CN107028919B - Compound aescin A, B liposome hydrogel patch - Google Patents
Compound aescin A, B liposome hydrogel patch Download PDFInfo
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- CN107028919B CN107028919B CN201710325262.9A CN201710325262A CN107028919B CN 107028919 B CN107028919 B CN 107028919B CN 201710325262 A CN201710325262 A CN 201710325262A CN 107028919 B CN107028919 B CN 107028919B
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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
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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
- A61K31/60—Salicylic acid; Derivatives thereof
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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Abstract
The invention discloses an anti-swelling pharmaceutical composition, which consists of aescin A or salt thereof, aescin B or salt thereof, and diethylamine salicylate in a ratio of 0.3-1.5: 0.5-1: 2-5. The invention also discloses a compound aescin A, B liposome hydrogel patch containing the composition and a preparation method thereof. Compared with the prior art, the invention has better transdermal absorption effect, anti-swelling effect and safety.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to an anti-swelling pharmaceutical composition, and also relates to a compound aescin A, B liposome hydrogel patch containing the composition and a preparation method thereof.
Background
Aescin, also called as aescin acid, is the general name of total saponin extracted from aesculus plant seed of aesculaceae, β -aescin or isoaescin, and belongs to the class of triterpenoid saponin, which has relatively low water solubility and is prepared into sodium salt for raising its solubility.
The aescin has low oral bioavailability and great irritation to blood vessel, and reaches inside body via skin permeation with external medicine application, and has the advantages of ① being capable of avoiding the first pass effect of liver and the degradation of medicine in gastrointestinal tract, reducing medicine application difference, ② being capable of making medicine enter body at constant rate for long time, reducing medicine application frequency, prolonging medicine application interval, ③ being capable of avoiding peak valley of blood medicine concentration caused by oral medicine application and lowering toxic side effect.
The existing aescin external preparation has the defects of poor transdermal absorption effect, short treatment time, large skin irritation, unsatisfactory swelling resistance effect and the like.
The diethylamine salicylate has antiinflammatory and analgesic effects, and can be used for treating rheumatism and rheumatoid arthritis.
Disclosure of Invention
The invention aims to provide an anti-swelling pharmaceutical composition, a compound aescin A, B liposome hydrogel patch containing the composition and a preparation method thereof, aiming at the defects of poor transdermal absorption effect, large skin irritation, short treatment time, unsatisfactory anti-swelling effect and the like of the existing aescin external preparation.
The anti-swelling pharmaceutical composition provided by the invention comprises aescin A or a salt thereof, aescin B or a salt thereof, and diethylamine salicylate, wherein the weight ratio of the aescin A or the salt thereof, the aescin B or the salt thereof, and the diethylamine salicylate is 0.3-1.5: 0.5-1: 2-5.
The compound aescin A, B liposome hydrogel patch provided by the invention comprises an adhesive layer, a back lining layer and liposome hydrogel covering the adhesive layer, wherein the active ingredients of the liposome hydrogel are the anti-swelling pharmaceutical composition, and the balance is liposome hydrogel matrix.
Preferably, the liposome hydrogel consists of the following components in parts by weight:
further preferably, the liposome hydrogel is composed of the following components in parts by weight:
preferably, the phospholipid is soybean phospholipid or lecithin.
Preferably, the antioxidant is ascorbic acid.
Preferably, the gel matrix polymer material is one or more of cellulose derivatives, carbomer, alginate, polyvinyl alcohol, polyvinylpyrrolidone, tragacanth, gelatin and carrageenan. Among these, cellulose derivatives include, but are not limited to, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and the like.
Preferably, the humectant is one or more of glycerin, sorbitol, propylene glycol.
Preferably, the penetration enhancer is one or more of azone, borneol and mint.
Preferably, the solvent is an ethanol solution with a weight concentration of 20-50%.
The preparation method of the compound aescin A, B liposome hydrogel patch provided by the invention comprises the following steps:
1) dissolving phospholipid, cholesterol and an antioxidant in a solvent, adding aescin A or a salt thereof, aescin B or a salt thereof and diethylamine salicylate, uniformly mixing, placing in a constant-temperature water bath at the temperature of 30-50 ℃, performing rotary evaporation to form a film, adding a buffer solution with the pH of 5-7, stirring and shaking to form a suspension, and filtering to obtain a liposome solution;
2) taking a gel matrix polymer material, adding a solvent, stirring and fully swelling, adding a humectant, a penetration enhancer and the liposome solution obtained in the step 1), adjusting the pH value to 4.0-6.5, continuously stirring and uniformly mixing, ultrasonically degassing until no bubbles exist, coating on an adhesive layer, airing until the surface is solidified, then covering a back lining layer, cutting into a proper size, sealing and packaging to obtain the gel matrix polymer material.
The invention has the beneficial effects that:
1. compared with the common patch, the invention has better transdermal absorption effect, which is mainly embodied in the following two points: 1) the total transmittance is high; 2) has the effect of sustained and controlled release, and the medicament can be slowly released at a certain speed, thereby forming constant blood concentration in the skin and being beneficial to prolonging the treatment time of the medicament.
2. Has better anti-swelling capacity, and the aescin A, the aescin B and the diethylamine salicylate have obvious synergistic effect.
3. Has low skin irritation and high safety.
Detailed Description
The present invention will be described in detail below with reference to examples.
Example 1
The preparation method comprises the following steps: 1) putting 25g of soybean phospholipid, 5g of cholesterol and 0.5g of ascorbic acid into a container, adding 200g of 30% ethanol solution for dissolving, then adding aescin A1g, 0.6g of aescin B and 2.5g of diethylamine salicylate, uniformly mixing, placing in a constant-temperature water bath at 45 ℃, carrying out rotary evaporation to remove the solvent until a film is formed, then adding PBS buffer solution with the pH of 6, stirring and shaking until a suspension is formed, filtering, and collecting filtrate to obtain 65g of liposome solution;
2) taking 5g of carbomer, adding 60g of 30% ethanol solution, stirring for full swelling, adding 2g of glycerol, 3.5g of azone and 65g of liposome solution obtained in the step 1), adjusting the pH value to 6 with hydrochloric acid, continuously stirring, uniformly mixing, ultrasonically degassing until no bubbles exist to obtain 135g of compound aescin liposome hydrogel, coating, airing until the surface is solidified, covering a back lining layer, cutting into a proper size, sealing, and packaging to obtain the patch containing 100g of liposome hydrogel.
Example 2
The preparation method comprises the following steps: 1) putting 15g of lecithin, 8g of cholesterol and 0.2g of ascorbic acid into a container, adding 150g of 40% ethanol solution for dissolving, adding 1.2g of sodium aescinate A, 0.5g of sodium aescinate B and 2g of diethylamine salicylate, uniformly mixing, placing in a constant-temperature water bath at the temperature of 40 ℃, rotationally evaporating to remove the solvent until a film is formed, then adding PBS (phosphate buffer solution) with the pH of 5.5, stirring and shaking until a suspension is formed, filtering, and collecting the filtrate to obtain 55g of liposome solution;
2) taking 3g of hydroxypropyl methyl cellulose, adding 70g of 40% ethanol solution, stirring and fully swelling, then adding 1.5g of glycerol, 0.5g of propylene glycol, 1.5g of borneol and 1g of mint, and 55g of liposome solution obtained in the step 1), adjusting the pH value to 5 by using hydrochloric acid, continuously stirring and uniformly mixing, ultrasonically degassing until no bubbles exist to obtain 132g of compound aescin liposome hydrogel, coating, airing until the surface is solidified, covering a back lining layer, cutting into proper size, sealing and encapsulating to obtain the patch containing 100g of liposome hydrogel.
Example 3
The preparation method comprises the following steps: 1) putting 20g of lecithin, 3g of cholesterol and 0.8g of ascorbic acid into a container, adding 150g of a 25% ethanol solution for dissolving, adding 0.5g of aescin A lysine salt, 1g of aescin B lysine salt and 4g of diethylamine salicylate, uniformly mixing, placing in a constant-temperature water bath at 50 ℃, carrying out rotary evaporation to remove the solvent until a film is formed, adding a PBS (phosphate buffer solution) with the pH of 7, stirring and shaking until a suspension is formed, filtering, and collecting filtrate to obtain 70g of a liposome solution;
2) taking 4g of sodium alginate and 2g of gelatin, adding 60g of 25% ethanol solution, stirring and fully swelling, adding 1g of glycerol, 2g of azone and 70g of liposome solution obtained in the step 1), adjusting the pH value to 5.5 by using hydrochloric acid, continuously stirring and uniformly mixing, ultrasonically degassing until no bubbles exist to obtain 139g of compound aescin liposome hydrogel, coating, airing until the surface is solidified, covering a back lining layer, cutting into proper size, sealing, and packaging to obtain the patch containing 100g of liposome hydrogel.
Test examples
1. Transdermal absorption test
Taking SD rat, adopting 10% Na2Removing hair on the back with the aqueous solution, cutting off the neck the next day, immediately cutting off the skin on the back, removing subcutaneous tissues and fat, repeatedly washing with normal saline, cutting into proper size, and checking the integrity of the skin. The improved Franz vertical double-chamber diffusion cell (effective area is 2.92 cm)2) The liposome hydrogel patch prepared in examples 1 to 3 was precisely 0.5g taken and placed in the supply chamber, and 7M L receiving solution, which was PBS buffer (0.01M, ph7.4), was added to the receiving chamber, and constant temperature water bath was set at 32 ℃, and magnetic stirring was performed at 150r/min, 0.5M L receiving solution was taken at 2, 4, 6, 8, 10, and 12 hours, while 0.5M L PBS buffer was supplemented, and after filtration through a 0.45 μ M filter membrane, 20 μ L was injected to measure escin a or its salt, escin B or its salt, and diethylamine salicylate, and the drug concentration and cumulative transmittance were calculated.
The results of the cumulative transmittance-time of escin A or its salt, escin B or its salt, and diethylamine salicylate are shown in tables 1-3.
Table 1 cumulative transmittance (%)
Table 2 cumulative transmittance (%)
Table 3 cumulative transmittance (%)
From the above results, 1) the invention has higher total transmittance, wherein the 12-hour total transmittance of the aescin A or the salt thereof is more than 35%, the 12-hour total transmittance of the aescin B or the salt thereof is more than 28%, and the 12-hour total transmittance of the diethylamine salicylate is more than 27%, which are all obviously higher than that of the common patch; 2) the sustained-release patch has sustained and controlled-release effects, can be slowly released at a certain speed, so that constant blood concentration is formed in the skin, the treatment time of the drug is prolonged, and the release speed of the common patch is high, and the peak value can be reached within about 4 hours.
2. Anti-swelling test
A mouse ear swelling model is adopted, a blank group, an aescin A group, an aescin B group, a diethylamine salicylate group and an aescin A + aescin B + diethylamine salicylate composition group are arranged, 10 animals in each group are subjected to swelling degree measurement after medicine application, and the results are shown in table 4.
Table 4 test results of swelling resistance (n ═ 10)
The results show that the anti-swelling capacity of the composition is obviously better than that of the single use of the aescin A, the aescin B and the diethylamine salicylate, and the results prove that the three have synergistic effect.
3. Skin irritation test
20 healthy rabbits (2.0 +/-0.2 kg) were randomly divided into 2 groups, each of which was divided into two halves, and the skin irritation of the liposome hydrogel patch prepared in example 1 and the escin A conventional patch (not containing escin B and diethylamine salicylate) prepared by a conventional method was examined 24 hours before administration, both side hairs of the spinal column of the animal were removed with a 10% sodium sulfide solution, the hair removal range of each side was about 3cm × 3cm, and the epidermis could not be damaged.
Table 5 skin irritation test results
From the above results, it can be seen that the skin irritation reaction incidence of the invention is low, no erythema or edema appears in 1 case, while the skin irritation reaction incidence of the escin a common patch is high, the symptoms are more serious, the improvement is slow, and after stopping the drug for 6 hours, 1 case has slight erythema and edema, which indicates that the safety of the invention is better than that of the common patch.
Claims (3)
1. A compound aescin A, B liposome hydrogel patch comprises an adhesive layer, a back lining layer and liposome hydrogel covering the adhesive layer, and is characterized in that: the liposome hydrogel comprises the following components in parts by weight:
the phospholipid is soybean phospholipid or lecithin;
the antioxidant is ascorbic acid;
the gel matrix high polymer material is one or more of ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, carbomer, alginate, polyvinyl alcohol, polyvinylpyrrolidone, tragacanth, gelatin and carrageenan;
the humectant is one or more of glycerol, sorbitol and propylene glycol;
the penetration enhancer is one or more of azone, borneol and mint;
the solvent is an ethanol solution with the weight concentration of 20-50%.
3. a method for preparing the compound aescin A, B liposome hydrogel patch as claimed in claim 1 or 2, which comprises the following steps:
1) dissolving phospholipid, cholesterol and an antioxidant in a solvent, adding aescin A or a salt thereof, aescin B or a salt thereof and diethylamine salicylate, uniformly mixing, placing in a constant-temperature water bath at the temperature of 30-50 ℃, performing rotary evaporation to form a film, adding a buffer solution with the pH of 5-7, stirring and shaking to form a suspension, and filtering to obtain a liposome solution;
2) taking a gel matrix polymer material, adding a solvent, stirring and fully swelling, adding a humectant, a penetration enhancer and the liposome solution obtained in the step 1), adjusting the pH value to 4.0-6.5, continuously stirring and uniformly mixing, ultrasonically degassing until no bubbles exist, coating on an adhesive layer, airing until the surface is solidified, then covering a back lining layer, cutting into a proper size, sealing and packaging to obtain the gel matrix polymer material.
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Families Citing this family (7)
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CN107496358A (en) * | 2017-09-06 | 2017-12-22 | 苏州大学 | A kind of enhanced hydrogel of liposome and its application |
CN108635524A (en) * | 2018-07-27 | 2018-10-12 | 山东今古医疗科技有限公司 | Nano traditional Chinese medicine liposome aqueogel for treating anorectal disease and preparation method |
CN108837056A (en) * | 2018-07-27 | 2018-11-20 | 山东今古医疗科技有限公司 | For treating the nano traditional Chinese medicine liposome aqueogel and preparation method of skeletal joint disease |
CN108567885A (en) * | 2018-07-27 | 2018-09-25 | 山东今古医疗科技有限公司 | Nano traditional Chinese medicine liposome aqueogel and preparation method for treating fat and fatty liver |
CN109464623A (en) * | 2018-11-23 | 2019-03-15 | 山东今古医疗科技有限公司 | For treating thyroid nodule Chinese medicine alcohol ester body cold compress gel and preparation method |
CN111249226B (en) * | 2020-03-24 | 2021-06-15 | 中南大学 | Aescin injectable hydrogel and preparation method and application thereof |
CN112546083A (en) * | 2020-12-22 | 2021-03-26 | 黑龙江迪龙制药有限公司 | Compound preparation containing sodium aescinate for relieving swelling and pain and preparation method thereof |
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CN102048745A (en) * | 2009-10-30 | 2011-05-11 | 重庆医药工业研究院有限责任公司 | Compound sodium aescinate cataplasm |
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