CN114306288A - Rivastigmine long-acting percutaneous absorption patch and preparation method thereof - Google Patents
Rivastigmine long-acting percutaneous absorption patch and preparation method thereof Download PDFInfo
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- CN114306288A CN114306288A CN202210045829.8A CN202210045829A CN114306288A CN 114306288 A CN114306288 A CN 114306288A CN 202210045829 A CN202210045829 A CN 202210045829A CN 114306288 A CN114306288 A CN 114306288A
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- China
- Prior art keywords
- rivastigmine
- sensitive adhesive
- ionic liquid
- pressure
- patch
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- 238000010521 absorption reaction Methods 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- 239000002608 ionic liquid Substances 0.000 claims abstract description 84
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- 229940079593 drug Drugs 0.000 claims abstract description 32
- 150000007524 organic acids Chemical class 0.000 claims abstract description 20
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a long-acting percutaneous absorption patch of rivastigmine, belonging to the technical field of medicines. The transdermal absorption patch is suitable for an application period of at least three days, and comprises a back lining layer, a medicine-carrying pressure-sensitive adhesive layer and an anti-adhesion layer. The medicine-carrying pressure-sensitive adhesive layer comprises rivastigmine free alkali or organic acid ionic liquid thereof, pressure-sensitive adhesive and percutaneous absorption enhancer. The weight of the rivastigmine free alkali or the organic acid ionic liquid accounts for 5-45 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the weight of the pressure-sensitive adhesive accounts for 50-90 wt% of the total weight of the pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 1-20 wt% of the total weight of the pressure-sensitive adhesive layer. Wherein, in the rivastigmine organic acid ionic liquid, the free alkali of rivastigmine is different from that of rivastigmineThe organic acid is in a molar ratio of 0.5:1 to 2: 1. In the patch, the accumulative penetration of the rivastigmine in 72 hours can reach 2.8mg/cm2. The patch has the advantages of simple preparation technology, low cost, constant-speed drug release, safety, effectiveness, good stability and convenient use.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a rivastigmine long-acting percutaneous absorption patch, and a preparation method and application thereof.
Background
Alzheimer's disease is a progressive, irreversible neurodegenerative disease, the most common cause of progressive intellectual decline in people over 65 years of age. Alzheimer's disease is characterized by three main groups of symptoms: cognitive dysfunction, psychiatric and behavioral disorders, degradation of activities of daily living and behaviors, respectively. These deficiencies develop over time, often accompanied by behavioral disturbances such as aggression, depression, wandering and wandering. The prevalence rate of global Alzheimer's disease in 2018 is 5000 million, and the global economic loss approaches to $ 1 trillion. It is predicted by the United nations population that by 2050, the population over 80 years will increase by approximately 3.7 times, at which time the predicted number of episodes for the disease will reach 1.52 million people. In China, patients suffering from Alzheimer disease spend up to $ 2 ten thousand in 2015, and the economic burden of China caused by Alzheimer disease is estimated to reach $ 2.54 billion and $ 9.12 billion in 2050 by 2030.
The only two types of drugs available for the effective treatment of Alzheimer's disease are cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. Tacrine, donepezil, rivastigmine and galantamine are the first class of drugs and memantine is the second class of drugs. Tacrine is rarely used clinically due to its hepatotoxic effects. Tacrine, donepezil, rivastigmine and galantamine are approved for mild to moderate alzheimer's disease and memantine is approved for moderate to severe alzheimer's disease. 13.3mg of rivastigmine transdermal patch was approved in 2013 for once-daily treatment of alzheimer's disease of moderate to severe severity. Rivastigmine is the only transdermal patch available on the market that can be used in all stages of the disease.
The existing rivastigmine patch is administrated once a day, and a treatment scheme is simplified, the administration frequency is reduced, and adverse reactions are reduced, so that the patient compliance is improved. Meanwhile, the production process is simplified, and the production cost is reduced. Replacing the once-a-day transdermal patch with a rivastigmine long acting transdermal patch would be a simple and effective way to improve patient compliance and drug safety.
The key issues in preparing long-acting transdermal patches are increasing the drug loading and controlling the transdermal rate of the drug during transdermal administration.
The general technique for preparing long acting patches is to place the drug in a drug reservoir and use a controlled release membrane to control the release of the drug.
CN113616625A discloses a long-acting transdermal patch of rivastigmine, which comprises a back lining layer, a drug-containing pressure-sensitive adhesive layer, a controlled release membrane, an adhesive layer and a protective layer; the controlled release film is an EVA film with the mass fraction of vinyl acetate monomer of 19 percent and is used for controlling the release of the rivastigmine, and the pressure-sensitive adhesive in the medicine-containing pressure-sensitive adhesive layer is acrylic pressure-sensitive adhesive containing carboxyl groups; the medicine-containing pressure-sensitive adhesive layer contains acrylic acid pressure-sensitive adhesive, rivastigmine, polyacrylic resin and DL-alpha-tocopherol; the adhesive layer contains organic silicon pressure-sensitive adhesive, dimeticone and DL-alpha-tocopherol; the membrane controlling the release of rivastigmine is CoTran 9712. The patch of the patent still needs to adopt a controlled release membrane to control the release of the rivastigmine, the structure of the patch is complex, and an antioxidant DL-alpha-tocopherol needs to be added into a medicine-containing pressure-sensitive adhesive layer.
Disclosure of Invention
In view of the above, the present invention aims to provide a long-acting transdermal absorption patch of rivastigmine with controlled release over a period of three days.
The invention also aims to provide a preparation method and application of the rivastigmine long-acting percutaneous absorption patch.
In order to achieve the above object, the present invention provides the following technical solutions:
the long-acting percutaneous absorption patch of the rivastigmine consists of a back lining layer, a medicine-carrying pressure-sensitive adhesive layer and an anti-sticking layer, and is characterized in that the medicine-carrying pressure-sensitive adhesive layer comprises rivastigmine free alkali or organic acid ionic liquid thereof, pressure-sensitive adhesive and a percutaneous absorption promoter; wherein the total weight of the rivastigmine free alkali or the organic acid ionic liquid thereof accounts for 5-45 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 50-90 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 1-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer. Preferably, the total weight of the rivastigmine free alkali or organic acid ionic liquid thereof accounts for 15-35 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 60-75 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 5-15 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer. Wherein the organic acid in the rivastigmine organic acid ionic liquid is C4-C20 organic acid, preferably C6-C12 unsaturated aromatic organic acid.
The rivastigmine organic acid ionic liquid is rivastigmine pharmaceutically acceptable organic acid ionic liquid, and is one or more of rivastigmine benzoate ionic liquid, rivastigmine isobutyrate ionic liquid, rivastigmine maleate ionic liquid, rivastigmine fumarate ionic liquid, rivastigmine octanoate ionic liquid, rivastigmine salicylate ionic liquid, rivastigmine n-butyrate ionic liquid, rivastigmine tartrate ionic liquid and rivastigmine laurate ionic liquid, preferably one or more of rivastigmine benzoate ionic liquid, rivastigmine isobutyrate ionic liquid, rivastigmine salicylate ionic liquid and rivastigmine tartrate ionic liquid.
The molar ratio of the rivastigmine free alkali to different organic acids in the rivastigmine organic acid ionic liquid is 0.5: 1-2: 1, and preferably 1: 1.
The rivastigmine organic acid ionic liquid is synthesized by the following method: dissolving rivastigmine free alkali in acetone, adding organic acid in proportion, stirring at room temperature for 1-2 hours at a constant speed, and removing the solvent by rotary evaporation to obtain the rivastigmine.
The weight ratio of the rivastigmine free alkali or the equivalent amount of rivastigmine-containing ionic liquid to the pressure-sensitive adhesive is 0.05: 0.95-0.50: 0.50, preferably 0.20: 0.80-0.50: 0.50.
The pressure-sensitive adhesive is one or more of polyisobutylene, organic silicon, polyacrylate and polyurethane, preferably polyacrylic resin pressure-sensitive adhesive containing hydroxyl functional groups, and the dosage of the pressure-sensitive adhesive is 50-90 wt%.
The polyacrylic resin pressure-sensitive adhesive containing the hydroxyl functional group has the performance of high drug loading and high release amount. The pressure-sensitive adhesive is preferably synthesized by polymerization using a hard monomer, a soft monomer and a functional monomer. Wherein the hard monomer comprises methyl methacrylate, styrene, methyl acrylate and acrylonitrile, and the using amount is 30-60 wt%; the soft monomer comprises ethyl acrylate, butyl acrylate, isooctyl acrylate and isooctyl methacrylate, and the using amount is 20-40 wt%; the functional monomer is hydroxyethyl acrylate, and the using amount is 5-30 wt%. The pressure-sensitive adhesive is synthesized from one of a hard monomer, a soft monomer and a functional monomer.
Furthermore, the preferable hard monomer of the polyacrylic resin pressure-sensitive adhesive containing the hydroxyl functional group is methyl methacrylate or styrene or methyl acrylate and acrylonitrile, the soft monomer is ethyl acrylate or butyl acrylate or isooctyl methacrylate, the functional monomer is hydroxyethyl acrylate, and the ratio of the hard monomer to the soft monomer to the functional monomer is 55:30: 5-25.
In order to increase the cumulative amount of drug passing through the patch, various transdermal absorption enhancers may be added. The percutaneous absorption enhancer comprises one or more of higher fatty alcohols, fatty acids, fatty acid esters, lactams, hydrocarbons, silicones, surfactants and terpene compounds, and the dosage is 1-20 wt%, preferably 5-15%.
Further, the percutaneous absorption enhancer is azone, menthol, span 60, span 80, tween 80, isopropyl myristate, oleic acid, caprylic/capric acid polyethylene glycol glyceride, polyglycerol oleate (polyethylene glycol oleate) (polyethylene glycol monooleate), or a mixture thereof
Oleique CC497), one or more of propylene glycol, preferably polyglycerol oleate.
The backing layer is made of one of a polyethylene composite film, an ethylene/vinyl acetate copolymer film, a polyurethane film, a polyester composite film or non-woven fabric.
The anti-sticking layer is made of one of polyester film with silicon oil surface or fluorine-containing polyester film and fluoropolymer coating polyester film.
The preparation method of the rivastigmine long-acting percutaneous absorption patch is characterized by comprising the following steps: dissolving rivastigmine free alkali or organic acid ionic liquid thereof in an organic solvent, adding a percutaneous absorption enhancer, fully stirring at a constant speed to uniformly disperse the medicine on the pressure-sensitive adhesive, coating the pressure-sensitive adhesive on an anti-sticking layer, drying at 25-85 ℃ for 5-25 min, covering a back lining layer, and punching to obtain the product. The thickness of the medicine-carrying pressure-sensitive adhesive is 40-180 mu m.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. For reasons of space, they are not described in detail here.
Advantageous effects
The synthetic rivastigmine organic acid ionic liquid replaces rivastigmine free alkali, and polyacrylic acid pressure-sensitive adhesive containing hydroxyl is automatically synthesized, so that the drug loading rate and the high release amount of the drug are improved, and meanwhile, the percutaneous absorption enhancer is used for improving the percutaneous permeability of rivastigmine, so that the rivastigmine long-acting percutaneous absorption patch which can reach the target dose and can be transdermally penetrated at a constant speed is obtained. The cumulative penetration of rivastigmine in 72 hours can reach 2.8mg/cm2。
The patch has the advantages of simple preparation technology, low cost, constant-speed drug release, safety, effectiveness, good stability and convenient use.
Drawings
FIG. 1 is a table showing the screening of ionic liquid species in accordance with the cumulative permeation amount of the rivastigmine ionic liquid transdermal patch prepared in each of examples 15 to 21;
FIG. 2 is a screening of the types of pressure-sensitive adhesives of the rivastigmine long-acting percutaneous absorption patches prepared in examples 22 to 32 respectively, based on the cumulative permeation amount;
FIG. 3 is a table showing the screening of the types of percutaneous absorption enhancers in the rivastigmine long-acting percutaneous absorption patches prepared in examples 33 to 38, respectively, based on the cumulative permeation amount;
FIG. 4 is an in vitro transdermal test of the rivastigmine long-acting transdermal absorption patch prepared in examples 33 and 39 and a commercially available patch;
FIG. 5 is a plot of plasma concentration versus time in rabbits for example 33 and commercially available patches.
Detailed Description
The invention is illustrated in more detail by the following examples, it being clear that: the present invention is by no means limited to the embodiments or only expressed as the embodiments. Modifications such as conventional alterations, additions, and the like to the elements of the embodiments are possible within the scope of the invention without departing from the spirit thereof.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Term(s) for
As used herein, the terms "comprising," "including," or "including" mean that the various ingredients may be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
In the present invention,%, percentages, ratios and parts are by weight unless otherwise specified.
In the present invention, the backing layer to be used is not particularly limited as long as it can be used for a patch, and a polyethylene composite film, an ethylene/vinyl acetate copolymer film, a polyurethane film, a polyester composite film, or a nonwoven fabric is preferably used.
The release layer to be used is not particularly limited, and any release layer commonly used in adhesive patches may be used, and a polyester film having a silicone oil release treatment or a fluorine-containing polyester film or a fluoropolymer-coated polyester film is preferable.
Preparation example
Preparation of rivastigmine organic acid ionic liquid
Example 1
Dissolving 0.1mol of rivastigmine free base in 100ml of acetone, adding 0.1mol of n-butyric acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rivastigmine ionic liquid of n-butyric acid.
Example 2
Dissolving 0.1mol of rivastigmine free alkali in 100ml of acetone, adding 0.1mol of n-octanoic acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rivastigmine ionic liquid.
Example 3
Dissolving 0.1mol of rivastigmine free base in 100ml of acetone, adding 0.1mol of lauric acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rivastigmine laurate ionic liquid.
Example 4
Dissolving 0.1mol of rivastigmine free base in 100ml of acetone, adding 0.1mol of ibuprofen into the mixture under stirring, continuing stirring for 2 hours, and performing rotary evaporation to evaporate the solvent to obtain the rivastigmine ionic liquid.
Example 5
Dissolving 0.1mol of rivastigmine free base in 100ml of acetone, adding 0.1mol of benzoic acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rivastigmine benzoate ionic liquid.
Example 6
Dissolving 0.1mol of rivastigmine free base in 100ml of acetone, adding 0.1mol of salicylic acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rivastigmine ionic liquid.
Preparation of polyacrylate pressure-sensitive adhesive containing hydroxyl
Example 7
Uniformly mixing 55.56g of monomer isooctyl acrylate, 33.33g of methyl acrylate and 5.56g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 8
And uniformly mixing 57.89g of monomer isooctyl acrylate, 31.58g of methyl acrylate and 10.53g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to obtain the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 9
Uniformly mixing 55g of monomer isooctyl acrylate, 30g of methyl acrylate and 15g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 10
Uniformly mixing 52.38g of monomer isooctyl acrylate, 28.57g of methyl acrylate and 19.05g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 11
Uniformly mixing 52.38g of monomer isooctyl methacrylate, 28.57g of methyl acrylate and 19.05g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 12
Uniformly mixing 52.38g of monomer isooctyl acrylate, 28.57g of methyl methacrylate and 19.05g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 13
Uniformly mixing 52.38g of monomer isooctyl methacrylate, 28.57g of vinyl acetate and 19.05g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 14
Uniformly mixing 52.38g of monomer isooctyl acrylate, 28.57g of vinyl acetate and 19.05g of hydroxyethyl acrylate, adding 100g of ethyl acetate, heating to 80 ℃, adding 0.4g of initiator azobisisobutyronitrile, and reacting for 12 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Preparation of rivastigmine patch
Example 15
1mmol of rivastigmine free base was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and uniformly coated on an anti-sticking layer, dried at 50 ℃ for 20min, and then covered with a backing material including PVC or non-woven fabric, and die-cut to prepare a patch having a thickness of 75 μm.
Example 16
1mmol of rivastigmine n-butyrate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and thoroughly mixed, uniformly coated on an anti-sticking layer, dried at 50 ℃ for 20min, then covered with a backing material comprising PVC or non-woven fabric, and die-cut to prepare a patch having a thickness of 75 μm.
Example 17
1mmol of rivastigmine n-octanoate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material comprising PVC or non-woven fabric, and die-cut to prepare a patch having a thickness of 75 μm.
Example 18
1mmol of rivastigmine laurate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and uniformly coated on an anti-sticking layer, dried at 50 ℃ for 20min, and then covered with a backing material including PVC or non-woven fabric, and die-cut to prepare a patch having a thickness of 75 μm.
Example 19
1mmol of ibuprofen rivastigmine ionic liquid is dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and fully mixed, and the mixture is uniformly coated on an anti-sticking layer, dried at 50 ℃ for 20min, covered by a backing material comprising PVC or non-woven fabric, and punched to prepare a patch with the thickness of 75 μm.
Example 20
1mmol of rivastigmine benzoate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and uniformly coated on an anti-sticking layer, dried at 50 ℃ for 20min, and then covered with a backing material comprising PVC or non-woven fabric, and die-cut to prepare a patch having a thickness of 75 μm.
Example 21
1mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material including PVC, and die-cut to prepare a patch having a thickness of 75 μm.
Example 22
Dispersing 0.3mmol of rivastigmine salicylate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive without group
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 75 μm.
Example 23
Dispersing 0.3mmol of rivastigmine salicylate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive
87-2287 mixing, spreading on the release layer, drying at 50 deg.C for 20min, covering with backing material, and die cutting to obtain patch with thickness of 75 μm.
Example 24
Dispersing 0.3mmol of rivastigmine salicylate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive
87-2510, mixing, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and die cutting to obtain patch with thickness of 75 μm.
Example 25
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 7) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 26
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 8) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 27
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 9) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 28
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10) and mixed well, and the mixture was coated on an anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 29
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 11) and mixed well, and the mixture was coated on an anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 30
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 12) and mixed well, and the mixture was coated on an anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 31
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 13) and mixed well, and coated on the anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Example 32
0.3mmol of rivastigmine salicylate ionic liquid was dispersed in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 14) and mixed well, and the mixture was coated on an anti-sticking layer uniformly, dried at 50 ℃ for 20min, and then covered with a backing material, and die-cut to prepare a patch 75 μm thick.
Selection test of percutaneous absorption enhancer
Example 33
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive containing hydroxyl (example 10), mixing well, adding 0.1g of polyglycerol oleate (poly (glycerol oleate)) (
Oleique CC497), mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Example 34
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10), mixing completely, adding 0.1g of oleic acid, mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Example 35
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10), mixing completely, adding 0.1g of span-80, uniformly coating on an anti-sticking layer after mixing completely, drying at 50 ℃ for 20min, covering with a backing material, and punching to prepare a patch with the thickness of 120 μm.
Example 36
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10), mixing completely, adding 0.1g of azone, mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Example 37
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10), mixing completely, adding 0.1g of menthol, mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Example 38
Dispersing 1mmol of rivastigmine salicylate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 10), mixing completely, adding 0.1g of isopropyl myristate, mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Example 39
Dispersing 1mmol of rivastigmine benzoate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive containing hydroxyl (example 10), mixing well, adding 0.1g of polyglycerol oleate(s) (i.e., (s))
Oleique CC497), mixing completely, coating on the anti-sticking layer, drying at 50 deg.C for 20min, covering with backing material, and punching to obtain patch with thickness of 120 μm.
Effect test
Test example 1
In vitro transdermal experiments:
preparing in vitro skin:
taking healthy pig ear skin, removing hair, subcutaneous fat layer and connective tissue on the skin surface, washing the skin with normal saline, and determining the skin integrity. Placing the intact skin into a refrigerator of-70 deg.C for freezing storage.
The test method comprises the following steps:
a Franz horizontal double-chamber diffusion cell is adopted, fresh pig ear skin is used as a transdermal barrier, a receiving medium is phosphate buffer solution with the pH value of 7.4, magnetic stirring is continuously carried out in the test process, the stirring speed is 350-750 rpm, the system temperature is kept at 32 ℃, and the cumulative permeation quantity of the Rivastigmine in the patch of the embodiment is measured for 72 hours.
The screening of ionic liquid species of the rivastigmine ionic liquid transdermal patch preparations prepared in examples 15 to 21, respectively, was performed using the cumulative permeation amount and transdermal permeation rate as standards, and the results are shown in fig. 1 and table 1.
TABLE 1 transdermal permeation rates of rivastigmine or its ionic liquids at different time periods
And (4) conclusion: the cumulative permeation amount and the permeation rate of the patch prepared after the rivastigmine and the organic acid are synthesized into the ionic liquid in 72 hours are lower than those of the rivastigmine free base patch. In addition, the patches in example 19 (ibuprofen rivastigmine ionic liquid), example 20 (benzoic acid rivastigmine ionic liquid RVS-BA) and example 21 (salicylic acid rivastigmine ionic liquid RVS-SA) keep relatively stable flux in the whole experimental process, and can achieve the aim of constant drug release.
The screening of the types of pressure-sensitive adhesives of the rivastigmine long-acting percutaneous absorption patches prepared in examples 22 to 32, respectively, using the cumulative permeation amount as a standard is shown in fig. 2.
And (4) conclusion: the cumulative permeation amount of the hydroxyl group-containing polyacrylate pressure-sensitive adhesive (example 10) was the highest, so that the hydroxyl group-containing polyacrylate pressure-sensitive adhesive (example 10) was preferable as the pressure-sensitive adhesive.
The results of screening the types of percutaneous absorption enhancers using the cumulative permeation amounts as criteria for the rivastigmine long-acting percutaneous absorption patches prepared in examples 33 to 38, respectively, are shown in fig. 3.
And (4) conclusion: compared with the medicine without percutaneous absorption enhancer, azone, menthol, span 80, isopropyl myristate and oleic acid do not obviously enhance the cumulative permeation amount of rivastigmine, and polyglycerol oleate (A), (B), (C) and (C)
Oleique CC497) (example 33) for kappaThe most remarkable penetration-promoting effect of latine is preferably polyglycerol oleate (A), (B), (C) and (C)
Oleique CC497) as a percutaneous absorption enhancer.
In vitro transdermal experiments performed on the rivastigmine long-acting transdermal absorption patches prepared in examples 33 and 39 and commercially available patches, respectively, showed the results shown in fig. 4.
And (4) conclusion: the 72 hour cumulative permeation of examples 33 and 39 were 3 times that of the commercially available patch and released at a constant rate, indicating that a three day long acting transdermal patch can be prepared by combining rivastigmine ionic liquid with a high hydroxyl content polyacrylate pressure sensitive adhesive.
Test example 2
Using commercially available patches
Patches (9.5mg/24h, Nowa European pharmaceuticals Co., Ltd.) and example 33 Rabbit pharmacokinetic experiments were carried out. 12 rabbits were randomly divided into two groups, and the patches were applied to the rabbits where hairs were removed from the abdomen, blood was taken from the marginal veins of the ears at predetermined time points, blood concentration was measured, and the patches were removed after 72 hours, and the results are shown in table 2 and fig. 4 and 5.
TABLE 2 commercially available Patches and in vivo pharmacokinetic parameters for rabbits from example 33
And (4) conclusion: as shown in FIG. 4, in the rabbit pharmacokinetic experiment, the administration area (10 cm) of the prescribed patch set (example 33) is preferable2) With commercially available patches
The patches (9.5mg/24h, Nowa European pharmaceuticals Co., Ltd.) were identical, and the cumulative permeation over 24h was identical, and the cumulative permeation over 72h was about 3 times that of the commercially available patch. The cumulative permeation curve is almost linear, therefore, example 33 can reduce the number of administrations from 1 time per day to 1 time per day for 3 days, and improve the patientAnd (4) compliance.
As shown in table 2 and fig. 5, the drug concentration in the plasma of example 33 slowly increased and exhibited a stationary phase (12h to 54h), the drug concentration in the plasma was maintained at about 100ng/mL, and the absorption time was significantly prolonged. At 72h, the relative bioavailability of the patch of example 33 relative to the commercially available patch was 87.07%, with no significant difference in AUC values (P)>0.05). T for the patch of example 33, compared with the commercially available patchmaxDelay, t1/2And MRT0-tAnd the extension proves that the patch in the example 33 can effectively control the absorption of the rivastigmine in vivo, and the aim of long-acting constant-speed release is achieved.
Claims (10)
1. The long-acting percutaneous absorption patch of the rivastigmine consists of a back lining layer, a medicine-carrying pressure-sensitive adhesive layer and an anti-sticking layer, and is characterized in that the medicine-carrying pressure-sensitive adhesive layer comprises free alkali of the rivastigmine or organic acid ionic liquid thereof, pressure-sensitive adhesive and a percutaneous absorption promoter; wherein the total weight of the rivastigmine free alkali or the organic acid ionic liquid thereof accounts for 5-45 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 50-90 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 1-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer.
2. The long-acting transdermal absorption patch of rivastigmine according to claim 1, wherein the pressure sensitive adhesive is a hydroxyl group-containing polyacrylic resin pressure sensitive adhesive.
3. The long-acting transdermal absorption patch of rivastigmine according to claim 1, wherein the pressure sensitive adhesive is synthesized by polymerization of a hard monomer, a soft monomer and a functional monomer, wherein the hard monomer is selected from methyl methacrylate, styrene, methyl acrylate and acrylonitrile, the soft monomer is selected from ethyl acrylate, butyl acrylate, isooctyl acrylate and isooctyl methacrylate, and the functional monomer is hydroxyethyl acrylate.
4. The long-acting transdermal absorption patch of rivastigmine according to claim 3, wherein the hard monomer is contained in an amount of 20 to 40 wt%, the soft monomer is contained in an amount of 30 to 60 wt%, and the functional monomer is contained in an amount of 5 to 30 wt%.
5. The long-acting transdermal absorption patch of rivastigmine according to claim 1 or 2, wherein the organic acid is an organic acid of C4-C20.
6. The rivastigmine long-acting transdermal absorption patch according to claim 1 or 2, wherein the rivastigmine organic acid ionic liquid is rivastigmine pharmaceutically acceptable organic acid ionic liquid, and is one or more of rivastigmine ionic liquid, n-octanoic acid rivastigmine ionic liquid, n-butanoic acid rivastigmine ionic liquid, tartaric acid rivastigmine ionic liquid, and lauric acid rivastigmine ionic liquid, preferably one or more of rivastigmine ionic liquid, iso-butanoic acid rivastigmine ionic liquid, salicylic acid rivastigmine ionic liquid, and tartaric acid rivastigmine ionic liquid.
7. The rivastigmine long-acting transdermal absorption patch according to claim 1 or 2, wherein the rivastigmine organic acid ionic liquid is prepared by reacting rivastigmine free base with an organic acid, and the molar ratio of the rivastigmine free base to the organic acid is 0.5: 1-2: 1, preferably 1: 1.
8. The rivastigmine long-acting transdermal absorption patch according to claim 1 or 2, wherein the weight ratio of the rivastigmine free base or ionic liquid thereof to the pressure-sensitive adhesive is 0.05: 0.95-0.50: 0.50, preferably 0.20: 0.80-0.50: 0.5.
9. The long-acting percutaneous absorption patch of rivastigmine according to claim 1 or 2, wherein the percutaneous absorption enhancer comprises one or more of higher aliphatic alcohols, fatty acids, fatty acid esters, lactams, hydrocarbons, silicones, surfactants, and terpene compounds, preferably polyglycerol oleate.
10. The preparation method of the rivastigmine long-acting percutaneous absorption patch according to claim 1, wherein rivastigmine free alkali or organic acid ionic liquid thereof is dissolved in an organic solvent, a percutaneous absorption enhancer is added, the mixture is fully stirred at a constant speed to uniformly disperse the drug in the pressure-sensitive adhesive, then the mixture is coated on an anti-sticking layer, the mixture is dried at 25-85 ℃ for 5-25 min, a back lining layer is covered, and the patch is obtained by punching.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210045829.8A CN114306288A (en) | 2022-01-16 | 2022-01-16 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210045829.8A CN114306288A (en) | 2022-01-16 | 2022-01-16 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
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| CN114306288A true CN114306288A (en) | 2022-04-12 |
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| CN202210045829.8A Pending CN114306288A (en) | 2022-01-16 | 2022-01-16 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110638792A (en) * | 2019-10-16 | 2020-01-03 | 沈阳药科大学 | Rotigotine percutaneous absorption patch and preparation and application thereof |
| CN113616625A (en) * | 2021-08-26 | 2021-11-09 | 大连科翔科技开发有限公司 | Long-acting transdermal patch of rivastigmine |
-
2022
- 2022-01-16 CN CN202210045829.8A patent/CN114306288A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110638792A (en) * | 2019-10-16 | 2020-01-03 | 沈阳药科大学 | Rotigotine percutaneous absorption patch and preparation and application thereof |
| CN113616625A (en) * | 2021-08-26 | 2021-11-09 | 大连科翔科技开发有限公司 | Long-acting transdermal patch of rivastigmine |
Non-Patent Citations (2)
| Title |
|---|
| CHAO LIU等: "A systemic evaluation of drug in acrylic pressure sensitive adhesive patch in vitro and in vivo: The roles of intermolecular interaction and adhesive mobility variation in drug controlled release", JOURNAL OF CONTROLLED RELEASE, vol. 252, pages 83 * |
| YU CAI等: "Development of long-acting rivastigmine drug-in-adhesive patch utilizing ion-pair strategy and characterization of controlled release mechanism", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 161, pages 105774 * |
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