Cataplasma of bulleyaconitine A
Technical field
The present invention relates to a kind of exterior-applied formulation-cataplasma that can be used for various treatment of pain and have the bulleyaconitine A of certain antiinflammatory, analgesic drawn game anaesthetic effect.
Background technology
Cataplasma system is with medicine dissolution or be mixed in natural and the synthesizing water-solubility macromolecular material substrate, and the stand is applied on the back lining materials, for sticking external preparation in skin, plays general action or local action through Transdermal absorption, also belong to Percutaneously administrable preparation, its original shape is " poultice ".Because developing rapidly of fields such as modern fine chemistry industry and polymer material science provides the adjuvant of more superior performances for pharmaceutics.Therefore, cataplasma was at first succeeded in developing by Japan in the seventies in last century.In developed country such as American-European-Japanese a large amount of cataplasmas listings are arranged by now, be subjected to doctor and patient's favorable comment deeply.China began this dosage form is studied in the eighties in last century, but its development is slower, has only the product of minute quantity to appear on the market till now.
Cataplasma is that a kind of high in technological content, the applied range in the world today, novel external easy to use stick agent, at the seventies initial stage, states such as Japan, Europe have begun to develop medical cataplasma, continuous development along with medical industry, this novel form develops to some extent in China in recent years, according to World Health Organization's prediction, in afterwards 20~30 years, to there be the medicine more than 30% will make percutaneous drug administration preparation into, will starts the new upsurge of an inner disease outer treat.Compare with traditional external plaster, cataplasma has the following advantages: biocompatibility, affinity, breathability, absorption of perspiration to skin are good, and are not easy allergy; Owing to adopt the water-soluble macromolecule bio-matrix, use back noresidue, not pollution clothes; Because performance of keeping humidity is good, can make the skin keratin cell hydration very soon, helps the Transdermal absorption of medicine, has rapid-action advantage,, use comfortable because permeability is good; To skin nonirritant and sensitization; Can take off subsides repeatedly, not affect the treatment.
Bulleyaconitine A is the secondary metabolism composition of yanaconitine class for the diterpene dibasic acid esters alkaloid that extraction separation the Ranunculaceae aconitum plant tap Aconitum carmichjaelii Debx. (AconitumLongtounense T.L.Ming) that produces from Yunnan comes out.
Bulleyaconitine A (Bulleyaconitione A) chemistry is by name: 3-removes the hydroxyl yanaconitine, English chemistry Aconita-8 by name, 13,14-triol-20-ethyl-1,6,16-trimethoxy-4-(methoxymethyl-8-acetate 14-(4 '-methoxybenzoate), (1 α, 6 α, 14 α, 16 β), fusing point is 166~168 ℃, specific optical rotation
Structural formula:
Molecular formula: C
35H
49O
10N, molecular weight: 643.77, be colourless rib shape crystal.Dissolve in ether, alcohol, sour water, water insoluble, have stronger analgesia and tangible antiinflammatory action.The analgesic activity that experiment showed, this product is a central, and with brain in the level of 5-hydroxy tryptamine close getting in touch arranged, onset time is than morphine slow (average 37.8min), but hold time long (average 9.3h), and does not have addiction.Its antiinflammatory action is not by adrenal gland's system, and relevant with inhibition PG level, this product still has analgesic drawn game anaesthetic effect.After the medication to more no abnormal change before patient's electrocardio, brain electricity, hepatic and renal function and routine urianlysis and the medication.Clinically this product to rheumatic arthritis, rheumatoid arthritis, lumbar muscle strain, scapulohumeral periarthritis, extremity sprain, contusion etc. has curative effect preferably, also can be used for cancer pain, herpes zoster.This product is harmless to the heart, liver,kidney,spleen, stomach function under the therapeutic dose, does not also have obvious toxic-side effects.
The dosage form of the clinical use of bulleyaconitine A has injection and oral formulations (tablet, capsule and oral liquid) etc.Oral administration ubiquity oral cavity is numb, and reactions such as feeling sick also appears in part patient, vomiting, gastrointestinal upset have limited the extensive use clinically of this medicine in a way.Compare with oral Preparation, drug administration by injection is rapid-action, and is evident in efficacy.But because the bulleyaconitine A therapeutic index is narrower, toxic dose and effective dose difference are little, therefore, the higher blood drug level peak value of drug administration by injection is unfavorable for the control of toxic and side effects, in addition, bulleyaconitine A has serious muscle irritation, has shortcomings such as injection site pain, redness, use inconvenience, and patient's compliance is relatively poor.In order to make bulleyaconitine A bring into play clinical efficacy better, press for a kind of safe, easy to use and new formulation that compliance is good clinically.
What the patent of publication number CN1507866A was related is a kind of transdermal patch of bulleyaconitine A, this patch main feature is to have controlled-release function, release is 1~12 day continuously, this transdermal pastes every subsides, and to contain the principal agent bulleyaconitine A be 0.1mg~100mg, because of this transdermal paste poor to biocompatibility, affinity, breathability, the absorption of perspiration of skin, irritated easily; And this transdermal paste onset sticked in the skin time slowly, continuously longer, bigger to skin irritation, be prone to the skin malaise symptoms.
Summary of the invention
Purpose of the present invention aims to provide a kind of safe, effective, side effect is little, compliance is good bulleyaconitine A exterior-applied formulation-cataplasma of bulleyaconitine A.
Cataplasma of bulleyaconitine A of the present invention is the described cataplasma of being made by the pharmaceutical excipient that allows on the bulleyaconitine A of therapeutic dose and the pharmaceutics to add of any pharmaceutics.
Cataplasma of bulleyaconitine A of the present invention is made up of backing layer, ointment-containing body and lid lining (protecting film) three parts.Ointment-containing body contains bulleyaconitine A and one or more excipient of therapeutic dose, comprises in the materials such as sticker, wetting agent, filler, cross-linking agent, transdermal enhancer, pH regulator agent, cross-linking agent one or more; The amount that contains bulleyaconitine A in every plaster is 0.5mg~30mg, and the preferred amounts that contains bulleyaconitine A in every plaster is 2.0mg~10mg.
Ointment-containing body contains following composition or is grouped into by following one-tenth by weight percentage:
Bulleyaconitine A 0.01%~0.1%
Sticker 0~20%
Wetting agent 1%~70%
Filler 5%~20%
Thickening agent 1%~20%
Cross-linking agent 0~2%
Transdermal enhancer 2%~10%
The employed back lining materials of backing layer can be a kind of in cotton, non-woven fabrics, the paper etc.; Lid lining employed lid lining material can be a kind of in separate paper, plastic sheeting, polyester, aluminium foil-polyethylene composite film, the hard gauze etc.
The preparation method of cataplasma of the present invention is:
(1) sticker is dissolved or swelling with suitable quantity of water, add thickening agent;
(2) with wetting agent with filler, mix in the adding (1);
(3) add medicine, transdermal enhancer;
(4) add pH regulator agent, crosslinked adjustment etc. at last.
Its preparation process is as follows:
Bulleyaconitine A of the present invention can add in a variety of forms, can add by common coarse powder, also can other delivery of particulate forms add, as micronization, solid dispersion, clathrate, microsphere, liposome and nanoparticle etc.Medicine is made different carriers with specific macromolecular material, can obtain the cataplasma of different absorption rates and degree of absorption, carriers such as solid dispersion, clathrate, microsphere, liposome and nanoparticle help the chemical stability of bulleyaconitine A in cataplasma simultaneously.
Sticker of the present invention and thickening agent can be one or more in sodium alginate, tragcanth, Resina persicae, arabic gum, corn starch, gelatin, methylcellulose and carboxymethyl cellulose and sodium salt, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, carbomer, polyacrylic acid and the sodium salt thereof etc.Carbomer comprises: Carbopol 934p and sodium salt thereof, Carbopol 971p etc.Polyvinylpyrrolidone comprises: PVPK-30, PVPK-90 etc.
Transdermal enhancer in the preparation of the present invention can be one or more in the transdermal enhancers such as sulfoxide class, pyrrolones, azone (Azone) and analog, fatty acid and ester thereof, surfactant, alcohols, polyalcohols, terpenoid, amine, amide-type, cyclodextrin, aminoacid and ester thereof, macrocyclic compound, organic solvent class, phospholipid.Specifically can be in azone, oleic acid, propylene glycol, dimethyl sulfoxide, Oleum menthae, menthol, Mentholum, Borneolum Syntheticum, the Camphora etc. one or more.
Wetting agent of the present invention can be one or more in glycerol, propylene glycol, Polyethylene Glycol, the sorbitol etc.
Filler of the present invention can be one or more in Kaolin, kaolin, kieselguhr, micropowder silica gel, calcium carbonate, the magnesium hydroxide etc.
Cross-linking agent of the present invention can be disodiumedetate metal-chelators such as (EDTA), aluminum chloride, aluminum glycinate, titanium dioxide, the contour valent metal oxide of zinc oxide, one or more in the pH regulator agent etc.The pH regulator agent can be one or more in triethanolamine, the citric acid etc.
In the cataplasma of bulleyaconitine A of the present invention, can add 0.01%~0.2% Borneolum Syntheticum, Oleum menthae, menthol or Mentholum etc., not only have transdermal enhancing effect, and cooling feeling is arranged, can improve the burning sensation of bulleyaconitine A.
The present invention is for making things convenient for clinical practice and make things convenient for the patient to use, and be convenient to produce etc., specifications design is contained bulleyaconitine A 0.5mg~30mg for each subsides, preferably 2.0mg~10mg uses subsides every day.
Cataplasma of the present invention compared with prior art possesses following characteristics:
1, biocompatibility, affinity, breathability, the absorption of perspiration to skin is good, and is not easy allergy;
2, performance of keeping humidity is good, can make the skin keratin cell hydration very soon, helps the Transdermal absorption of medicine, has rapid-action advantage,
3, permeability is good, uses comfortable;
4, to skin nonirritant and sensitization, be not easy allergy; And this cataplasma is subsides every day one, and therefore every patch amount is less, and the skin malaise symptoms takes place less.
Product of the present invention is through pharmacodynamics test, and its exercising result at antiinflammatory, ease pain is as follows:
One. antiinflammatory action
1. rat carrageenan foot swelling method
The result shows, the obviously swelling of control rats right side foot, and thickness increases, and two foots differ greatly, and administration group two sufficient obvious differences are lower than matched group, show that this product antiinflammatory action is clear and definite, and act on enhancing with the dosage increase, show certain dose-effect relationship.
2. mouse peritoneal vascular permeability
The result shows that this product can be resisted H
+Stimulate increasing of caused mouse peritoneal capillary permeability, inhibitory action strengthens with dosage.
Two. analgesic activity
1. mouse writhing method
The result shows that when giving bulleyaconitine A 0.5mg/kg, the suppression ratio that mice " writhing response " is taken place is 47%; 0.75mg/kg suppression ratio reach 68%, effect is better than aspirin 200mg/kg.
2. mice hot plate method
The result shows, gives bulleyaconitine A 0.5 and 0.75mg/kg, and behind the 45min, the pain response time is delayed, and along with the increase of dosage, action intensity also strengthens, and shows certain dose-effect relationship.
Three. mice formaldehyde shock reaction method (pain model of itching)
The result shows, licks behind normal saline and the blank solvent group injection formaldehyde and stings the metapedes strong reaction, and whole body is restless, anxious.Give this product and can reduce mice and lick and sting the metapedes time, mice is comparatively quiet, and along with dosage increases and effect is strengthened, presents certain dose-effect relationship.Give bulleyaconitine A 0.75mg/kg action intensity greater than aspirin 200mg/kg.
Results of pharmacodynamic test shows that this product has obvious antagonism physics or chemistry pain caused (mice hot plate or writhing method); Suppress shock reaction (mice formaldehyde method) and permeability and increase (mouse peritoneal dye method); Significantly the foot swelling of antagonism rat arthritis model presents the dose-effect relationship mode, and this test provides necessary pharmacodynamics foundation for cataplasma of bulleyaconitine A is used for clinical antalgic and inflammation relieving.
Four, product irritation test of the present invention
The molding cataplasma of bulleyaconitine A is affixed on 10 trial volunteer wrist backs, to film residual, skin tracing ability, comfort, skin malaise symptoms, take off and pull pain etc. and estimate, the results are shown in following table:
The result shows: product of the present invention to film residual, skin tracing ability, comfort, skin malaise symptoms, take off that to pull pain all better, can take off repeatedly and pull and apply ointment or plaster.It is good to biocompatibility, affinity, breathability, the absorption of perspiration of skin that results suggest the present invention produces product, and be not easy allergy.
The specific embodiment
The following examples are to further specifying of inventing, but it is not meaned to any restriction to invention.
Embodiment 1
Backing layer: non-woven fabrics
Lid lining: polyester film
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A (micronization) 0.05 gram
Gelatin 1.3 grams
Tragcanth 1.8 grams
Polyethylene Glycol-400 2.2 gram
Polyacrylic acid 1.8 grams
Glycerol 1.8 grams
Zinc oxide 0.13 gram
Azone 1.0 grams
Borneolum Syntheticum 0.05 gram
Preparation method: bulleyaconitine A is carried out micronization pulverize, take by weighing gelatin, tragcanth by recipe quantity, add 65 gram water, heating in water bath makes dissolving, with polyacrylic acid and glycerol, zinc oxide mix homogeneously, adds in the above-mentioned glue, mix, add with Polyethylene Glycol-400 again and disperse Borneolum Syntheticum, bulleyaconitine A, add azone at last, get mastic.Be uniformly coated on then on the non-woven fabrics, cover polyester film, shear and promptly get 10000 subsides cataplasma of bulleyaconitine A.
Embodiment 2
Backing layer: non-woven fabrics
Lid lining: aluminium foil-polyethylene composite film
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A 0.06 gram
Sodium polyacrylate 2.0 grams
Gelatin 1.5 grams
Polyvinyl alcohol 2.5 grams
Glycerol 2.5 grams
Zinc oxide 0.2 gram
Azone 0.3 gram
Propylene glycol 1.0 grams
Menthol 0.06 gram
Preparation method: preparation bulleyaconitine A solid dispersion, pulverize; Take by weighing gelatin, sodium polyacrylate, polyvinyl alcohol by recipe quantity, add 72 gram water and make swelling, mix, with glycerol, zinc oxide mix homogeneously, add in the above-mentioned swelling solution, mix, add the suspension that disperses menthol, bulleyaconitine A with propylene glycol and azone again, get mastic.Be uniformly coated on then on the non-woven fabrics, cover polyester film, cut into suitable size, promptly get 10000 and paste cataplasma of bulleyaconitine A.
Embodiment 3
Backing layer: non-woven fabrics
Lid lining: polyethylene film
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A (micronization) 0.07 gram
Sodium polyacrylate 1.3 grams
Carbomer 934 p 0.1 gram
Glycerol 5.3 grams
Propylene glycol 1.4 grams
Kaolin 1.3 grams
Citric acid 0.04 gram
Aluminum chloride 0.08 gram
Mentholum 0.07 gram
Preparation method: bulleyaconitine A is carried out micronization pulverizes, by 1. by recipe quantity take by weighing sodium polyacrylate, carbomer 934 p adds purified water 55 grams makes swelling, adds aluminum chloride, mix; 2. will add behind glycerol and the Kaolin mixing in 1; 3. add in 2 after with propylene glycol Mentholum, bulleyaconitine A dispersion liquid; 4. add citric acid at last, mix, get mastic.Be uniformly coated on then on the non-woven fabrics, cover polyethylene film, cut into the piece of suitable size, promptly get 10000 and paste cataplasma of bulleyaconitine A.
Embodiment 4
Backing layer: non-woven fabrics
Lid lining: polyester film
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A 0.04 gram
Gelatin 0.2 gram
Sodium carboxymethyl cellulose 0.8 gram
Methylcellulose 1.4 grams
Sodium polyacrylate 0.1 gram
Kaolin 0.8 gram
Propylene glycol 0.7 gram
Polyethylene Glycol-400 2.0 gram
Sorbitol 4.0 grams
Mentholum 0.04 gram
Preparation method: take by weighing gelatin, sodium carboxymethyl cellulose, methylcellulose, sorbitol by recipe quantity, adding purified water 46 grams soaks, the heating in water bath swelling, other gets sodium polyacrylate, Kaolin, propylene glycol and mixes the back and add in the above-mentioned swelling solution, behind the stirring and evenly mixing, the suspension that adds Polyethylene Glycol-400, Mentholum and bulleyaconitine A again, stirred for several minute promptly gets mastic.Be uniformly coated on then on the non-woven fabrics, cover polyester film, cut into suitable size, promptly get 10000 and paste cataplasma of bulleyaconitine A.
Embodiment 5
Backing layer: artificial cloth
Lid lining: polypropylene film
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A (micronization) 0.02 gram
Gelatin 0.2 gram
Sodium carboxymethyl cellulose 0.8 gram
Polyvinylpyrrolidone (PVPK-30) 1.4 grams
Sodium polyacrylate 0.1 gram
Micropowder silica gel 0.8 gram
Propylene glycol 0.7 gram
Polyethylene Glycol-400 2.0 gram
Sorbitol 4.0 grams
Oleum menthae 0.02 gram
Preparation method: bulleyaconitine A is carried out micronization pulverize, take by weighing gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVPK-30), sorbitol by recipe quantity, adding purified water 48 grams soaks, the heating in water bath swelling, other gets sodium polyacrylate, micropowder silica gel, propylene glycol and mixes the back and add in the above-mentioned swelling solution, behind the stirring and evenly mixing, adds the suspension of Polyethylene Glycol-400, Oleum menthae and bulleyaconitine A again, stirred for several minute promptly gets mastic.Be uniformly coated on then on the non-woven fabrics, cover polyester film, cut into suitable size, promptly get 10000 and paste cataplasma of bulleyaconitine A.
Embodiment 6
Backing layer: artificial cloth
Lid lining: separate paper
Ointment-containing body layer component constitutes as follows by weight:
Bulleyaconitine A 0.1 gram
Gelatin 0.2 gram
Sodium alginate 0.8 gram
Polyvinylpyrrolidone (PVPK-90) 1.4 grams
Sodium polyacrylate 0.1 gram
Kaolin 0.8 gram
Propylene glycol 0.7 gram
Polyethylene Glycol-400 2.0 gram
Sorbitol 4.0 grams
Menthol 0.12 gram
Preparation method: take by weighing gelatin, sodium alginate, polyvinylpyrrolidone (PVPK-90), sorbitol by recipe quantity, adding purified water 62 grams soaks, the heating in water bath swelling, other gets sodium polyacrylate, kaolin, propylene glycol and mixes the back and add in the above-mentioned swelling solution, behind the stirring and evenly mixing, the suspension that adds Polyethylene Glycol-400, menthol and bulleyaconitine A again, stirred for several minute promptly gets mastic.Be uniformly coated on then on the non-woven fabrics, cover polyester film, cut into suitable size, promptly get 10000 and paste cataplasma of bulleyaconitine A.