CN113171359A - Chuangbuterol transdermal patch and preparation method thereof - Google Patents
Chuangbuterol transdermal patch and preparation method thereof Download PDFInfo
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- CN113171359A CN113171359A CN202110500759.6A CN202110500759A CN113171359A CN 113171359 A CN113171359 A CN 113171359A CN 202110500759 A CN202110500759 A CN 202110500759A CN 113171359 A CN113171359 A CN 113171359A
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to the technical field of medicines, and provides a Chuangbuterol transdermal patch and a preparation method thereof. The patch consists of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer, wherein the drug-loaded pressure-sensitive adhesive layer comprises 2-15 wt% of free base of the salbutamol or an organic acid ion pair compound thereof, 70-95 wt% of pressure-sensitive adhesive and 0-20 wt% of percutaneous absorption enhancer, and the molar ratio of the free base of the salbutamol to different organic acids in the compound of the free base of the salbutamol or the organic acid ion pair compound thereof is 1: 1. The Chuangbuterol transdermal patch provided by the invention can improve the transdermal penetration of the medicament, so that the medicament can better play a role, and the utilization rate of the patch is greatly improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and provides a Chuangbuterol transdermal patch and a preparation method thereof.
Background
In recent years, with the continuous improvement of the degree of industrialization, the harm caused by heavy industrial production is increasingly prominent, especially, the air quality is seriously polluted, the incidence and the death rate of bronchial asthma, which is a respiratory tract infection type disease, tend to rise year by year in the global range, become a public health problem concerned globally, and the main symptoms of bronchial asthma are recurrent wheezing, shortness of breath, chest distress or cough, and are often attacked or aggravated at night and in the early morning.
The current anti-asthma drugs are mainly divided into the following drugs: glucocorticoid, beta 2-adrenoceptor agonist, leukotriene receptor antagonist, anticholinergic preparation, theophylline medicine, immunotherapy, antiallergic therapy, traditional Chinese medicine and the like, wherein the beta 2-adrenoceptor agonist is one of the first-choice therapeutic drugs for acute asthma attack and is widely used at home and abroad in clinic.
The albuterol is a novel beta 2-adrenoceptor agonist which is researched and developed by pharmaceutical chemistry laboratories of Shenyang pharmaceutical university, has independent intellectual property rights, has the characteristics of small dosage, long action time, low toxic and side effects, strong specificity (only acts on beta 2 receptors but does not act on beta 1 receptors), capability of controlling nocturnal attacks and the like, and has remarkable asthma relieving effect.
Currently, the dosage forms of albuterol are tablets and aerosols. Research shows that the blood concentration reaches the maximum value after 0.75-2.0h of the healthy human body is administered with the albuterol, the peak reaching time is fast, and asthma usually attacks at night and does not accord with chronopharmacology; but also has side effects on the gastrointestinal tract after oral administration; meanwhile, asthma is frequently observed in children and the elderly, and has poor swallowing ability, so that it is not suitable for oral tablet administration. For the aerosol, the absorption is often incomplete due to more interference factors of lung absorption, and the aerosol needs a pressure-resistant container and a valve system, so the cost is higher; meanwhile, the aerosol is a pressurized container, has certain internal pressure, is easy to explode after being heated or impacted, and has low safety index for patients suffering from acute asthma. Therefore, the development of a new Chuangbuterol preparation which is convenient to use, does not need to be administrated for multiple times, avoids the first-pass effect of the liver and the side effect of the drug on the gastrointestinal tract and has higher safety and higher patient compliance has great significance.
Transdermal Drug Delivery Systems (TDDS) refers to a class of formulations in which a drug is absorbed into the systemic circulation through the skin via capillary blood vessels at a certain rate, thereby achieving a local or systemic therapeutic effect. Has the effects of preventing first pass effect of liver and adverse side effect of medicine on gastrointestinal tract; the constant blood concentration is maintained for a long time, and the toxic and side effects of the medicine are reduced; the administration times can be reduced, and the compliance of patients is improved; convenient use, can interrupt drug administration at any time when side effects are found, and the like.
At present, no commercial product of the Chuangbuterol patch is available at home and abroad, so that the preparation of the Chuangbuterol patch has important significance for preventing gastrointestinal irritation and poor safety of aerosol administration caused by oral administration of tablets, fixing the medicament absorption area, generating slow release effect and stabilizing blood concentration, thereby reducing administration frequency and achieving long-acting and stable treatment effect.
Disclosure of Invention
In order to solve the technical problems, the invention provides a Chuangbuterol transdermal patch with simple structure and good transdermal permeability and a preparation method thereof. The invention particularly adopts a method of combining the ion pair and the penetration enhancer, thereby increasing the cumulative penetration of the salbutamol and improving the utilization rate of the patch.
Specifically, the invention is realized by the following technical schemes:
in a first aspect, the invention provides a Chuangbuterol transdermal patch, which is composed of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer, wherein the drug-loaded pressure-sensitive adhesive layer comprises Chuangbuterol free base or an organic acid ion pair compound thereof, pressure-sensitive adhesive and a percutaneous absorption enhancer, wherein the dosage of the Chuangbuterol free base or the organic acid ion pair compound thereof is 2-15 wt%, the dosage of the pressure-sensitive adhesive is 70-95 wt%, and the dosage of the percutaneous absorption enhancer is 0-20 wt%.
Preferably, the amount of the free base or the organic acid ion pair compound of the albuterol accounts for 2-10 wt%, the amount of the pressure-sensitive adhesive accounts for 80-95 wt%, and the amount of the percutaneous absorption enhancer accounts for 0-10 wt%.
More preferably, the content of the free base or the organic acid ion pair compound of the albuterol is 2 to 8 weight percent, the content of the pressure-sensitive adhesive is 90 to 95 weight percent, and the content of the percutaneous absorption enhancer is 0 to 5 weight percent
Alternatively, in the above-mentioned salbutamol transdermal patch, the salbutamol organic acid ion pair complex is selected from one or more of salbutamol salicylate ion pair complex, salbutamol benzoate ion pair complex, salbutamol p-aminobenzoate ion pair complex, salbutamol tetradecanoate ion pair complex, or salbutamol oleate ion pair complex.
Alternatively, in the above-mentioned salbutamol transdermal patch, the compound of salbutamol organic acid ion pair is prepared by reacting free salbutamol base with different organic acids, wherein the molar ratio of the free salbutamol base to the different organic acids is 1:1, and the organic acids are selected from salicylic acid, benzoic acid, p-aminobenzoic acid, tetradecanoic acid or oleic acid.
Preferably, the albuterol free base is provided in professor in sheng yang medicine science.
In addition, preferably, the compound of the albuterol organic acid ion pair is synthesized by the following method:
(1) dissolving the free base of the albuterol in acetone;
(2) according to the kind of the prepared albuterol organic acid ion pair compound, salicylic acid, benzoic acid, p-aminobenzoic acid, myristic acid or oleic acid are added in proportion;
(3) and uniformly stirring the mixture at room temperature for 2 hours, and evaporating the solvent to dryness to obtain the compound of the organic acid ion pair of the salbutamol.
Alternatively, in the above-mentioned albuterol transdermal patch, the base material of the pressure-sensitive adhesive is an acrylic polymer containing no functional group and a derivative thereof.
Preferably, the matrix material of the pressure-sensitive adhesive is selected from one or more of silicone, polyisobutylene, polyacrylate or cellulose and derivatives thereof,
more preferably, the pressure-sensitive adhesive is the pressure-sensitive adhesive with the code number DT-4098.
Alternatively, in the above-mentioned albuterol transdermal patch, in order to further increase the cumulative permeation amount of the drug, the percutaneous absorption enhancer to be added is one or more selected from the group consisting of alcohols, sulfoxides, fatty acids and esters, surfactants, terpenes, amines, amides, amino acids and esters thereof, and phospholipid compounds.
Preferably, the percutaneous absorption enhancer is selected from one or more of span 80, tween 80, azone, menthol, isopropyl myristate, propylene glycol, glycerol, polyglycerol fatty acid ester or diethylene glycol monoethyl ether.
More preferably, the percutaneous absorption enhancer is selected from polyglycerin fatty acid esters.
Optionally, in the above-mentioned albuterol transdermal patch, the backing layer is made of a material selected from an aluminum-polyethylene composite film, a polyester composite film, a polyurethane film, a polyethylene single-layer film, a polyolefin single-layer film, an ethylene vinyl acetate film, or an elastic nonwoven fabric.
Alternatively, in the above-mentioned albuterol transdermal patch, the material for the release layer is selected from a silicone oil release-treated or fluorine-containing polyester film or paper, a fluoropolymer-coated polyester film release film, or a polyester fluoropolymer-coated polyester film release film.
Optionally, in the above albuterol transdermal patch, the drug-loaded pressure-sensitive adhesive layer further comprises one or more of inert filler, plasticizer, tackifier or antioxidant, and if used, the amount of the one or more of inert filler, plasticizer, tackifier or antioxidant is 1-10 wt%, the thickness of the drug-loaded pressure-sensitive adhesive layer is 30-100 μm, and the patch area is 1.13cm2。
In a second aspect, the invention provides a method for preparing a albuterol transdermal patch according to the first aspect, wherein the albuterol free base or the albuterol organic acid ion pair complex and the transdermal enhancer are dissolved in a suitable organic solvent according to the dosage ratio of the first aspect, and a suitable amount of one or more of inert filler, plasticizer, tackifier or antioxidant is added or not added according to the requirement, the pressure-sensitive adhesive is added according to the dosage ratio of the first aspect, the mixture is fully mixed and then is transfer-coated on the anti-sticking layer, and after drying at 40-80 ℃, the backing layer is covered and punched into a certain size and specification, thus the albuterol transdermal patch is prepared.
Optionally, in the preparation method of the albuterol transdermal patch, the organic solvent is a ketone, a fatty alcohol ester, or a mixture of two or more thereof.
In a third aspect, the present invention provides the use of a salbutamol transdermal patch according to the first aspect above in the manufacture of a medicament for the treatment of bronchial asthma.
Compared with the prior art, the invention has the following beneficial effects:
the Chuangbuterol transdermal patch adopts a method of combined application of ion pairs and transdermal enhancers, thereby increasing the cumulative permeation amount of the Chuangbuterol and improving the utilization rate of the patch; the preparation agent of the patch has simple technology, good mechanical property and convenient use.
Drawings
FIG. 1: the screening experiment result of the pressure-sensitive adhesive type prescription of the Chuangbuterol transdermal patch.
FIG. 2: the screening experiment result of the drug-loading prescription of the Chuangbuterol transdermal patch.
FIG. 3: the counter ion type prescription of the Chuangbuterol transdermal patch screens the experimental result.
FIG. 4: the screening experiment result of the transdermal enhancer type prescription of the Chuangbuterol transdermal patch.
FIG. 5: the screening experiment result of the type formula of the back lining layer of the Chuangbuterol transdermal patch.
FIG. 6: the result of the screening experiment of the transdermal enhancer content prescription of the Chuangbuterol transdermal patch.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
0.052mmol of free albuterol and 2g of acrylate pressure-sensitive adhesive DT-2510 are mixed uniformly, transferred and coated on an anti-sticking layer, dried at 50 ℃ for 10min, and then subjected to CoTranTM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 2
0.052mmol of free base of Chuanbuterol is mixed with 2g of pressure-sensitive acrylate adhesive DT-4098, transferred and coated on the anti-sticking layer, dried at 50 ℃ for 10min, and then applied with CoTranTM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 3
0.052mmol of free base of Chuanbuterol is mixed with 2g of pressure-sensitive acrylate adhesive DT-2852, transferred and coated on the anti-sticking layer, dried at 50 ℃ for 10min, and then applied with CoTranTM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
In vitro transdermal permeation assay:
taking healthy male Wistar rats with the weight of 180-220g, anesthetizing with 20% (w/v) urethane, shaving off long hairs on the abdomen with a pet trimmer, removing residual short hairs on the abdomen with an electric shaver, removing cervical vertebrae, killing, taking down the skin on the abdomen, removing subcutaneous fat and tissues, washing with normal saline, and storing at-70 ℃ for later use.
Adopting horizontal double-chamber diffusion cell to perform in vitro percutaneous permeation experiment, removing the anti-sticking layer from the patch, sticking the patch to stratum corneum of in vitro rat skin, fixing between the horizontal double-chamber diffusion cells, placing a rotor, adding 3.5mL of receiving medium PBS (pH 7.4) into the receiving cell, wherein the effective diffusion area is 1.13cm2At a temperature of 32 c,stirring at a constant speed of 500-600rpm, sampling 2mL at a specified time point, and supplementing 2mL of blank receiving solution.
Table 1: 24h cumulative transmission of Chuangbuterol free base in different pressure-sensitive adhesives (mean value soil S.D.) (n ═ 3)
And (4) conclusion: the highest amount of transterol was found in the pressure-sensitive adhesive containing hydroxyl functional groups, followed by the pressure-sensitive adhesive without functional groups, and the lowest amount of transterol was found in the pressure-sensitive adhesive containing carboxyl functional groups. Since the mechanical properties of the pressure-sensitive adhesive patch containing a hydroxyl functional group are not so good, the mechanical properties and the drug permeation amount of the patch are considered in combination, and therefore, a pressure-sensitive adhesive having no functional group is preferable.
Example 4
Mixing 0.077mmol of free base of Chuanbuterol with 2g of pressure-sensitive acrylate adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 5
Mixing 0.129mmol of free base of Chuanbuterol with 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 6
Mixing 0.258mmol of free base of Chuanbuterol with 2g of pressure-sensitive acrylate adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Table 2: 24h cumulative penetration of free albuterol base (mean value soil S.D.) (n ═ 3) at different drug loading rates
And (4) conclusion: the cumulative permeation amount of the albuterol increases with the increase of the drug-loading amount in the patch, and after the utilization rate of the patch is calculated, the skin permeation amount and the utilization rate are comprehensively considered, and the drug-loading amount is preferably 5%.
Example 7
Dissolving 0.1mol of free base of the salbutamol in 40mL of acetone, adding 0.1mol of salicylic acid while stirring, continuing stirring for 2 hours, and evaporating to evaporate the solvent by rotation to obtain the salbutamol salicylate ion pair compound.
Example 8
Dissolving 0.1mol of free base of the salbutamol in 40mL of acetone, adding 0.1mol of benzoic acid while stirring, continuing stirring for 2 hours, and evaporating the solvent by rotation evaporation to obtain the salbutamol benzoate ion pair compound.
Example 9
Dissolving 0.1mol of free albuterol in 40mL of acetone, adding 0.1mol of p-aminobenzoic acid while stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the compound of the albuterol ion pair of p-aminobenzoic acid.
Example 10
Dissolving 0.1mol of free base of the salbutamol in 40mL of acetone, adding 0.1mol of tetradecanoic acid while stirring, continuing stirring for 2 hours, and performing rotary evaporation to volatilize the solvent to obtain the salbutamol tetradecanoic acid ion pair compound.
Example 11
Dissolving 0.1mol of free base of the salbutamol oleate in 40mL of acetone, adding 0.1mol of oleic acid while stirring, continuing stirring for 2 hours, and evaporating the solvent by rotation evaporation to obtain the salbutamol oleate ion pair compound.
Example 12
Mixing 0.129mmol of salbutamol salicylate ion pair complex with 2g of acrylate pressure sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 13
Mixing 0.129mmol of Chuanbuterol benzoate ion pair compound with 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and then using CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 14
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair compound with 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and then using CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 15
Mixing 0.129mmol of Chunbuterol myristate ion pair complex with 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 16
Mixing 0.129mmol of Chuanbuterol oleate ion pair compound with 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Table 3: influence of organic acid on cumulative drug penetration in a Chuangbuterol transdermal patch (mean value of the soil S.D.) (n ═ 3)
And (4) conclusion: the cumulative permeation amount is increased only when the salbutamol base and the p-aminobenzoic acid form an ion pair complex, and is reduced to different degrees when the salbutamol base and the other 5 organic acids form the ion pair complexes, so that the salbutamol base and the salbutamol base form the ion pair complex preferably.
Example 17
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 18
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair compound, 0.08g of span 80 and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and then using CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 19
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of isopropyl myristate and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 20
Mixing 0.129mmol of p-aminobenzoic acid-Chunbuterol ion-pair complex, 0.08g of azone and 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and coating with CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 21
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of menthol and 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and coating with CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 22
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair compound, 0.08g of diethylene glycol monoethyl ether and 2g, fully and uniformly mixing the acrylate pressure-sensitive adhesive DT-4098, transferring and coating the mixture on an anti-sticking layer, drying the mixture for 10min at 50 ℃, and then using CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 23
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of Tween 80 and 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 24
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair compound, 0.08g of propylene glycol and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and then using CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 25
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of glycerol and 2g of acrylate pressure-sensitive adhesive DT-4098, coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9733 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Table 4: influence of different promoters on cumulative drug penetration of the trometamol p-aminobenzoate ion in the composite patch (mean s.d.) (n ═ 3)
And (4) conclusion: compared with the group without the transdermal enhancer, the transdermal enhancer such as polyglycerol fatty acid ester, span 80, isopropyl myristate, azone and menthol can increase the cumulative penetration of the medicament to different degrees, while the transdermal enhancer such as diethylene glycol monoethyl ether, tween 80, propylene glycol and glycerol has different inhibiting effects, wherein the polyglycerol fatty acid ester has the largest transdermal effect on the salbutamol and the highest 24h cumulative penetration of the medicament, so the polyglycerol fatty acid ester is preferably used as the transdermal enhancer of the patch.
Example 26
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9720 backing, die-cut to size, gauge patch. The thickness of the glue layer is 70 μm.
Example 27
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9728 backing, die cut to size, gauge patch. The thickness of the glue layer is 70 μm.
Example 28
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9705 backing is covered and die-cut into patch of certain size and specification. The thickness of the glue layer is 70 μm.
Example 29
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.08g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9680 backing, and die cutting to obtain patch with certain size and specification. The thickness of the glue layer is 70 μm.
Table 5: effect of different backing layers on cumulative drug penetration of salbutamol p-aminobenzoate ions in the composite patch (mean s.d.) (n ═ 3)
And (4) conclusion: the effects of the five backing materials on the cumulative amount of drug penetration are not very different due to CoTran TM9720 the CoTran is preferred because the drug has a higher 24h cumulative permeation amount and better mechanical problems such as air permeability and followability TM9720 backing.
Example 30
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion-pair complex, 0.024g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and adding CoTran TM9720 backing, die-cut to size, gauge patch. The thickness of the glue layer is 70 μm.
Example 31
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.04g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9720 backing, die-cut to size, gauge patch. The thickness of the glue layer is 70 μm.
Example 32
Mixing 0.129mmol of p-aminobenzoic acid-Chuanbuterol ion pair complex, 0.064g of polyglycerol fatty acid ester and 2g of acrylate pressure-sensitive adhesive DT-4098, transferring and coating on the anti-sticking layer, drying at 50 deg.C for 10min, and performing CoTran TM9720 backing, die-cut to size, gauge patch. The thickness of the glue layer is 70 μm.
Table 6: influence of different content of polyglycerol fatty acid ester on cumulative drug permeability of tromethamine aminobenzoate in compound patch (average value soil S.D.) (n ═ 3)
And (4) conclusion: the cumulative permeation amount of the drug increases with the increase of the amount of the permeation enhancer, and considering the cumulative permeation amount of the drug and the irritation of the permeation enhancer in combination, the amount of the polyglycerin fatty acid ester is preferably 1.9 wt%.
In conclusion, the invention successfully prepares the Chuangbuterol transdermal patch by particularly adopting a method of combining the ion pair with the transdermal enhancer. The transdermal patch increases the cumulative permeation amount of the salbutamol, and improves the utilization rate of the patch. In addition, the preparation agent of the patch has simple technology, good mechanical property and convenient use.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A Chuangbuterol transdermal patch is characterized in that: the transdermal patch consists of a back lining layer, a drug-loaded pressure-sensitive adhesive layer and an anti-sticking layer, wherein the drug-loaded pressure-sensitive adhesive layer comprises the free base of the salbutamol or the organic acid ion pair compound thereof, the pressure-sensitive adhesive and a percutaneous absorption enhancer, the dosage of the free base of the salbutamol or the organic acid ion pair compound thereof accounts for 2-15 wt%, the dosage of the pressure-sensitive adhesive accounts for 70-95 wt%, and the dosage of the percutaneous absorption enhancer accounts for 0-20 wt%, preferably, the dosage of the free base of the salbutamol or the organic acid ion pair compound thereof accounts for 2-10 wt%, the dosage of the pressure-sensitive adhesive accounts for 80-95 wt%, and the dosage of the percutaneous absorption enhancer accounts for 0-10 wt%, and more preferably, the dosage of the free base of the salbutamol or the organic acid ion pair compound thereof accounts for 2-8 wt%, and the dosage of the pressure-sensitive adhesive accounts for 90-95 wt%, and the dosage of the percutaneous absorption enhancer is 0-5 wt%.
2. The Chuangbuterol transdermal patch according to claim 1, characterized in that: the compound of the salbutamol organic acid ion pair is selected from one or more of a salbutamol salicylate ion pair compound, a salbutamol benzoate ion pair compound, a salbutamol p-aminobenzoate ion pair compound, a salbutamol tetradecanoate ion pair compound or a salbutamol oleate ion pair compound.
3. A salbutamol transdermal patch according to claim 1 or claim 2, wherein: the compound of the salbutamol organic acid ion pair is prepared by reacting salbutamol free alkali with different organic acids, wherein the molar ratio of the salbutamol free alkali to the different organic acids is 1:1, and the organic acids are selected from salicylic acid, benzoic acid, p-aminobenzoic acid, tetradecanoic acid or oleic acid.
4. A salbutaterol transdermal patch according to any one of claims 1 to 3, wherein: the matrix material of the pressure-sensitive adhesive is acrylic polymer without functional groups and derivatives thereof.
5. A salbutamol transdermal patch according to any one of claims 1 to 4, wherein: the percutaneous absorption enhancer is selected from one or more of alcohols, sulfoxides, fatty acids and esters, surfactants, terpenes, amines, amides, amino acids and esters thereof or phospholipid compounds, and preferably, the percutaneous absorption enhancer is selected from one or more of span 80, tween 80, azone, menthol, isopropyl myristate, propylene glycol, glycerol, polyglycerol fatty acid ester or diethylene glycol monoethyl ether.
6. A salbutamol transdermal patch according to any one of claims 1 to 5, wherein: the backing layer is made of a material selected from an aluminum polyethylene composite film, a polyester composite film, a polyurethane film, a polyethylene single-layer film, a polyolefin single-layer film, an ethylene vinyl acetate film or an elastic non-woven fabric, and/or the anti-sticking layer is made of a material selected from a polyester film or paper with the surface subjected to silicone oil anti-sticking treatment or containing fluorine, a fluorine polymer coating polyester film release film or a polyester fluorine polymer coating polyester film release film.
7. A salbutamol transdermal patch according to any one of claims 1 to 6, wherein: the medicine-carrying pressure-sensitive adhesive layer also comprises an inert filler,One or more of plasticizer, tackifier or antioxidant, if used, the dosage is 1-10 wt%, the thickness of the medicine-carrying pressure-sensitive adhesive layer is 30-100 μm, and the patch application area is 1.13cm2。
8. A method of preparing a albuterol transdermal patch according to any of claims 1-7, wherein: dissolving the free base or the organic acid ion pair compound of the albuterol and the percutaneous promoter in a proper organic solvent according to the dosage proportion of any one of claims 1 to 7, adding or not adding a proper amount of one or more of inert fillers, plasticizers, tackifiers or antioxidants according to the dosage proportion of any one of claims 1 to 7, fully mixing, transferring and coating the pressure-sensitive adhesive on the anti-adhesion layer, drying at 40 to 80 ℃, covering the back lining layer, and punching into a certain size and specification to obtain the albuterol transdermal patch.
9. The method of preparing a Chuangbuterol transdermal patch according to claim 8, characterized in that: the organic solvent is ketone, fatty alcohol ester or a mixture of two or more of them.
10. Use of a salbutamol transdermal patch according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of bronchial asthma.
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