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 (contrast prescription A2) and comparative example 3 (contrast prescription A2)

Comparative formulation A2 and comparative formulation A3 contained liquid lactic acid and oleic acid in the absence of povidone, crospovidone CLM or Eudragit E100. Although no crystals formed after 48 days at room temperature, their physical properties and skin adhesion were unacceptable, as described in the Skin Adhesion, Fingertip, and Physical Properties sections.

Comparative example A4 (comparative prescription A4)

In order to prepare the comparative prescription A4, the mixed solution, olanzapine solution and excipient solution were prepared according to Table 2-1, Table 2-2 and Table 2-3 respectively. Wet formulation formulation A was then prepared according to Tables 2-4. The final dry formulation composition Recipe A is shown in Tables 2-5.

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

Table 2-4. Wet Recipe A

Table 2-5. Dry Recipe A

Embodiment A26 (prescription A26):

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 amount of Dura-Tak387-2287 (64.9g) of the adhesive Dura-Tak387-2287 of the prescription A into a glass bottle. DL-alpha tocopherol (0.0825 g), ascorbyl palmitate NF (0.0006 g), sodium metabisulfite (0.0004 g), 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 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 A27 was prepared using a similar method. At the time of writing this formulation did not form crystals. Povidone and Eudragit E100 effectively inhibited olanzapine crystal formation for 49 days at room temperature and 40 days at a storage temperature of 40°C.

Embodiment A28 (implementing prescription A28) and comparative example A7 (comparing prescription A7):

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

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 A7 (comparative prescription A7):

Olanzapine (3.15 g), DMSO (5.6 g) and oleic acid (3.5 g) were added to a glass jar. Mix to dissolve and form a clear solution. 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 A29 (prescription A29):

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

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

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 32 °C 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 A1 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 A 2 and Formulation A 8) remained much higher than that of the comparative formulation A 1.

Table 3. skin permeation flux (ug/cm2/hr): embodiment A1, embodiment A8 and comparative example A1

The in vitro skin flux of amorphous formulation A22 containing 15% by weight of crospovidone CL-M was higher than that of comparative formulation A2 without crospovidone CL-M or povidone K30 (Table 4, Figure 5). As will be described in the Skin Adhesion, Finger Test and Physical Properties section, Comparative Formulation A2 observed some adhesive transfer to the finger in the finger test (Comparative Example A12, 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 A22 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 A3 and comparative formulation A5 without crospovidone CL-M or povidone K30 (Table 4, Figure 5) . Physical properties of Comparative Formulation A3 and Comparative Formulation A5 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 A13, 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 A23 by increasing adhesive matrix cohesion and thus reducing adhesive transfer to the skin.

Although the in vitro skin flux of US20070148218A1 Example A1 was good due to the presence of skin penetration enhancers, as shown in Table 11 of the present application, excessive adhesive transfer to the finger was observed and formed in the finger test Binder flow (Comparative Example A15, Table 11), therefore the physical properties of Example A in 20070148218A1 are not acceptable.

Comparative Example A4: 4.6% fatty ester (lauryl lactate) was added to formulation A23 to obtain comparative formulation A4. The average skin flux of Comparative Example A4 was low relative to Example A23, indicating that the addition of liquid lauryl lactate reduced the average skin flux (Table 4, Figure 5). The addition of liquid lauryl lactate also reduced the integrity of the adhesive matrix. Therefore, there was some adhesive transfer to the finger in the finger test (Comparative Example A14, Table 11).

Table 4. Skin permeation flux (g/cm ² /hr): Examples A22-23, Comparative Examples A2-5

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

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

The average epidermal flux of Comparative Example A6 was similar to that of Example A25, and the results are shown in Table 6 (Figure 7). The fatty alcohol nonanol did not increase the skin penetration of olanzapine.

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

Example A26

The composition of prescription A26 of embodiment A26 is: 10% olanzapine, 10% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-alpha-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% coke Sodium Sulfite NF, 0.1% BHT, 59.5965% Dura-Tak 387-2287.

The prescription A contains a polymer skin penetration enhancer (10% povidone K90) and 10% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1). The skin penetration rate of this prescription A7 days is higher (Table 7, Figure 8), and from 100GSM (grams per square meter), 200GSM, 300GSM, 400GSM, the skin penetration rate increases with the increase of matrix thickness (coating weight) . 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 A39, Table 11).

Example A27

The prescription A27 of embodiment A27 consists of: 10% olanzapine, 15% oleic acid, 10% Eudragit E100, 10% K90, 0.3% D-alpha-tocopherol, 0.002% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.1% BHT, 54.5965 Dura-Tak 387-2287 (400GSM matrix layer).

This formulation A contains a polymer skin penetration enhancer (10% povidone K90) and 15% oleic acid. This system effectively inhibited the crystal formation of olanzapine (Table 1). Compared with Example A26, the 7-day skin penetration rate of this formulation A at 400GSM is higher (Table 7, Figure 8). At the same time the polymer skin penetration enhancer (10% Povidone K90) increased the cohesion of the adhesive, thereby reducing the transfer of the adhesive to the finger in the finger test (Example A40, Table 11).

Table 7. Skin permeation flux (μg/cm ² /hr): Example A26, Example A27

Embodiment A28 and Comparative Example A7

The composition of prescription A28 of embodiment A28 is: 9% olanzapine, 10% oleic acid, 16% DMSO (2.7% after drying), 65% Duro-Tak 87-900A (110GSM matrix layer).

The composition of the comparative prescription A7 of comparative example A7 is: 9% olanzapine, 10% oleic acid, 16% DMSO (3.5% after drying), 3.5% isopropyl palmitate, 3% myristyl alcohol, 3.5% GMO ( Glyceryl Monooleate), 55% Duro-Tak 87-900A (120GSM matrix layer).

The average epidermal flux of Comparative Example A7 was similar to that of Example A28, and the results are shown in Table 8 (Figure 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 A12, Table 11).

Example A28 and comparative formulation A7 did not contain the polymeric skin penetration enhancer povidone. Thus, both formulations formed olanzapine crystals on day 1. The skin flux of both formulations was much lower than that of formulations A26, 27 and 29 prepared according to preparation method 2 containing 10% povidone K90 and 10% oleic acid.

Table 8. Skin permeation flux (μg/cm ² /hr): Example A28 and Comparative Example A7

Example A29

The composition of prescription A29 of embodiment A29 is: 10% olanzapine, 15% oleic acid, 10% povidone K90, 0.5% DL-alpha tocopherol, 0.1% ascorbyl palmitate NF, 0.0015% sodium metabisulfite NF, 0.5% BHT, 63.8985% Duro-Tak 387-2510, 0.56% Polybutylate (600GSM matrix layer).

The formulation A29 of Example A29 contains a polymer skin penetration enhancer (10% povidone K90) and 10% to 20% oleic acid. This system was able to effectively inhibit the crystal formation of olanzapine (Table 1). The 14-day skin penetration rate of this formulation A is very high (Table 9, Figure 10), and it is the first formulation among all drug transdermal systems whose skin flux can satisfy the drug effect for up to 14 days. 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 A40, Table 11).

Table 9. Skin permeation flux (μg/cm ² /hr): Example A29

Embodiment A30 and comparative example A8

The composition of prescription A30 of Example A30 is: 8% olanzapine, 16% oleic acid, 5% KollidonCL-M, 0.5% butyl hydroxytoluene, 70.5% Duro-Tak87-900A.

The composition of the comparative prescription A8 of embodiment A8 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% KollidonCL-M, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87-900A .

Example A30 (prescription A30) did not contain 10% isopropyl palmitate, and Comparative Example A8 (comparative prescription A8) contained 10% isopropyl palmitate. The skin flux of Example A30 was higher than that of comparative formulation A8 (Table 10, Figure 11). In the finger test, comparative formulation A8 transferred more adhesive to the finger than formulation A30 (Table 11).

Example A31 and Comparative Example A9

The composition of prescription A31 of Example A31 is: 8% olanzapine, 16% oleic acid, 15% KollidonCL-M, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87-900A.

The composition of the comparative prescription A9 of embodiment A9 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% KollidonCL-M, 0.5% butyl hydroxytoluene, 50.5% Duro-Tak87-900A .

Example A31 (prescription A31) did not contain 10% isopropyl palmitate, and Comparative Example A9 (comparative prescription A9) contained 10% isopropyl palmitate. The skin flux of Example A31 was higher than that of Comparative Example A9 (Table 10, Figure 11). In the finger test, Comparative Formulation A9 transferred more adhesive to the finger than Formulation A31 (Table 11).

Example A32 and Comparative Example A10

The composition of prescription A32 of Example A32 is: 8% olanzapine, 16% oleic acid, 5% copovidone Kollidon64, 0.5% butylhydroxytoluene, 70.5% Duro-Tak87-900A.

The composition of the comparative prescription A10 of embodiment A10 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 5% copovidone Kollidon64, 0.5% butyl hydroxytoluene, 60.5% Duro-Tak87- 900A.

Example A32 (prescription A32) did not contain 10% isopropyl palmitate, and Comparative Example A10 (comparative prescription A10) contained 10% isopropyl palmitate. The skin flux of Example A32 was higher than that of Comparative Example A10 (Table 10, Figure 11). In the finger test, comparative formulation A10 transferred more adhesive to the finger than formulation A20 (Table 11).

Example A33 and Comparative Example A11

The composition of prescription A33 of embodiment A33 is: 8% olanzapine, 16% oleic acid, 15% copovidone Kollidon64, 0.5% butylated hydroxytoluene, 60.5% Duro-Tak87-900A.

The composition of the comparative formulation A11 of Example A11 is: 8% olanzapine, 16% oleic acid, 10% isopropyl palmitate, 15% copovidone Kollidon64, 0.5% 50.5% Duro-Tak87-900A.

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

Table 10. Skin permeation flux (ug/cm ² /hr): Examples A30-33, Comparative Examples A9-11

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 feel the front of your index finger for stickiness. 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 is expected to transfer from the patch adhesive to the finger and the lower the tack. Refer to Table 11 for the finger test results of each Example A.

Examples A34 and 35:

As shown in Table 11, formulation A8 (Example A34) and formulation A9 (Example A35) contained 15% by weight and 22% by weight of crospovidone CL-M, respectively, and no adhesive transfer to the index finger was observed.

Embodiment A36-37 and comparative example A12-13:

Formulation A22 (Example A36) and Formulation A23 (Example A37) containing 15% crospovidone CL-M also had no adhesive transfer to the fingers. In contrast, Comparative Formulation A2 (Comparative Example A12) and Comparative Formulation A3 (Comparative Example A13), which did not contain Crospovidone CL-M, Povidone K30, or Eudragit E100, had adhesive transfer to the fingers.

Comparative example A14 (comparative prescription A4):

The 4.6% lauryl lactate of Comparative Formulation A4 (Comparative Example A14) increased adhesive transfer to the fingers relative to Example A37 (Formulation A23).

Comparative example A15 (comparative prescription A5):

Comparative formulation A5 (comparative example A15) not only contained a very high content of liquid oleic acid (17.17%) and liquid isopropyl palmitate (8.59%), but also did not contain crospovidone CL-M, povidone K30 or EudragitE100, so severe adhesive transfer was observed in the finger test.

Embodiment A38 (prescription A24):

Formulation A24 contained the polymer Eudragit E100 and there was no adhesive transfer to the finger in the finger test.

Embodiment A39-40 (prescription A26-27):

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 A41 (prescription A28) and comparative example A16 (comparison prescription A7):

Example A41 contained no fatty acid esters or fatty alcohols, and despite the adhesive transfer due to the presence of high amounts of DMSO, the liner was still peeled off cleanly. Comparative Example A16 contained fatty acid ester isopropyl ester and fatty alcohol myristyl alcohol, and in the finger test, the release liner could not be removed and a large amount of adhesive transfer to the finger was observed.

Embodiment A42 (prescription A29):

Formulation A29 in Example A42 contained a sufficient amount of polymeric cohesion promoter that no adhesive transfer to the finger was observed in the finger test.

Embodiment A43 (prescription A30) and comparative example A17 (comparison prescription A8):

Example A43 with 5% curing agent Kolliodn CL-M (i.e. crospovidone CL-M) had only a small amount of adhesive transfer to the finger, but Comparative Example A17 with 10% isopropyl palmitate had a lot of adhesion The solution is transferred to the fingers.

Embodiment A44 (prescription A31) and comparative example A18 (comparative prescription A8):

Example A44 containing 15% curing agent Kolliodn CL-M (i.e. crospovidone CL-M) did not observe adhesive transfer to the fingers, but Comparative Example A18 containing 10% isopropyl palmitate had a lot of stickiness. The mixture is transferred to the fingers.

Embodiment A45 (prescription A32) and comparative example A19 (comparative prescription A8):

Example A45 with 5% curing agent copovidone VA64 had only a small amount of adhesive transfer to the finger, but Comparative Example A19 with 10% isopropyl palmitate had a large amount of adhesive transfer to the finger.

Embodiment A46 (prescription A33) and comparative example A20 (comparative prescription A8):

Example A46 with 15% curing agent copovidone VA64 had no adhesive transfer to the finger, but Comparative Example A20 with 10% isopropyl palmitate had substantial adhesive transfer to the finger.

Table 11. Summary of Finger Test Results

Placebo patch wear test

Placebo Patch Formulation A1 and Placebo Patch Formulation A2 described in Table 14 and Table 15 were prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain the olanzapine base . For placebo formulation A1, patches were prepared in two coating weights (454 GSM (grams per square meter of olanzapine)). One healthy volunteer participated in Placebo Wear Study #1 (Example A47). The skin on the left and right outer arms was cleaned with wet paper towels and dried with dry paper towels. The Formulation 1 patch was applied on the left upper outer arm. Apply the prescription A22 patch to the upper right outer arm. After the patches are applied, smooth them out to ensure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily. Adhesion was scored using a five-point scale from 0 to 4, as shown in Table 12. Primary skin irritation was scored using a 0-7 point scoring system as shown in Table 13.

The Skin Adhesion Score and Major Skin Irritation Score for Placebo Wear Study #1 (Example A47) are reported in Tables 16 and 17. Both the placebo prescription A1 patch and the placebo prescription A2 patch had low cohesion because insufficient amounts of crospovidone CLM or povidone K30 were used to avoid the use of large amounts of liquid excipients (lactic acid and lauryl lactate). As a result, in the finger test, a large amount of adhesive was transferred to the index finger (Table 11). Due to the low cohesion of the adhesive layer, in the placebo wear study, the placebo prescription A1 patch was very slippery, and the patch moved by itself on the upper arm after 28 hours of wearing, while the placebo prescription A2 patch had 80 % of the patch, lift after 12 hours of wearing.

Table 12. Skin Tackiness Score

黏附程度degree of adhesion	分数Fraction
≥90％(基本上不会从皮肤上翘起)≥90% (Basically no lifting from the skin)	00
≥75％至＜90％(只有一些边缘从皮肤上翘起)≥75% to <90% (only some edges are lifted from the skin)	11
≥50％至＜75％(不到一半的贴剂从皮肤上翘起)≥50% to <75% (less than half of the patch lifted from the skin)	22
＞0％至＜50％(超过一半的贴剂从皮肤上翘起但没有分离)>0% to <50% (more than half of the patch lifted from the skin but did not detach)	33
0％(贴剂完全从皮肤上分离)0% (patch completely detached from the skin)	44

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 A1 (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 formulation A2 (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 A1 (454GSM Adhesive Layer Thickness)

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

Table 17. Placebo Patch Wearing Test 1: Scoring of Placebo Patch Prescription A2 (426GSM Adhesive Layer Thickness)

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

Placebo patch wear test

Embodiment A47 (placebo prescription A3)

Placebo patch formulation A3 described in Table 18 was prepared using the same procedure described earlier for the olanzapine-containing patch formulation, except that it did not contain olanzapine. For placebo formulation A3, the 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 A47). Clean the outer skin of the upper arm with a damp paper towel and dry with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily.

The skin adhesion scores and major skin irritation scores for Placebo Wear Study #3 (Example A47) 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 A3 (backing film is Scotchpak 9733)

Table 21. Placebo patch prescription A4 (backing film is Scotchpak 9733)

Embodiment A48 (placebo patch prescription A4)

For placebo formulation A4, the coating weight of the patch was 400 GSM (grams per square meter). One healthy volunteer wore both patches in Placebo Wear Study #3 (Example 48). The skin of the upper left foreleg was cleaned with a wet paper towel and dried with a dry paper towel. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Adhesion and irritation scores (based on skin itching and skin appearance such as redness) were recorded daily.

The skin adhesion scores and major skin irritation scores for Placebo Wear Study 3 (Example A48) 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.

Example B1

Take each composition component by weighing according to table 24 and prepare prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50°C. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 24, the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment B, the weight ratio of rotigotine to soluble povidone is 9:3, and the ratio of rotigotine to insoluble povidone is 9:6.8.

Example B2

Take each composition component by weighing according to table 24 and prepare prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C and mixed with insoluble crospovidone CL-M at room temperature for 24 hours. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50°C. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 24, the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment B, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble povidone is 9:8.

Example B3

Take each composition component by weighing according to table 24 and prepare prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 heated to 50°C. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 24, the patch samples did not form crystals when stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment B, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:9.

Table 24. Comparative Examples B1 to B5, Examples B1 to B3

Comparative Example B6

Take each composition component by weighing according to table 25 and prepare prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in toluene at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of polyisobutylene binders Oppanol B12 and Oppanol N100 in toluene at room temperature was added and mixed. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, crystal formation was observed as early as day 8 for patch samples stored at 40°C. In this Example B, without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 9:3. In this Comparative Example B, the wet mixture was maintained at room temperature, ie not heated above room temperature, to maintain the dissolution of rotigotine in the wet mixture.

Comparative Example B7 to Comparative Example B11

The patch samples of Comparative Example B7 to Comparative Example B11 were prepared using a method similar to that of Comparative Example B6. Take each composition component by weighing according to table 25 and prepare prescription. The amount of insoluble crospovidone was increased to 10%, 13%, 16.65%, 18% and 20%, respectively. The patch samples of Comparative Example B7 to Comparative Example B11 all formed crystals, but as the amount of insoluble crospovidone increased, the formation of crystals was more and more delayed. In these Comparative Examples B, the wet mixture was maintained at room temperature, ie not heated above room temperature, to maintain the dissolution of rotigotine in the wet mixture.

Example B4

Take each composition component by weighing according to table 25 and prepare prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in toluene at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in toluene heated to 50°C was added and mixed. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed for patch samples stored at 60°C for 10 days and stored at 40°C for 1 month. In this Example B, without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 9:21. In this Example B, the wet mix was maintained at 50°C to maintain rotigotine dissolved in the wet mix prior to coating.

Example B5

Take each composition component by weighing according to table 25 and prepare prescription. Example B5 was prepared using a method similar to that of Example B4. As shown in Table 25, no crystals were observed for the patch samples after 10 days of storage at 60°C and 1 month at 40°C. In this Example B, without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 7.5:20 or 9:24. In this Example B, the wet mix was maintained at 50°C to maintain rotigotine dissolved in the wet mix prior to coating.

Example B6

Take each composition component by weighing according to table 25 and prepare prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in isopropanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed on the 10th day of storage of the patch samples at 60°C. In this Example B, without soluble povidone, the ratio of rotigotine to insoluble crospovidone was 7.5:20 or 9:24. In this Example B, the wet mix was maintained at 50°C to maintain rotigotine dissolved in the wet mix prior to coating.

Comparative Example B12

Take each composition component by weighing according to table 25 and prepare prescription. Povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in isopropanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, crystallization was observed on day 3 of patch samples stored at room temperature. In this embodiment B, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:3.6.

Example B7

Take each composition component by weighing according to table 25 and prepare prescription. Povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in isopropanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed on the patch samples stored at 60°C for 10 days, and no crystals were observed at 40°C for 1 month. In this embodiment B, the weight ratio of rotigotine to crospovidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:12.

Example B8

Take each composition component by weighing according to table 25 and prepare prescription. Povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in isopropanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. A solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C was added and mixed. The suspension was incubated at 50 °C, coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 25, no crystals were observed on the patch samples stored at 60°C for 10 days, and no crystals were observed at 40°C for 1 month. In this embodiment B, the ratio of rotigotine to crospovidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:18.

Table 25. Comparative Examples B6 to 12, Examples B4 to B8

Comparative Example B13

Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, crystals were observed in patch samples stored at room temperature for 6 months and at 40°C on day 22. In this example B, the ratio of rotigotine to insoluble crospovidone is 7.5:6 or 9:7.2.

Comparative Example B14

Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, crystals were observed on day 62 of patch samples stored at 40°C. In this example B, the ratio of rotigotine to insoluble crospovidone is 7.5:10 or 9:12.

Comparative example B15

Take each composition component by weighing according to table 26 and prepare prescription. Soluble povidone K90, ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol at 50°C and then mixed at room temperature for 24 hours. The solution was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, crystals were observed when the patch samples were stored at room temperature for 6 months. In this embodiment B, the weight ratio of rotigotine to soluble povidone is 9:4.

Example B9

Take each composition component by weighing according to table 26 and prepare prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble crospovidone CL-M was mixed for 24 hours at room temperature. The solution was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, no crystals were observed for the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this Example B, the ratio of rotigotine to insoluble soluble crospovidone was 9:20.

Example B10

Take each composition component by weighing according to table 26 and prepare prescription. The formulation in Example B10 was prepared using the same method as in Example B9. As shown in Table 26, no crystals were observed in the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this embodiment B, the weight ratio of rotigotine to insoluble crospovidone is 9:22.8.

Example B11

Take each composition component by weighing according to table 26 and prepare prescription. Soluble povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Crospovidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C, rotigotine was added and dissolved completely as indicated by microscopic analysis. Add and mix Bio-PSA 7-4502 and Duro-Tak 387-2287. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 26, no crystals were observed for the patch samples stored at room temperature for 11 months and at 40°C for 6 months. In this embodiment B, the weight ratio of rotigotine to insoluble povidone is 9:5, and the weight ratio of rotigotine to soluble povidone is 9:3.

Examples B12 to B14

Take each composition component by weighing according to table 26 and prepare prescription. The formulations of Examples B12 to 14 were prepared using the same method as Formulation 11 of Example B11. As shown in Table 26, no crystals were observed for the patch samples stored at room temperature for 9 months and at 40°C for 6 months.

Table 26. Comparative Examples B13 to 15 and Examples B9 to B14

Example C1

Take each composition component by weighing according to table 27 and prepare prescription. Soluble povidone K90 was dispersed in ethyl acetate, and oleic acid and Eudragit EPO were added to form a solution. Add Crospovidone CL-M and mix for 24 hours at room temperature. Donepezil free base was added with mixing and microscopic analysis indicated complete dissolution. Add and mix Duro-Tak 387-2516. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 27, no crystals were observed in patch samples stored at room temperature for 9 days or 24 days, stored at 40°C for 1 month, and stored at 60°C for 1 month for 9-10 days.

Example C2

Take each composition component by weighing according to table 27 and prepare prescription. Dissolve HPMC K15M in a mixture of isopropanol and water (90:10), add oleic acid and Eudragit EPO to form a solution. Add Crospovidone CL-M and mix for 24 hours at room temperature. Donepezil free base was added with mixing and microscopic analysis indicated complete dissolution. Add and mix Duro-Tak 387-2516. The suspension was coated on a release film and dried at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent. As shown in Table 27, no crystals were observed in patch samples stored at room temperature for 9 days or 24 days, stored at 40°C for 1 month, and stored at 60°C for 1 month for 9-10 days

Table 27

Example C3

In vitro permeation tests were performed using the same vertical statically modified Franz cell as olanzapine. See Table 28 for the measurement results of the skin penetration flux of donepezil, and see Figure 12 for the measurement curve of the skin flux.

Table 28 Skin Permeation Flux (ug/cm ² /hr): Examples C1-C2

Claims

A transdermal drug delivery system comprising:

1) backing layer;

2) a matrix layer comprising a drug or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting crystallization of the drug, and a pressure-sensitive adhesive;

3) Release layer.
The transdermal drug delivery system according to claim 1, wherein the stabilizer for inhibiting drug crystallization is polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer (preferably povidone K30, povidone K90, Povidone K12, Povidone K17, Povidone K25, Plasmidone K29/32, Copovidone VA64, Crospovidone CL-M, Crospovidone CL, Crospovidone CL- F, crospovidone CL-SF), hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose One or more of propylbetad, α, β, λ cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, or carrageenan.
The transdermal drug delivery system according to claim 1, wherein the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizer for inhibiting drug crystallization, soluble stabilizer for inhibiting drug crystallization or a combination thereof.
The transdermal drug delivery system according to claim 3, wherein the insoluble stabilizer for inhibiting drug crystallization is selected from insoluble cross-linked povidone, preferably insoluble cross-linked povidone CL-M, cross-linked povidone CL, crospovidone CL-F, crospovidone CL-SF.
The transdermal drug delivery system according to claim 4, wherein the stabilizer for inhibiting drug crystallization further comprises a soluble stabilizer for inhibiting drug crystallization on the basis of an insoluble drug crystallization inhibitor; preferred soluble drug crystallization inhibitor The crystallization stabilizer is selected from soluble povidone, more preferably povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, copovidone VA64 one or more of.
The drug delivery system according to any one of claims 1-5, wherein the matrix layer further comprises other pharmaceutically acceptable adjuvants, and the other pharmaceutically acceptable adjuvants are preferably skin penetration enhancers, thickeners One or more of agents, cohesion-promoting additives.
According to the drug delivery system according to any one of claims 1 to 6, relative to the total weight of the matrix layer, the matrix layer comprises the following components:

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

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

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

4) Tackifier 0-50%;

5) Skin penetration enhancer 0-30%;

6) Cohesion-promoting additive 0-20%;

The amount of each component in the matrix layer is 100% in total.
According to the transdermal drug delivery system according to any one of claims 1 to 3, the matrix layer further comprises 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.
The transdermal drug delivery system according to any one of claims 1-4, wherein the pressure-sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene- One of isoprene-styrene block copolymer adhesives, styrene-butadiene-styrene copolymer adhesives, silicone adhesives, acrylic-copolysiloxane copolymer adhesives one or more kinds;

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 and mineral oil tackifier from Ineos ;

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-PSA7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, so Said solvent is selected from one or more of n-heptane, ethyl acetate and toluene or hot melt.
The transdermal drug delivery system according to any one of claims 1-9, wherein the drug or its pharmaceutically acceptable salt content is 5% to 20% of the total weight of the matrix layer, preferably 5% to 15% , or 5% to 12%, 7.5%.
The rotigotine transdermal delivery system according to any one of claims 1-11, wherein the content of the stabilizer for inhibiting drug crystallization is 6% to 40% of the total weight of the matrix layer, preferably 6% to 30% %, 6% to 20%, 6.7%-20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.
The transdermal drug delivery system according to any one of claims 1-11, wherein the content of the insoluble stabilizer for inhibiting drug crystallization is 5 to 40% of the total weight of the matrix layer, preferably 5%, 7.5%, 10% %, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 30%, 35%, 40%, 45%; the preferred insoluble stabilizer for drug crystallization is selected from insoluble cross-linked polydimensional Ketone CL-M, Crospovidone CL, Crospovidone CL-F, Crospovidone CL-SF.
The transdermal drug delivery system according to any one of claims 1-12, wherein the content of the soluble stabilizer for inhibiting drug crystallization is 2 to 40% of the total weight of the matrix layer, preferably 2-30%, 5- 30%, 5-24%, 10-20%, 12.5-20%, 2.5%, 3.4%, 4%, 5%; the preferred soluble stabilizer for inhibiting drug crystallization is selected from soluble povidone, preferably vitamin One or more of ketone K30, povidone K90, povidone K12, povidone K17, povidone K25, plastone K29/32, and copovidone VA64.
The transdermal drug delivery system according to any one of claims 1-13, wherein the content of the pressure-sensitive adhesive is 35% to 90%, preferably 40% to 80%, and 35% to 90% of the total weight of the matrix layer. 90%, 45% to 65%, 65%, 70%, 75%, 80%, 90%.
The transdermal drug delivery system according to any one of claims 1-14, wherein the matrix layer further comprises other pharmaceutically acceptable adjuvants, and the other pharmaceutically acceptable adjuvants are preferably skin penetration enhancers, One or more of tackifiers and cohesion-promoting additives.
The transdermal drug delivery system according to claims 6-15, wherein the skin penetration enhancer includes one or more of C2 to C30 saturated or unsaturated fatty acids, surfactants, lauroazepine.
The transdermal drug delivery system according to claim 16, wherein the C2 to C30 saturated or unsaturated fatty acid is selected from C2 to C20 saturated or unsaturated fatty acid, preferably one of oleic acid, isostearic acid or stearic acid or Various.
The transdermal drug delivery system according to any one of claims 6-17, wherein the tackifier is selected from silicone oil, mineral oil, polybutene, terpene and mixtures thereof, preferably light mineral oil; further, the thickener The amount of adhesive used is 0-50%, preferably 0-30%, of the total weight of the matrix layer.
According to the transdermal drug 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 transdermal drug delivery system described in any one of claims 1-19, the drug is selected from the group consisting of olanzapine (Olanzapine), rotigotine (rotigotine), donepezil (Donepezil), almotriptan (Almotriptan) ), aripiprazole, apixaban, asenapine, baricigtinib, bisoprolol, blonanserin, butyl Buprenorphine, Dextroamphetamine, Dexmedetomidine, Eletriptan, Escitalopram, Frovatriptan, Gravatriptan Granisetran, Indomethacin, Lasmiditan, Meloxicam, Naratriptan, Naproxen, Oxybutynin ( Oxybutynin, Piroxicam, Pramipexole, Rizatriptan, Ropinirole, Sumatriptan, Tolubuterol, Testosterone ( Testosterone) and Zolmitriptan (Zolmitriptan) or a pharmaceutically acceptable salt thereof.
A method for preparing the transdermal drug delivery system according to any one of claims 1-19, comprising the following steps:

Step 1. Dissolving the drug or its pharmaceutically acceptable salt in a solvent as premix A; preferably, the solvent includes but not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, One or more of dimethyl sulfoxide and ethyl acetate, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof;

Step 2. mix the pressure-sensitive adhesive solution with the stabilizer for inhibiting drug crystallization to obtain premix B; the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizer for inhibiting drug crystallization, soluble stabilizer for inhibiting drug crystallization Stabilizer or combination thereof; Mixing time is preferably 0.1 hour to 24 hours;

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

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

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

Step 6. Laminate the substrate layer to the backing layer.
A method for preparing the transdermal drug delivery system according to any one of claims 1-19, comprising:

Step 1. Dissolve the stabilizer that inhibits drug crystallization in a solvent and mix well. Preferably, the solvent includes but is not limited to water, toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, acetic acid One or more of ethyl esters, the solvent is more preferably water, toluene, ethanol, isopropanol, ethyl acetate or a mixed solvent thereof; the stabilizer for inhibiting drug crystallization is selected from insoluble stabilizers for inhibiting drug crystallization , a soluble stabilizer for inhibiting drug crystallization or a combination thereof; the mixing time is preferably 0.1 hour to 24 hours;

Step 2. Add the drug or its pharmaceutically acceptable salt, mix and dissolve until dispersed in an amorphous state;

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

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

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

Step 6. Laminate the substrate layer to the backing layer.
The method according to claim 21 or 22, wherein said step 2 includes the step of heating to 30-65°C to make the drug in a dissolved state; the heating temperature is preferably 35-60, 35-45, 45-55°C.
The method according to any one of claims 21-23, wherein said step 3 is to add a pressure-sensitive adhesive heated to 35-65°C and mix uniformly to obtain a wet mixture of medicine; the heating temperature is preferably 35-60°C, 35-45, 45-55°C.
The method according to any one of claims 21-23, wherein step 4 is to coat the wet drug mixture on the release film at 35-65° C.; the heating temperature is preferably 35-60, 35-45, 45-55°C.
Use of a therapeutically effective amount of the transdermal drug delivery system according to any one of claims 1-25 in the preparation of medicaments for treating or preventing diseases.
A method for treating or preventing a disease, comprising administering a therapeutically effective amount of the transdermal drug delivery system according to any one of claims 1-25 to a subject in need.