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CN110585174A - Transdermal sustained-release patch for resisting schizophrenia - Google Patents

Transdermal sustained-release patch for resisting schizophrenia Download PDF

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Publication number
CN110585174A
CN110585174A CN201910813455.8A CN201910813455A CN110585174A CN 110585174 A CN110585174 A CN 110585174A CN 201910813455 A CN201910813455 A CN 201910813455A CN 110585174 A CN110585174 A CN 110585174A
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China
Prior art keywords
sensitive adhesive
drug
transdermal
aripiprazole
release patch
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CN110585174B (en
Inventor
叶金翠
张琪
江昌照
高文彦
郑高利
曹晓春
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Hangzhou Pa Orchids Pharmaceutical Technology Co ltd
Zhejiang Academy of Medical Sciences
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Hangzhou Pa Orchids Pharmaceutical Technology Co ltd
Zhejiang Academy of Medical Sciences
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

A transdermal sustained-release patch for resisting schizophrenia belongs to the field of pharmaceutical preparations, and comprises a back lining layer, a pressure-sensitive adhesive storage layer and an anti-adhesion layer; the pressure sensitive adhesive storage layer comprises 1-12% of aripiprazole, 10-35% of a penetration enhancer, 60-80% of a viscous polymer and 0.5-2% of a drug stabilizer by weight ratio. The transdermal sustained-release patch can enable the drug to reach higher blood concentration through the skin within 24 hours, can keep the blood concentration stable within 5-6 days, and is expected to achieve the effects of long acting, convenient use and good drug compliance of patients in clinical application. The transdermal sustained-release patch pressure-sensitive adhesive storage layer comprises a drug, a transdermal enhancer, an adhesive polymer and a drug stabilizer. Wherein the adhesive polymer is a mixture of at least two lipophilic adhesive polymers and at least one hydrophilic adhesive polymer; wherein the penetration enhancer is a mixed penetration enhancer containing a penetration enhancer with an emulsifying effect.

Description

Transdermal sustained-release patch for resisting schizophrenia
Technical Field
The invention relates to the field of medicinal preparations, in particular to an anti-schizophrenia percutaneous sustained-release patch and a preparation method thereof.
Background
Schizophrenia affects 1% of the global population and is more frequent in young adults. Schizophrenia affects the patient's thinking, emotional control, and decision-making ability. Patients with positive schizophrenia may develop hallucinations and delusions, while patients with negative symptoms may avoid social interaction and lack of emotional changes. In the onset of the disease, the self-disorder is mainly taken as the core, so that the consciousness of a patient is lowered, the consciousness control is disordered, the cognition of things is deviated, and finally the serious consequence of the patient caused by hallucinations is caused. Clinically, the aripiprazole has obvious curative effects on positive and negative symptoms of schizophrenia, anxiety, depression and cognitive function, and has higher safety compared with a typical antipsychotic and a similar atypical antipsychotic. It has also been reported that the medicine can also be used for treating other mental disorder diseases, such as manic episode of affective disorder, senile dementia accompanied with mental disorder, anxiety, child behavior disorder, depression, etc.
Aripiprazole is a quininone derivative widely used for the treatment of various schizophrenia, and its pharmacological action is characterized by postsynaptic dopamine D2Receptor antagonistsAnd is presynaptic dopamine D2A receptor agonist. Also has agonism D1、D3、D4The action of the receptor; for 5-HT1AThe receptor has dual effects of partial receptor antagonism or activation; for 5-HT2AThe receptor has a completely antagonistic effect. By pair D2And 5-HT1APartial agonism of receptor and on 5-HT2AAntagonism of the receptor produces an anti-schizophrenic effect. Are distinct from the first generation and atypical antipsychotics and are therefore referred to as dopamine system stabilizers or third generation antipsychotics.
Currently, aripiprazole preparations are marketed at home and abroad in the form of tablets, orally disintegrating tablets and injections, and the elimination half-life of aripiprazole is long, but most patients need to continue administration for 14 days to reach a steady-state concentration of the active ingredient, with the concomitant side effects of gastrointestinal tract such as anorexia, nausea, vomiting, etc. Compared with the common pharmaceutical preparations such as oral administration, injection and the like, the aripiprazole transdermal sustained-release patch has the unique advantages that: the medicine generates stable and lasting blood concentration through skin, has no peak valley phenomenon of oral blood concentration, can avoid gastrointestinal degradation of the medicine and liver first pass effect, and has small side effect; the stable and effective blood concentration is kept, so that the administration times are reduced, the administration interval is prolonged, and the medication compliance of a patient is improved; the medicine can be withdrawn at any time according to the treatment requirement so as to interrupt the administration, thereby improving the safety of the medicine, being convenient to use and being particularly suitable for the old, children, patients who are not suitable for oral administration and the like.
So far, no reports on the market of aripiprazole transdermal drug delivery preparations are seen at home and abroad, and the invention provides the transdermal sustained-release patch with long effect, safety, convenient use and good patient compliance for resisting schizophrenia.
Disclosure of Invention
In order to overcome the defects of the existing aripiprazole preparations, in particular to the problem of poor compliance of patients to long-term use of aripiprazole, the invention provides a transdermal sustained-release patch of aripiprazole.
The purpose of the invention is realized by the following technical scheme: a transdermal sustained release patch for resisting schizophrenia comprises a back lining layer, a pressure-sensitive adhesive storage layer and an anti-adhesion layer; the pressure sensitive adhesive storage layer comprises 1-12% of aripiprazole, 10-35% of a penetration enhancer, 60-80% of a viscous polymer and 0.5-2% of a drug stabilizer by weight ratio. The penetration enhancer is a mixed penetration enhancer containing a penetration enhancer with an emulsifying effect, and the penetration enhancer with the emulsifying effect accounts for 30-50% of the weight of the mixed penetration enhancer. The viscous polymer is composed of lipophilic viscous polymer and hydrophilic viscous polymer, wherein the lipophilic viscous polymer is a mixture of at least two kinds of lipophilic viscous polymers, and the mixture of the lipophilic viscous polymers accounts for 75-95% of the total viscous polymers. The penetration enhancer with emulsification function is one or more of caprylic acid monoglyceride of lauric acid, oleic acid, linoleic acid monoglyceride, ethyl oleate, glyceryl behenate, span 20, span 40 and span 80 which are mixed according to any proportion.
Further, the content of the drug aripiprazole is preferably 2-10%.
Further, the hydrophilic adhesive polymer is a cyclodextrin derivative such as hydroxypropyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, methyl- β -cyclodextrin, sulfonic- β -cyclodextrin and glucosyl- β -cyclodextrin, and one or more of chitosan, polyvinylpyrrolidone and cellulose derivative are mixed in an arbitrary ratio; the lipophilic adhesive polymer includes polyacrylate pressure sensitive adhesive, polyisoprene, polyisobutylene, and silicone copolymer.
Further, the cyclodextrin derivative is preferably hydroxypropyl- β -cyclodextrin or hydroxyethyl- β -cyclodextrin.
Further, the lipophilic viscous polymer is preferably polyacrylate pressure-sensitive adhesive and polyisobutylene, and the polyacrylate pressure-sensitive adhesive accounts for 37-75% of the weight of the lipophilic viscous polymer.
Further, the mixed penetrant also comprises two or more of laurocapram, 1, 2-propylene glycol, diethylene glycol monoethyl ether, lauryl alcohol, oleyl alcohol, menthol, caprylic/capric polyethylene glycol glyceride, dodecyl methyl sulfoxide, dimethyl sulfoxide, caprylic monoglyceride, tween-80 and polyoxyethylene castor oil, wherein one of the two or more is 1, 2-propylene glycol and accounts for 30% -65% of other penetration enhancers. The content of the mixed penetrant is preferably 10-30%.
Further, the drug stabilizer is one or more of dibutyl phenol, butyl hydroxy toluene, vitamin E, propyl perlate, anhydrous sodium sulfite and sodium metabisulfite which are mixed according to any proportion.
A preparation method of a transdermal sustained-release patch for resisting schizophrenia specifically comprises the following steps:
(1) weighing 1-12% of aripiprazole, 10-35% of transdermal enhancer, 60-80% of viscous polymer and 0.5-2% of drug stabilizer according to the weight ratio.
(2) Adding 1-12% aripiprazole into the whole amount of penetration enhancer with emulsifying effect and the whole amount of other oil-soluble promoters for dissolving, adding the whole amount of 1, 2-propylene glycol under stirring, adding 60-80% viscous polymer and 0.5-2% drug stabilizer, mixing uniformly, degassing to obtain the pressure-sensitive adhesive storage layer.
(3) And coating the pressure-sensitive adhesive storage layer on the anti-sticking layer, drying at 80 ℃ for 35-45min, and covering the back lining layer on the surface of the pressure-sensitive adhesive storage layer to obtain the aripiprazole transdermal sustained-release patch.
The invention has the following beneficial effects: the aripiprazole sustained-release patch can be used for treating schizophrenia, mania, depression, anxiety and children mental disorder diseases, and has the advantages of slow and long-acting release, stable blood concentration and high patient compliance. The invention requires the transdermal enhancer with emulsification, mainly the drug aripiprazole has small water solubility and fat solubility, and the skin permeation with larger molecular weight is difficult, but the transdermal enhancer with emulsification has good transdermal effect on the drug, and also has good promotion effect on the dissolution of the drug in a formula, so that the drug is not crystallized, and has unexpected effect; the content of the mixed penetration enhancer accounts for 10-35% of the total weight, if the content of the mixed penetration enhancer is lower than 10%, the medicine cannot reach effective concentration due to poor skin penetration performance, and if the content of the mixed penetration enhancer is higher than 35%, the medicine adhesion effect is influenced; the main medicine in the pressure-sensitive adhesive storage layer accounts for 1-12% by weight, if the weight ratio is less than 1%, the medicine cannot meet the skin permeation requirement, the treatment effect is reduced due to insufficient dosage, and if the weight ratio is higher than 12%, the medicine is easy to crystallize; the adhesive polymer in the pressure sensitive adhesive storage layer has pressure sensitive characteristic, so that the pressure sensitive adhesive storage layer can be adhered to the skin, the adhesive polymer in the invention accounts for 60-80% by weight, if the dosage is less than 60%, the adhesive capacity is insufficient to cause the falling of the patch in the medication process, if the dosage is more than 80%, the transdermal permeability of the drug is affected due to the fact that the dosage accounts for too high, meanwhile, the lipophilic adhesive polymer in the adhesive polymer accounts for 75-95% of the total adhesive polymer, if the lipophilic adhesive polymer is less than 75%, the drug cannot be completely dissolved, the treatment effect of the drug is reduced, and if the lipophilic adhesive polymer is more than 95%, the skeleton of the drug storage layer is too tight, so that the permeation rate of the drug is reduced. The lipophilic adhesive polymer in the pressure-sensitive adhesive reservoir layer of the present invention, which is composed of a mixture of two or more lipophilic adhesive polymers, is intended for regulating the skin permeability of a drug in a patch and the adhesion of the patch, and achieves a significant effect in regulating the drug permeability and the adhesion of the patch, compared to the use of one lipophilic adhesive polymer. The drug stabilizer in the pressure-sensitive adhesive storage layer is used for protecting aripiprazole so that the quality of the aripiprazole is stable, the content of the drug stabilizer accounts for 0.5-2% of the total weight, if the dosage is less than 0.5%, the drug protection effect is poor, the requirements of the drug using, storing and transporting process are not met, and if the dosage is more than 2%, the dosage exceeds the use limit of the substances in the drug due to overlarge dosage. The aripiprazole transdermal sustained-release patch of the present invention is a safe and effective transdermal patch capable of effectively supplying aripiprazole for a plurality of days.
Drawings
FIG. 1 is the cumulative transdermal flux of the drug of example 1;
FIG. 2 is the cumulative transdermal flux of the drug of example 2;
FIG. 3 shows the pharmacodynamic evaluation results;
FIG. 4 is the cumulative transdermal flux of the drug of example 3;
FIG. 5 is a graph showing the cumulative transdermal permeation amounts of the drugs of comparative example 1, comparative example 2 and example 4;
FIG. 6 shows the results of pharmacokinetic experiments.
Detailed Description
Aripiprazole was originally developed by Otsuka Pharmaceutical corporation of Japan and marketed in the United states 11 months in 2002, but such oral drugs require long-term daily administration, and aripiprazole tablets reach a maximum blood concentration within 2-4 hours and then gradually decrease, and the peak-valley phenomenon of the blood concentration is obvious. The long-acting aripiprazole injection can be stably kept above 42.980ng/mL (intermediate blood concentration) from 69 days to 83 days, and the drug can be remained in the body for a long time after being injected once, so that the onset time can reach 1 month, but the drug can not be withdrawn at any time after being injected, and although the compliance of a patient to the drug administration is improved, the drug administration process can not be controlled or stopped, so that the adverse factor on the safety exists. The aripiprazole sustained-release patch provided by the invention can maintain the drug effect for 5-6 days after one-time administration, has stable blood concentration and convenient use, can be withdrawn at any time according to the requirement, and meets the requirements of effectiveness, safety and high compliance required by the drug.
In the pressure sensitive adhesive storage layer, the aripiprazole, the penetration enhancer, the adhesive polymer and the drug stabilizer respectively account for 1-12%, 10-35%, 60-80% and 0.5-2% of the total weight of the pressure sensitive adhesive storage layer.
The invention adopts the combination of the lipophilic viscous polymer and the hydrophilic viscous polymer, when the lipophilic viscous polymer accounts for 75 to 95 percent of the total viscous polymer, the reservoir layer skeleton loose degree of the preparation is optimum for drug release, and the skin permeation rate of the drug is obviously improved compared with other proportions.
The penetration enhancer adopted by the invention is a combination of two or more penetration enhancers with emulsification and other penetration enhancers. Such as linoleic acid monoglyceride, laurocapram, span 20, 1, 2-propanediol combinations, and the like, the combination of the penetration enhancers has a synergistic penetration enhancing effect on aripiprazole penetration enhancement.
The drug stabilizer in the pressure sensitive adhesive drug storage layer has the protection effect on the aripiprazole so as to keep the drug quality stable. It can be one or more of dibutyl phenol, butyl hydroxy toluene, vitamin E, propyl perylate, anhydrous sodium sulfite and sodium metabisulfite, and the total amount accounts for 0.5-2% of the total weight of the pressure sensitive adhesive storage layer.
The backing layer used in the present invention is used to cover and protect the drug reservoir layer, and the backing layer is a flexible and soft and comfortable impermeable film applied on the skin, and can be made of high density polyethylene, low density polyethylene, polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, polyester, pyrrolidone, polyvinyl alcohol, polyurethane, metal aluminum foil, or the like, or a composite film of the aforementioned high polymer and metal aluminum foil.
The anti-adhesion layer used in the present invention is used to cover and protect the drug reservoir layer, and for easy removal before use, the anti-adhesion layer may be formed of a polyester film or paper, a polyethylene film, a polystyrene film, a polypropylene film, a siliconized polyester film, an aluminum foil, a siliconized aluminum foil, or a silicon paper, the surface of which is treated with silicone oil for anti-adhesion.
The patch provided by the invention is used for evaluating the realizability of the transdermal drug permeation target and the treatment effect through in-vitro skin permeation test, pharmacokinetics and pharmacodynamics research.
The following are specific evaluation methods:
in vitro skin permeation test: a Valia-Chien double-chamber permeation cell is used for carrying out an in-vitro skin permeation test to evaluate the percutaneous permeation condition of the medicine, the dehaired skin on the back of an in-vivo rabbit (mouse) is fixed on the permeation cell, the epidermal layer faces outwards, a patch is attached to the epidermal layer, and 4mL of physiological saline containing 40% of polyethylene glycol 400 is added into a receiving chamber. The effective area of the pool opening is about 0.65cm2The sample was taken at a constant temperature of 32 ℃ through a jacket of a water bath in a permeation cell while stirring with star-shaped magnetic particles at 500rpm, and an equal amount of the receiving solution was added after sampling. The concentration of drug in the permeate was determined by HPLC. The skin permeation rate of the drug was calculated by plotting the cumulative permeation Q over time versus time t.
Rat pharmacokinetic experiments: the blood concentration is determined by a liquid chromatography-mass spectrometry (LC-MS) method, and the oral administration is carried out by aripiprazole suspensionFor control, the pharmacokinetics of the aripiprazole sustained release patch through the dorsal skin of rats was studied. Patch group: removing hair on the back of rat with electric shaver, cleaning hair-removed part with clear water, wiping, and applying 20cm aripiprazole slow-release patch2And removing the patch at 144 hours (6 days), and taking 0.5mL of blood at the 4 th, 10 th, 16 th, 24 th, 32 th, 48 th, 56 th, 72 th, 96h, 120h and 144h before administration (0h) and after administration (from the patch application) and at the 24 th and 48 th tail breakage after removing the patch, placing the blood in a heparin anticoagulation test tube, centrifuging, taking the blood plasma, storing the blood plasma in a refrigerator at 20 ℃ below zero, and storing the blood plasma for testing. Oral suspension group: preparing aripiprazole suspension (2mg/mL) by using 1% sodium carboxymethylcellulose, performing intragastric administration according to the dose of 10mg/kg, respectively performing tail breaking and blood taking for 0.5h before (0h) and after (0.25 h, 0.5h, 1,2, 4, 6, 8, 10, 24h and 48 h), placing a heparin anticoagulation test tube, centrifuging, and storing plasma in a refrigerator at-20 ℃ for cold storage to be tested.
Rat pharmacodynamic test: an overactive rat model is established by a method of injecting 5-hydroxytryptophan (5-HTP) into the abdominal cavity of a rat at 300mg/kg/2h to induce the rat to swing. After the first injection, the rat back is unhaired by an electric shaver, the unhaired part is cleaned and wiped dry by clear water, and the aripiprazole sustained-release patch provided by the invention is pasted by 20cm2Counting the number of times of shaking heads of mice for 10min after observing 1h, 24h, 48h, 72h, 96h, 120h, 144h and 168h after administration, counting the number of times of shaking heads of mice with the aripiprazole patches and control mice without administration, and observing the effect of the medicament.
The optimized combined formula is obtained through the pharmaceutics research of the aripiprazole transdermal drug delivery patch, the patch can enable the drug to reach higher blood concentration within 24 hours after penetrating through the skin, and the drug can keep the blood concentration stable within 5-6 days, the patch is expected to be used clinically to achieve the effects of long acting, convenient use and good drug compliance of patients, and the defect of poor compliance caused by the fact that the patients need to take the drug for multiple times for a long time when the drug is orally taken is overcome.
The present invention will be described in detail below with reference to the drawings and examples, and the object and effect of the present invention will become more apparent.
Example 1:
prescription (100g charge):
adding aripiprazole into ethyl oleate, span-20 and menthol for dissolving, adding 1, 2-propylene glycol under high-speed homogeneous stirring, then respectively adding polyacrylate and polyisobutylene, stirring uniformly, finally adding hydroxypropyl-beta-cyclodextrin and anhydrous sodium sulfite, stirring uniformly, removing bubbles by ultrasonic waves, standing and completely eliminating bubbles to obtain a pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, covering the backing layer on the surface of the pressure sensitive adhesive storage layer, and cutting into 50cm2The aripiprazole transdermal sustained-release patch is prepared.
The aripiprazole transdermal sustained-release patch is subjected to a Valia-Chien permeation cell human in-vitro skin permeation test, and a receiving solution is 40% polyethylene glycol physiological saline. As shown in FIG. 1, the permeation rate of the above patch to the excised skin was measured to be 4.2. mu.g/cm2The medicinal preparation has long-term stable administration characteristics, 50cm2The patch corresponds to a daily oral dosage of 5.04mg, corresponding to the smallest size tablet.
Example 2
Prescription (total 100 g):
adding aripiprazole into the monoglyceride linoleate, span 20 and laurocapram to dissolve, adding 1, 2-propylene glycol under high-speed homogeneous stirring, then respectively adding polyacrylate and polyisobutylene, stirring uniformly, finally adding chitosan and dibutylphenol, stirring uniformly, removing bubbles by ultrasonic waves, standing until the bubbles completely disappear, and obtaining the pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, covering the backing layer on the surface of the pressure sensitive adhesive storage layer, and cutting into 50cm2The aripiprazole transdermal sustained-release patch is prepared.
The aripiprazole transdermal sustained-release patch passes through a Valia-Chien permeation pool to the human in-vitro skinAnd (4) performing an osmotic test, wherein the receiving solution is 40% polyethylene glycol physiological saline. As shown in FIG. 2, the permeation rate of the above patch to the excised skin was measured to be 24.8. mu.g/cm2The medicinal preparation has long-term stable administration characteristics, 50cm2The patch corresponds to a daily oral dosage of 29.76 mg. As shown in figure 3, according to the evaluation result of drug effect, after the skin of the rat is administered with the prazole transdermal sustained-release patch, the times of head shaking of the rat after administration and the times of head shaking of the rat without administration are observed to be obviously reduced, which proves that the drug has the inhibition effect on 5-HT receptors, and the phenomenon of over-activity of the rat is obviously reduced compared with the group without administration.
Example 3
Prescription (total 100 g):
adding aripiprazole into monoglyceride, caprylic acid monoglyceride and diethylene glycol monoethyl ether according to the prescription amount for dissolving, adding 1, 2-propylene glycol under high-speed homogeneous stirring, then respectively adding polyacrylate and polyisoprene, stirring uniformly, finally adding hydroxypropyl-beta-cyclodextrin and anhydrous sodium sulfite, stirring uniformly, removing bubbles by ultrasonic waves, standing and completely eliminating bubbles to obtain the pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, covering the backing layer on the surface of the pressure sensitive adhesive storage layer, and cutting into 50cm2The aripiprazole transdermal sustained-release patch is prepared.
The aripiprazole transdermal sustained-release patch is subjected to a Valia-Chien permeation cell human in-vitro skin permeation test, and a receiving solution is 40% polyethylene glycol physiological saline. As shown in FIG. 4, the permeation rate of the above patch to the excised skin was measured to be 16.9. mu.g/cm2The above experimental examples show that the pharmaceutical preparation has a long-term stable administration characteristic, which is 50cm2The daily dose of the patch corresponds to a dose of 20.28mg of the oral preparation.
Example 4
Prescription (total 100 g):
adding aripiprazole into glyceryl behenate, polyoxyethylene castor oil and span 40 according to the prescription amount to dissolve, adding 1, 2-propylene glycol under high-speed homogeneous stirring, then respectively adding polyacrylate and polyisobutylene, stirring uniformly, finally adding polyvinylpyrrolidone and butyl hydroxy toluene, stirring uniformly, removing bubbles by ultrasonic waves, standing until bubbles completely disappear, and obtaining the pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, covering the backing layer on the surface of the pressure sensitive adhesive storage layer, and cutting into 50cm2The aripiprazole transdermal sustained-release patch is prepared.
Comparative example 1: contains no penetration enhancer with emulsifying effect
Adding aripiprazole into laurocapram, menthol and 1, 2-propylene glycol according to the prescription amount for dissolving, then respectively adding polyacrylate and polyisobutylene, stirring uniformly, finally adding polyvinylpyrrolidone and butyl hydroxy toluene, stirring uniformly, removing bubbles by ultrasonic waves, standing, and completely eliminating bubbles to obtain a pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, covering the backing layer on the surface of the pressure sensitive adhesive storage layer, and cutting into 50cm2The aripiprazole transdermal sustained-release patch is prepared.
Comparative example 2: using a lipophilic adhesive polymer
Adding aripiprazole into lauric acid and polyoxyethylene castor oil according to the prescription amount to dissolve, adding 1, 2-propylene glycol under high-speed homogeneous stirring, then adding polyacrylate, stirring uniformly, finally adding polyvinylpyrrolidone and butyl hydroxy toluene, stirring uniformly, removing bubbles by ultrasonic, standing, and completely eliminating bubbles to obtain a pressure-sensitive adhesive storage layer. Coating the pressure sensitive adhesive storage layer on the anti-sticking layer, drying at 80 deg.C for 45min, and coating the pressure sensitive adhesive storage layer on the anti-sticking layerCutting backing layer to 50cm on the surface of the pressure sensitive adhesive storage layer2The aripiprazole transdermal sustained-release patch is prepared.
The three aripiprazole transdermal sustained-release patches of example 4 and comparative examples 1 and 2 were subjected to a Valia-Chien permeation cell human in vitro skin permeation test, and the receiving solution was 40% polyethylene glycol physiological saline. As shown in FIG. 5, it was found that the skin permeation rate of example 4 and its comparative examples 1 and 2 was 8.3. mu.g/cm2/h、 4.0μg/cm2H and 3.5. mu.g/cm2/h，50cm2The patch is equivalent to the daily administration dosage of 9.96mg, 4.8mg and 4.2mg, and the comparison of skin permeation results of example 4 and comparative example 1 shows that the patch adopts the transdermal enhancer with the emulsification effect, so that the transdermal effect of the medicine is obviously better than that of the case without the emulsification effect promoter, the situation of the case is universal, in addition, the patch does not contain the transdermal enhancer with the emulsification effect, and the medicine is easy to crystallize after the patch is placed for a period of time. As can be seen from comparison of skin permeation results of example 4 and comparative example 2, in the case where two lipophilic adhesive polymers are used in example 4 under the same conditions of other components and preparation methods, the skin permeation of the drug is significantly higher than that of the drug using only one lipophilic adhesive polymer polyacrylate, and further, the two lipophilic adhesive polymers are used in example 4, the patch adhesion is more desirable than that of comparative example 2, and the patch adhesion can be adjusted as desired.
The patch prepared in the embodiment 4 is subjected to a pharmacokinetic experiment, and according to the pharmacokinetic experiment result, compared with an oral preparation, the sustained-release patch drug provided by the invention can keep an effective concentration for a longer period of time compared with an oral suspension, so that the purpose of long-acting administration is achieved, and the administration frequency can be effectively reduced.
The present invention has been illustrated by the above description and examples, which are not limitative and do not limit the scope of the claims of the invention.

Claims (8)

1. A percutaneous sustained-release patch for resisting schizophrenia is characterized by comprising a back lining layer, a pressure-sensitive adhesive storage layer and an anti-adhesion layer; the pressure sensitive adhesive storage layer comprises 1-12% of aripiprazole, 10-35% of a penetration enhancer, 60-80% of a viscous polymer and 0.5-2% of a drug stabilizer by weight ratio. The penetration enhancer is a mixed penetration enhancer containing a penetration enhancer with an emulsifying effect, and the penetration enhancer with the emulsifying effect accounts for 30-50% of the weight of the mixed penetration enhancer. The viscous polymer is composed of lipophilic viscous polymer and hydrophilic viscous polymer, wherein the lipophilic viscous polymer is a mixture of at least two kinds of lipophilic viscous polymers, and the mixture of the lipophilic viscous polymers accounts for 75-95% of the total viscous polymers. The penetration enhancer with emulsification function is one or more of caprylic acid monoglyceride of lauric acid, oleic acid, linoleic acid monoglyceride, ethyl oleate, glyceryl behenate, span 20, span 40 and span 80 which are mixed according to any proportion.
2. The transdermal sustained release patch according to claim 1, wherein the drug aripiprazole is contained in an amount of preferably 2 to 10%.
3. The transdermal sustained-release patch according to claim 1, wherein the hydrophilic adhesive polymer is a cyclodextrin derivative such as hydroxypropyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, methyl- β -cyclodextrin, sulfo- β -cyclodextrin and glucosyl- β -cyclodextrin, and one or more of chitosan, polyvinylpyrrolidone and cellulose derivative are mixed in an arbitrary ratio; the lipophilic adhesive polymer includes polyacrylate pressure sensitive adhesive, polyisoprene, polyisobutylene, and silicone copolymer.
4. The transdermal sustained-release patch according to claim 3, wherein the cyclodextrin derivative is preferably hydroxypropyl- β -cyclodextrin or hydroxyethyl- β -cyclodextrin.
5. The transdermal sustained release patch according to claim 3, wherein the lipophilic adhesive polymer is preferably polyacrylate pressure sensitive adhesive and polyisobutylene, the polyacrylate pressure sensitive adhesive comprising 37% to 75% by weight of the lipophilic adhesive polymer.
6. The transdermal sustained release patch of claim 1, wherein the mixed vehicle further comprises two or more of laurocapram, 1, 2-propanediol, diethylene glycol monoethyl ether, lauryl alcohol, oleyl alcohol, menthol, caprylic/capric macrogol glyceride, dodecyl methyl sulfoxide, dimethyl sulfoxide, caprylic monoglyceride, tween-80, polyoxyethylene castor oil, one of which is 1, 2-propanediol, accounting for 30% -65% of the other vehicle. The content of the mixed penetrant is preferably 10-30%.
7. The transdermal sustained release patch of claim 1, wherein the drug stabilizer is one or more selected from the group consisting of dibutylphenol, butylhydroxytoluene, vitamin E, propyl perylate, anhydrous sodium sulfite and sodium metabisulfite, which are mixed in an arbitrary ratio.
8. A method for preparing the transdermal sustained-release patch according to claim 1, which comprises the following steps:
(1) weighing 1-12% of aripiprazole, 10-35% of transdermal enhancer, 60-80% of viscous polymer and 0.5-2% of drug stabilizer according to the weight ratio.
(2) Adding 1-12% aripiprazole into the whole amount of penetration enhancer with emulsifying effect and the whole amount of other oil-soluble promoters for dissolving, adding the whole amount of 1, 2-propylene glycol under stirring, adding 60-80% viscous polymer and 0.5-2% drug stabilizer, mixing uniformly, degassing to obtain the pressure-sensitive adhesive storage layer.
(3) And coating the pressure-sensitive adhesive storage layer on the anti-sticking layer, drying at 80 ℃ for 35-45min, and covering the back lining layer on the surface of the pressure-sensitive adhesive storage layer to obtain the aripiprazole transdermal sustained-release patch.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114569730A (en) * 2022-01-25 2022-06-03 鑫稳生物医药科技(嘉善)有限公司 Felodipine transdermal drug delivery agent combination, felodipine transdermal drug delivery preparation and transdermal delivery device
CN117064866A (en) * 2023-07-10 2023-11-17 北京丰科睿泰医药科技有限公司 Burisperidone long-acting transdermal patch and preparation method thereof

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US20040170672A1 (en) * 2001-03-07 2004-09-02 Thorsten Selzer Transdermal therapeutic system for administration of partial dopamine-d2 agonists
CN102293761A (en) * 2010-06-22 2011-12-28 浙江省医学科学院 Percutaneous absorption patch containing antiemetic component

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Publication number Priority date Publication date Assignee Title
US20040170672A1 (en) * 2001-03-07 2004-09-02 Thorsten Selzer Transdermal therapeutic system for administration of partial dopamine-d2 agonists
CN102293761A (en) * 2010-06-22 2011-12-28 浙江省医学科学院 Percutaneous absorption patch containing antiemetic component

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114569730A (en) * 2022-01-25 2022-06-03 鑫稳生物医药科技(嘉善)有限公司 Felodipine transdermal drug delivery agent combination, felodipine transdermal drug delivery preparation and transdermal delivery device
CN117064866A (en) * 2023-07-10 2023-11-17 北京丰科睿泰医药科技有限公司 Burisperidone long-acting transdermal patch and preparation method thereof
CN117064866B (en) * 2023-07-10 2024-04-19 北京丰科睿泰医药科技有限公司 Burisperidone long-acting transdermal patch and preparation method thereof

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