CN110638792B - Rotigotine percutaneous absorption patch and preparation and application thereof - Google Patents
Rotigotine percutaneous absorption patch and preparation and application thereof Download PDFInfo
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- 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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The invention belongs to the technical field of medicines, and relates to a rotigotine percutaneous absorption patch, and preparation and application thereof. The patch can obviously improve the crystallization phenomenon of the rotigotine patch and provide good skin permeability. The rotigotine percutaneous absorption patch provided by the invention is composed of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer; the drug-loaded pressure-sensitive adhesive layer comprises rotigotine free alkali or organic acid ionic liquid thereof, a pressure-sensitive adhesive and a percutaneous absorption enhancer. Wherein the weight of rotigotine free alkali or organic acid ionic liquid thereof accounts for 2.0-20 wt% of the total weight of the drug-carrying pressure-sensitive adhesive layer, the weight of the pressure-sensitive adhesive accounts for 77-90 wt% of the total weight of the pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 0-10 wt% of the total weight of the pressure-sensitive adhesive layer. In the rotigotine organic acid ionic liquid, the molar ratio of rotigotine free alkali to different organic acids is 0.5:1-2: 1. In the patch, the 24-hour cumulative permeation amount of the rotigotine can reach 0.5mg/cm2. The preparation method of the patch has the advantages of simple technology, good stability of the patch and convenient use.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to a rotigotine percutaneous absorption patch, and preparation and application thereof. The patch can obviously improve the crystallization phenomenon of the rotigotine patch and provide good skin permeability.
Background art:
parkinson's disease is also called parkinsonism, one of the most common central nervous system degenerative diseases of middle-aged and elderly people is a chronic central nervous system neurodegenerative disease caused by extrapyramidal system dysfunction. Typical symptoms include motor symptoms such as resting tremor, muscular rigidity, bradykinesia, abnormal gait posture, and non-motor symptoms such as anxiety, depression, olfactory disorder, sleep disorder, numbness and pain. According to statistics, over 1000 million Parkinson disease patients exist in the world, and nearly 300 million patients exist in China. More than 10 ten thousand patients are newly added in China every year, and the trend of the disease is also younger in recent years. Parkinson's disease has become the "third killer" for the elderly following tumors, cardiovascular and cerebrovascular diseases.
The therapeutic agents for parkinson's disease include agents for increasing the dopamine content and agents for improving the function of dopamine receptors. The former is mainly a dopa preparation, which represents a levodopa compound preparation to be orally taken, but the symptoms of fluctuation, dyskinesia and the like can appear after long-term taking; and selegiline, rasagiline, entecamine, tokamamine that increase the bioavailability of dopamine in the brain. The latter are mainly dopamine receptor agonists (DAs) -pramipexole, piribedil, ropinirole orally; apomorphine for subcutaneous injection and rotigotine for transdermal sustained delivery. Rotigotine belongs to a non-ergot class of selective dopamine receptor agonists (D1/D2/D3) and is used in the adjuvant treatment of early and late parkinson's disease, by acting through stimulation of dopamine receptors in the body and mimicking the neurotransmitter dopamine. Rotigotine has a very low affinity for the 5HT2B receptor compared to ergot (ergolic) compounds, and therefore has a low risk of causing fibrosis. Rotigotine has significant D1 activity, contributing to a stronger physiological effect than other non-ergot dopamine agonists.
CN106604748A discloses a rotigotine percutaneous absorption preparation, which comprises a polysiloxane-containing adhesive, at least one antioxidant and rotigotine. CN106511319A discloses a rotigotine pressure-sensitive adhesive dispersion type patch, which comprises polyacrylate pressure-sensitive adhesive and rotigotine.
The existing rotigotine percutaneous absorption patch has the problems of crystallization hidden trouble, inaccurate administration dosage, influence on the normal drug effect of the drug and the like.
Compatibility of the drug with the matrix is an important reason for affecting patch stability. Poor compatibility of the drug with the matrix can lead to devitrification of the drug molecules and inaccurate dosing. The main reason for causing the drug crystallization phenomenon in the patch is the poor compatibility between the drug and the pressure-sensitive adhesive.
Therefore, a preparation method is needed to overcome the problem of crystallization of the rotigotine transdermal patch, so that the rotigotine transdermal patch can be better applied to clinic.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a rotigotine percutaneous absorption patch.
The invention also aims to provide a preparation method of the rotigotine transdermal absorption patch and an application of the rotigotine transdermal absorption patch in preparation of the transdermal absorption patch.
The invention is realized by the following technical scheme:
in order to improve the drug crystallization phenomenon of the rotigotine percutaneous absorption patch, the drug and organic acid are synthesized into the ionic liquid with melting point lower than room temperature and proper oil-water distribution coefficient, and the polyacrylate pressure-sensitive adhesive and the percutaneous absorption enhancer are used in combination, so that the percutaneous permeation rate of the rotigotine is ensured, and the drug crystallization problem of the patch is solved.
The rotigotine percutaneous absorption patch provided by the invention is composed of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer; the drug-loaded pressure-sensitive adhesive layer comprises rotigotine free alkali or organic acid ionic liquid thereof, a pressure-sensitive adhesive and a percutaneous absorption enhancer. Wherein the weight of rotigotine free alkali or organic acid ionic liquid thereof accounts for 2.0-20 wt% of the total weight of the drug-carrying pressure-sensitive adhesive layer, the weight of the pressure-sensitive adhesive accounts for 77-90 wt% of the total weight of the pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 0-10 wt% of the total weight of the pressure-sensitive adhesive layer, preferably 2.0-8.0 wt%.
In the rotigotine organic acid ionic liquid, the molar ratio of rotigotine free alkali to different organic acids is 0.5:1-2:1, and the optimal ratio is 1: 1.
The rotigotine organic acid ionic liquid is organic acid ionic liquid which is pharmaceutically acceptable for rotigotine, and is one or more of rotigotine benzoate ionic liquid, rotigotine oleate ionic liquid, rotigotine lactate ionic liquid, rotigotine fumarate ionic liquid, rotigotine malate ionic liquid, rotigotine salicylate ionic liquid, rotigotine oxalate ionic liquid, rotigotine tartrate ionic liquid, rotigotine laurate ionic liquid and rotigotine p-aminobenzoate ionic liquid, preferably rotigotine benzoate ionic liquid, rotigotine oleate ionic liquid, rotigotine lactate ionic liquid and rotigotine fumarate ionic liquid.
The rotigotine organic acid ionic liquid is synthesized by the following method:
dissolving rotigotine free base in acetone; adding organic acid according to a proportion; and uniformly stirring at room temperature for 2-3 hours, and evaporating the solvent to obtain the rotigotine organic acid ionic liquid.
The organic acid is one or more of benzoic acid, oleic acid, lactic acid, fumaric acid, malic acid, salicylic acid and p-aminobenzoic acid.
The weight ratio of the rotigotine free alkali or the equivalent rotigotine-containing ionic liquid to the pressure-sensitive adhesive is as follows: 0.01: 0.99-0.40: 0.60, preferably the weight ratio of the ionic liquid containing equivalent rotigotine: the pressure-sensitive adhesive is 0.20: 0.80-0.40: 0.60.
The matrix material selected by the pressure sensitive adhesive is one or more of polyacrylate, polyisobutylene, silicone or cellulose and derivatives thereof, wherein the polyacrylate pressure sensitive adhesive containing hydroxyl functional groups is preferably selected, and the dosage of the polyacrylate pressure sensitive adhesive is 75-90 wt%.
The polyacrylate pressure-sensitive adhesive containing hydroxyl functional groups can achieve the performances of high drug loading and high release. Pressure sensitive adhesives preferably synthesized using hard monomers, soft monomers and functional monomers, wherein the hard monomers include methyl acrylate, methyl methacrylate, vinyl acetate; the soft monomer comprises ethyl acrylate, butyl acrylate, isooctyl acrylate and isooctyl methacrylate; the functional monomers include hydroxyethyl acrylate, (meth) acrylic acid, maleic acid and maleic anhydride, acrylamide, (meth) acrylamide, hydroxy-beta-ethyl (meth) acrylate and beta-hydroxy lactone (meth) acrylate, glycidyl (meth) acrylate, N-methylolacrylamide, itaconic acid, polyethylene glycol dimethacrylate, diethylbenzene, and the like.
The invention relates to polyacrylate pressure-sensitive adhesive containing hydroxyl functional groups, wherein: the hard monomer comprises methyl acrylate, methyl methacrylate and vinyl acetate, the using amount is 10-30 wt%, the soft monomer comprises ethyl acrylate, isooctyl acrylate and isooctyl methacrylate, the using amount is 40-70 wt%, the functional monomer is hydroxyethyl acrylate, the using amount is 10-30 wt%, and the pressure-sensitive adhesive is synthesized from any one of the hard monomer, the soft monomer and the functional monomer according to the proportion.
Further, the polyacrylate pressure-sensitive adhesive containing hydroxyl functional groups is preferably a pressure-sensitive adhesive composed of methyl acrylate or methyl methacrylate or vinyl acetate as a hard monomer, iso-ethyl acrylate or iso-octyl methacrylate as a soft monomer and hydroxyethyl acrylate as a functional monomer, wherein the proportion of the hard monomer, the soft monomer and the functional monomer is 30:60: 5-25. The content of functional group hydroxyl is obviously higher than that of the pressure-sensitive adhesive sold on the market, such as polyacrylate pressure-sensitive adhesive Duro-Tak 87-2510 and Duro-Tak 87-2287 of Germany Hangao company.
Furthermore, one or more of a plasticizer, an antioxidant, a tackifier or an inert filler can be added into the medicine-carrying pressure-sensitive adhesive layer, and the dosage of each component is 1-10 wt%.
In order to improve the cumulative penetration of the medicine, different percutaneous absorption promoters can be added, and the added percutaneous absorption promoters comprise amines, amides, fatty acids and esters, alcohols, sulfoxides, surfactants, amino acids and esters thereof, terpenes or phospholipid compounds. The dosage of the percutaneous absorption enhancer is 1.0-20.0 wt%.
Further, the percutaneous absorption enhancer is span 80, Tween 80, span 60,
Oleique CC497, Labrafil M1944CS, Labrasol, propylene glycol, azone, menthol, N-methylpyrrolidone, isopropyl myristate, or mixture thereof, preferably menthol.
When the percutaneous absorption enhancer is menthol, the dosage of the percutaneous absorption enhancer accounts for 5 to 20 percent of the total weight of the pressure sensitive adhesive layer.
The backing layer is made of polyurethane film, polyethylene single layer film, aluminum polyethylene composite film, polyester composite film, polyolefin single layer film, ethylene vinyl acetate film or elastic non-woven fabric.
The anti-sticking layer is made of polyester film with silicon oil anti-sticking surface or fluorine-containing polyester film or paper or fluoropolymer coating polyester film.
Dissolving rotigotine free alkali or organic acid ionic liquid thereof in an organic solvent, adding a transdermal accelerant after complete dissolution, or adding a proper amount of an antioxidant, a tackifier, an inert filler and the like, dispersing in pressure-sensitive adhesive with certain mass, transferring and coating on an anti-sticking layer after full stirring, drying for 5-20min at 45-70 ℃, covering a backing layer, and punching into a certain size and specification to obtain the rotigotine transdermal absorption patch. The thickness of the medicine-carrying pressure-sensitive adhesive can be 30-120 mu m.
The invention firstly synthesizes the rotigotine and ionic liquids of different organic acids to replace rotigotine free alkali, and simultaneously utilizes the self-made polyacrylate pressure-sensitive adhesive with high hydroxyl content to increase the compatibility of the medicament and the pressure-sensitive adhesive, thereby preventing the crystallization risk of the rotigotine, improving the medicament-carrying capacity, realizing the high-efficiency release of the medicament and simultaneously improving the transdermal permeability of the rotigotine. The 24-hour cumulative permeation of rotigotine can reach 0.5mg/cm2. The preparation method of the patch has the advantages of simple technology, good stability of the patch and convenient use.
Drawings
FIG. 1 shows the screening of the types of ionic liquids in the rotigotine ionic liquid transdermal patches prepared in examples 14 to 19, respectively, based on the cumulative permeation amount.
FIG. 2 is a screening of the maximum drug loading of the drugs in the pressure-sensitive adhesives of examples 20-31.
FIG. 3 shows the screening of the types of pressure-sensitive adhesives using the cumulative permeation amount as an index for rotigotine transdermal patches prepared in examples 16, 32-37, respectively.
FIG. 4 shows the screening of the types of percutaneous absorption enhancers using the cumulative permeation amounts as indices of the rotigotine percutaneous absorption patches prepared in examples 39 to 43, respectively.
Fig. 5 is a comparative photograph of crystallization of rotigotine ionic liquid patch of example 37, rotigotine ionic liquid and absorption enhancer menthol patch of example 41, and rotigotine free base patch of example 38, left at room temperature for six months.
FIG. 6 shows a commercial product (8 cm)23.6mg) and patch of example 37 (6 cm)23.6mg) and example 41(6 cm)23.6mg) in rats plasma concentration-time curve.
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.
Example 1
Dissolving 0.1mol of rotigotine free base in 40ml 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 rotigotine benzoate ionic liquid.
Example 2
Dissolving 0.1mol of rotigotine free base in 40ml of acetone, adding 0.1mol of oleic acid while stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rotigotine oleate ionic liquid.
Example 3
Dissolving 0.1mol of rotigotine free base in 40ml of acetone, adding 0.1mol of lactic acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rotigotine lactate ionic liquid.
Example 4
Dissolving 0.1mol of rotigotine free base in 40ml of acetone, adding 0.05mol of fumaric acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rotigotine fumarate ionic liquid.
Example 5
Dissolving 0.1mol of rotigotine free base in 40ml of acetone, adding 0.05mol of malic acid under stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the rotigotine malate ionic liquid.
Example 6
Mixing monomer methyl methacrylate, isooctyl methacrylate and hydroxyethyl acrylate in the ratio of 30:60:5, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding initiator azobisisobutyronitrile with the weight of 0.05 percent, and reacting for 24 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 7
Mixing monomer methyl methacrylate, isooctyl methacrylate and hydroxyethyl acrylate in the ratio of 30:60:10, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding initiator azobisisobutyronitrile of 0.05 wt%, and reacting for 24h to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 8
Mixing monomer methyl methacrylate, isooctyl methacrylate and hydroxyethyl acrylate in the ratio of 30:60:15, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding initiator azobisisobutyronitrile of 0.05 wt%, and reacting for 24h to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 9
Mixing monomer methyl methacrylate, isooctyl methacrylate and hydroxyethyl acrylate in the ratio of 30:60:25, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding initiator azobisisobutyronitrile 0.05%, and reacting for 24h to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 10
Mixing monomer methyl methacrylate, butyl acrylate and hydroxyethyl acrylate in a ratio of 30:60:25, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding initiator azobisisobutyronitrile with the weight of 0.05 percent, and reacting for 24 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 11
Mixing monomer methyl acrylate, ethyl acrylate and methyl hydroxyethyl acrylate in a ratio of 30:60:25, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding an initiator azodiisobutyronitrile 0.05 wt%, and reacting for 24 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 12
Mixing monomer vinyl acetate, isooctyl methacrylate and hydroxyethyl acrylate in a ratio of 30:60:25, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding an initiator of Azobisisobutyronitrile (AIBN) 0.05 wt%, and reacting for 24 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 13
Mixing monomer vinyl acetate, isooctyl acrylate and hydroxyethyl acrylate in a ratio of 30:60:25, adding ethyl acetate with the same weight as the monomer, heating to 70 ℃, adding an initiator azodiisobutyronitrile 0.05%, and reacting for 24 hours to generate the hydroxyl-containing polyacrylate pressure-sensitive adhesive.
Example 14
1mmol of rotigotine free alkali is dispersed in 2g of pressure-sensitive adhesive DURO
87-4098 (Hegao, Germany), uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 15
Dispersing 1mmol rotigotine benzoate ionic liquid in 2g pressure sensitive adhesive DURO
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 16
Dispersing 1mmol of rotigotine oleate ionic liquid in 2g of pressure-sensitive adhesive DURO
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 17
Dispersing 1mmol of rotigotine lactate ionic liquid in 2g of pressure-sensitive adhesive DURO
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 18
Dispersing 1mmol of rotigotine fumarate ionic liquid in 2g of pressure-sensitive adhesive DURO
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 19
Dispersing 1mmol of rotigotine malate ionic liquid in 2g of pressure-sensitive adhesive DURO
87-4098, uniformly coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with backing material comprising PVC or non-woven fabric, and die cutting to obtain patch with thickness of 40 μm.
Example 20
Measuring the maximum drug loading in the pressure-sensitive adhesive, dispersing a proper amount of rotigotine free alkali in 2g of non-functional group pressure-sensitive adhesive DURO
87-4098, and determining the maximum drug loading of the drug.
Example 21
Measuring the maximum drug loading in the pressure-sensitive adhesive, dispersing a proper amount of rotigotine oleate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive DURO without functional groups
87-4098, and determining the maximum drug loading of the drug.
Example 22
Maximum drug loading in pressure sensitive adhesiveMeasuring the amount of the rotigotine oleate ionic liquid, namely dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure-sensitive adhesive DURO
87-2287 (Hegao, Germany) and determining the maximum drug loading of the drug.
Example 23
The maximum drug loading in the pressure-sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive DURO containing hydroxyl
87-2510 (Heghao, Germany) was mixed thoroughly and the maximum drug loading of the drug was determined.
Example 24
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 6) and fully mixing to determine the maximum drug loading of the drug.
Example 25
The maximum drug loading in the pressure sensitive adhesive was determined by dispersing a suitable amount of rotigotine oleate ionic liquid in 2g of the hydroxyl-containing polyacrylate pressure sensitive adhesive (example 7) and mixing thoroughly to determine the maximum drug loading of the drug.
Example 26
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 8) and fully mixing to determine the maximum drug loading of the drug.
Example 27
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 9) and fully mixing to determine the maximum drug loading of the drug.
Example 28
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 10) and fully mixing to determine the maximum drug loading of the drug.
Example 29
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 11) and fully mixing to determine the maximum drug loading of the drug.
Example 30
The maximum drug loading in the pressure sensitive adhesive is determined by dispersing a proper amount of rotigotine oleate ionic liquid in 2g of hydroxyl-containing polyacrylate pressure sensitive adhesive (example 12) and fully mixing to determine the maximum drug loading of the drug.
Example 31
The maximum drug loading in the pressure sensitive adhesive was determined by dispersing a suitable amount of rotigotine oleate ionic liquid in 2g of the hydroxyl-containing polyacrylate pressure sensitive adhesive (example 13) and mixing thoroughly to determine the maximum drug loading of the drug.
Example 32
Dispersing 1mmol of rotigotine oleate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive DURO
87-2287 mixing, coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with anti-sticking material, and die cutting to obtain patch with thickness of 40 μm.
Example 33
Dispersing 1mmol of rotigotine oleate ionic liquid in 2g of polyacrylate pressure-sensitive adhesive DURO
87-2287 mixing, coating on the anti-sticking layer, drying at 50 deg.C for 15min, covering with anti-sticking material, and die cutting to obtain patch with thickness of 40 μm.
Example 34
Dispersing 1mmol rotigotine oleate ionic liquid in 2g hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 6), fully mixing, uniformly coating on an anti-sticking layer, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 35
Dispersing 1mmol rotigotine oleate ionic liquid in 2g hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 7), fully mixing, uniformly coating on an anti-sticking layer, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 36
Dispersing 1mmol rotigotine oleate ionic liquid in 2g hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 8), fully mixing, uniformly coating on an anti-sticking layer, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 37
Dispersing 1mmol rotigotine oleate ionic liquid in 2g hydroxyl-containing polyacrylate pressure-sensitive adhesive (example 9), fully mixing, uniformly coating on an anti-sticking layer, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 38
1mmol rotigotine free base was dispersed in 2g polyacrylate pressure sensitive adhesive (example 9), after thorough mixing, evenly coated on the anti-adhesive layer, dried at 50 ℃ for 15min, covered with an anti-adhesive material, die-cut and made into a patch with a thickness of 40 μm.
Example 39
Dispersing 1mmol rotigotine oleate ionic liquid in 2g polyacrylate pressure-sensitive adhesive containing hydroxyl (example 9), fully mixing, adding 0.1g span-80, uniformly coating on an anti-sticking layer after fully mixing, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 40
Dispersing 1mmol rotigotine oleate ionic liquid in 2g polyacrylate pressure-sensitive adhesive containing hydroxyl (example 9), fully mixing, adding 0.1g N-methyl pyrrolidone, uniformly coating on an anti-sticking layer after fully mixing, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare the patch with the thickness of 40 μm.
EXAMPLE 41
Dispersing 1mmol rotigotine oleate ionic liquid in 2g polyacrylate pressure-sensitive adhesive containing hydroxyl (example 9), fully mixing, adding 0.1g menthol, uniformly coating on an anti-sticking layer after fully mixing, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Example 42
1mmol rotigotine oleate ionic liquid is dispersed in 2g polyacrylate pressure-sensitive adhesive containing hydroxyl (example 9) and mixed well, 0.1g is added
Oleique CC497, after mixing thoroughly, is uniformly coated on the anti-sticking layer, dried at 50 deg.C for 15min, covered with anti-sticking material, and die-cut to obtain patch with thickness of 40 μm.
Example 43
Dispersing 1mmol rotigotine oleate ionic liquid in 2g polyacrylate pressure-sensitive adhesive containing hydroxyl (example 9), fully mixing, adding 0.1g propylene glycol, uniformly coating on an anti-sticking layer after fully mixing, drying at 50 ℃ for 15min, covering with an anti-sticking material, and punching to prepare a patch with the thickness of 40 μm.
Test example 1
In vitro transdermal drug delivery test:
a horizontal double-chamber diffusion cell is adopted, fresh rat abdominal skin is taken as a transdermal barrier, a receiving medium is phosphate buffer solution with pH6.5, a continuous magnetic stirrer is used in the test process, the stirring speed is 400-600rpm, and the system temperature is kept at 32 ℃ to measure the 24-hour cumulative permeation amount of rotigotine in the example patch.
The rotigotine ionic liquid transdermal patches prepared in examples 14 to 19, respectively, were screened for ionic liquid species based on the cumulative permeation amount, and the results are shown in fig. 1.
And (4) conclusion: after the rotigotine and the organic acid form the ionic liquid, the transdermal permeability of the rotigotine can be obviously enhanced, and the rotigotine transdermal permeability of the oleic acid ionic liquid (example 12) is the highest.
The results of the screening test of the types of pressure-sensitive adhesives of the rotigotine transdermal patches prepared in examples 16 and 32 to 37, respectively, using the cumulative permeation amount as a standard are shown in fig. 3.
And (4) conclusion: the highest cumulative permeation of the polyacrylate pressure-sensitive adhesive patch containing hydroxyl groups (example 37) was followed by example 36 in the case of the nonfunctional pressure-sensitive adhesive DURO
The permeability was the lowest among 87-4098 (example 16). Polyacrylate pressure-sensitive adhesives (pressure-sensitive adhesives prepared in example 9) having the highest hydroxyl group content are preferred as preferred pressure-sensitive adhesives.
The types of the penetration enhancers for the rotigotine transdermal patches prepared in examples 39 to 43 were screened based on the cumulative penetration amount, and the results are shown in fig. 4.
And (4) conclusion: compared with the group without the accelerator, the accelerator span 80, the N-methyl pyrrolidone,
Neither Oleique CC497 nor propylene glycol significantly increased the cumulative permeation of rotigotine, and menthol (example 31) increased the permeation the highest, so menthol was preferred as a transdermal absorption enhancer.
Test example 2
Short-term crystallization test, preparing the patch with the maximum drug-loading concentration, placing the patch at room temperature for one week, and observing the crystallization condition of the patch. The results of the short term devitrification tests of examples 20-31 are shown in FIG. 2 and Table 1.
TABLE 1 solubility of rotigotine or its ion pair in different pressure sensitive adhesives
| Examples | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 | 31 |
| Drug loading (. + -. 1%) | 8 | 13 | 18 | 16 | 13 | 17 | 20 | 24 | 24 | 23 | 24 | 23 |
And (4) conclusion: when the solubility of the rotigotine-oleic acid ionic liquid in the commercially available hydroxyl-containing pressure-sensitive adhesive and the home-made hydroxyl-containing pressure-sensitive adhesive is different, the test results of examples 27 to 31 show that the high-hydroxyl pressure-sensitive adhesive prepared by the method (the pressure-sensitive adhesives prepared in examples 9 and 13) can significantly improve the drug loading rate of rotigotine, and that the higher the hydroxyl content in the pressure-sensitive adhesive is, the stronger the dissolving capacity of the rotigotine ion pair is, and the lower the crystallization risk is.
Long-term crystallization test the prepared patches of example 37 carrying rotigotine ionic liquid and example 41 carrying rotigotine ionic liquid and the absorption enhancer menthol were left at room temperature for six months, and the control patch of example 38 carrying free rotigotine drug was observed for crystallization, the results are shown in FIG. 5.
And (4) conclusion: the rotigotine ionic liquid patch was loaded into the high hydroxyl content pressure sensitive adhesive (prepared in example 9) with or without the permeation enhancer, and the patch was stable at room temperature without crystallization. The rotigotine free base loaded patch (example 38) showed significant drug crystallisation in the pressure sensitive adhesive of example 9. The combination of the rotigotine ionic liquid and the high-hydroxyl-content pressure-sensitive adhesive can obviously inhibit the crystallization phenomenon of rotigotine.
Test example 3
Rat pharmacokinetic experiments were performed using the commercial formulation, example 37 and example 41. 12 male Wistar rats were randomly divided into two groups, test patches were separately administered to the abdomen of previously shaved rats, and orbital bleeds were performed at predetermined time points after the patches were torn off at 24h to determine plasma rotigotine levels in the rats, the results of which are shown in fig. 6, and the data are shown in table 2.
TABLE 2 pharmacokinetic data in rats for commercial products, example 37 and example 41
And (4) conclusion: in vivo pharmacokinetic experiments in ratsPreferably, the patch set (example 41) is administered in an area of 6cm2Is a commercially available product
Transdermal patch (8 cm)2Preferably, belgium, pharmaceutical company) but both are the same at a dose of 3.6mg, example 41 thus increases the drug delivery rate per unit area, decreases patch area, and further increases patient compliance. The blood concentration of the two patches reaches the highest value within 6-8 h, and then the sustained action can reach 48 h. Compared with the commercial product, the average residence time and the area under the curve of the drug time of the two products are not significantly different (p)>0.05), bioequivalence. Control Patch example 37(3.6mg, 6 cm) without absorption enhancer2) The area under the curve at time of application is significantly smaller than that of the commercially available patch (p)<0.05), indicating that the absorption enhancer has the function of remarkably promoting the absorption of the medicine in the patch.
Claims (12)
1. The rotigotine percutaneous absorption patch consists of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer, and is characterized in that,
the drug-loaded pressure-sensitive adhesive layer comprises rotigotine organic acid ionic liquid, pressure-sensitive adhesive and a percutaneous absorption enhancer; wherein the total weight of the rotigotine organic acid ionic liquid accounts for 2.0-20 wt% of the total weight of the drug-carrying pressure-sensitive adhesive layer, the total weight of the pressure-sensitive adhesive layer accounts for 77-90 wt%, and the dosage of the percutaneous absorption enhancer accounts for 0-10 wt% of the total weight of the drug-carrying pressure-sensitive adhesive layer;
the pressure-sensitive adhesive is a polyacrylate pressure-sensitive adhesive containing hydroxyl functional groups, and is synthesized by a hard monomer, a soft monomer and a functional monomer, wherein the hard monomer is selected from methyl acrylate, methyl methacrylate and vinyl acetate, the using amount of the hard monomer is 10-30 wt%, the soft monomer is selected from ethyl acrylate, isooctyl acrylate and isooctyl methacrylate, the using amount of the soft monomer is 40-70 wt%, and the functional monomer is hydroxyethyl acrylate, and the using amount of the functional monomer is 10-30 wt%.
2. The rotigotine transdermal patch according to claim 1, wherein:
the rotigotine organic acid ionic liquid is one or more of rotigotine benzoate ionic liquid, rotigotine oleate ionic liquid, rotigotine lactate ionic liquid, rotigotine fumarate ionic liquid, rotigotine malate ionic liquid, rotigotine salicylate ionic liquid, rotigotine oxalate ionic liquid, rotigotine tartrate ionic liquid, rotigotine laurate ionic liquid and rotigotine p-aminobenzoate ionic liquid, and is pharmaceutically acceptable.
3. The rotigotine transdermal patch according to claim 1, wherein: the pharmaceutically acceptable organic acid ionic liquid of the rotigotine is one or more of rotigotine benzoate ionic liquid, rotigotine oleate ionic liquid, rotigotine lactate ionic liquid and rotigotine fumarate ionic liquid.
4. The rotigotine transdermal patch according to claim 1 or 2, wherein:
the organic acid ionic liquid is prepared by reacting rotigotine free alkali with organic acid, and the molar ratio of the rotigotine free alkali to the organic acid is 0.5:1-2: 1.
5. The rotigotine transdermal patch according to claim 4, wherein the molar ratio of rotigotine free base to organic acid is 1: 1.
6. The rotigotine transdermal patch according to any one of claims 1 to 3, wherein:
the weight ratio of the rotigotine ionic liquid to the pressure-sensitive adhesive is 0.01: 0.99-0.40: 0.60.
7. The rotigotine transdermal patch according to any one of claims 1 to 3, wherein the ratio of the weight of rotigotine ionic liquid to the weight of pressure sensitive adhesive is 0.20: 0.80-0.40: 0.60.
8. The rotigotine transdermal patch according to claim 1, wherein:
the percutaneous absorption enhancer is menthol with the content of 1.9-7.2 wt%.
9. The rotigotine transdermal patch according to claim 1,
the rotigotine organic acid ionic liquid is synthesized by the following method:
(1) dissolving rotigotine free base in acetone;
(2) adding organic acid according to a proportion;
(3) uniformly stirring at room temperature for 2-3 hours, and evaporating the solvent to dryness to obtain the final product.
10. The rotigotine transdermal patch according to claim 1, wherein:
one or more of inert filler, plasticizer, tackifier or antioxidant is added into the medicine-carrying pressure-sensitive adhesive layer, and the dosage of each component is 1-10 wt%.
11. The rotigotine transdermal patch according to claim 1,
the back lining layer is made of an aluminum polyethylene composite film, a polyester composite film, a polyurethane film, an ethylene vinyl acetate film or an elastic non-woven fabric; the anti-sticking layer is made of polyester film with silicon oil anti-sticking surface or fluorine-containing polyester film or paper or fluoropolymer coating polyester film.
12. The method for preparing a rotigotine transdermal patch according to claim 1, wherein:
dissolving rotigotine organic acid ionic liquid in organic solvent, adding percutaneous absorption promoter after completely dissolving, or adding appropriate amount of inert filler, tackifier and antioxidant, dispersing in pressure sensitive adhesive of certain mass, stirring, transferring and coating on the anti-sticking layer, drying at 40-80 deg.C for 5-20min, covering with backing layer, and die-cutting.
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| CN113368083A (en) * | 2021-06-16 | 2021-09-10 | 华健医疗(深圳)有限公司 | Transdermal drug delivery system for cannabidiol CBD |
| CN113384560A (en) * | 2021-07-07 | 2021-09-14 | 华健医疗(深圳)有限公司 | Compound transdermal patch of rotigotine and nicotine for treating or preventing nervous system diseases and preparation method thereof |
| CN114306288A (en) * | 2022-01-16 | 2022-04-12 | 沈阳药科大学 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
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| US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
| US20130324585A1 (en) * | 2010-12-02 | 2013-12-05 | Christian Janssen | Rotigotine ionic liquid |
| CA2878376C (en) * | 2012-07-05 | 2018-08-07 | Sk Chemicals Co., Ltd. | Transdermally absorbable preparation containing rotigotine |
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Non-Patent Citations (2)
| Title |
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| "A systemic evaluation of drug in acrylic pressure sensitive adhesive patch;Chao Liu et al.;《Journal of Controlled Release》;20170306;第252卷;摘要 * |
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