CN102406840B - Gel binder for treating swelling and pain and its preparation method - Google Patents
Gel binder for treating swelling and pain and its preparation method Download PDFInfo
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Abstract
The invention relates to a compound preparation of an external use pharmaceutical composition for treating swelling and pain, which is a gel binder for treating swelling, and also provides its preparation method. The gel binder is prepared by 20-50% of swelling and pain medicine of the external use pharmaceutical composition for treating swelling and pain as well as proper pharmaceutical excipients. The gel binder for treating swelling is composed of a back lining layer, an ointment-containing body and a cover lining layer. The ointment-containing body, namely the kernel part, is prepared from the swelling and pain medicine, a basic polymer, a cross-linking agent, an organic acid, an excipient, a humectant, an adhesive and the like in certain ratio. The gel binder has the advantages of fast effect, good moisture preservation, high permeability and comfortable use. The product has merits of convenient usage, small irritation on skin and high compliance of patients.
Description
Technical field
The present invention relates to field of pharmaceutical technology, specifically one can be used for traumatic injury, rheumatic arthritis, scapulohumeral periarthritis, gouty arthritis, gel ointment that swells and ache (external preparation) of cyclomastopathy treatment and preparation method thereof.
Background technology
We disclose at Chinese patent 200510010901.X the externally-applied medicinal composition (patent No. ZL200510010901.X that a kind for the treatment of swells and ache, patentee: Yunnan Pharmaceutical Institute), be the exterior-applied formulation be made up of the raw material of following weight proportion: Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) 160-200, Radix Notoginseng 160-200, Radix Aconiti Brachypodi (Radix Aconiti Szechenyiani) 160-200, Delavay ampelopsis root 160-200, Folium Craibiodendri Yunnanensis 160-200, Herba Veratri Taliensis 160-200, Radix Psammosilenes 160-200, Radix Aconiti Kusnezoffii 160-200, colguhoumia root 160-200, Herba Erigerontis 160-200, Radix et Rhizoma Dysosmatis 160-200, Rhizoma Paridis 160-200, Fructus Gardeniae 160-200, Pseudobulbus Bletillae (Rhizoma Bletillae) 160-200, Radix Angelicae Dahuricae 160-200, Radix Glycyrrhizae 50-70, Borneolum Syntheticum 50-70, Mentholum 50-70, Moschus 0.4-1.Exterior-applied formulation described in Chinese patent 200510010901.X is the liniment, aerosol, liniment, rubber-emplastrum, cataplasma, gel etc. that described raw material and corresponding pharmaceutic adjuvant are made through common process.In Chinese patent 200510010901.X embodiment, also disclose the preparation method of the gel of described externally-applied medicinal composition, liniment, aerosol simultaneously, but not yet disclose the gel ointment and preparation method thereof that swells and ache of the present invention.
The externally-applied medicinal composition that a kind for the treatment of is swollen and ache is the ethnic drug that we develop according to Yi nationality, distributed over Yunnan, Sichuan and Guizhou's secret recipe, develop after scientific validation.Because this Yi nationality, distributed over Yunnan, Sichuan and Guizhou's secret recipe is throughout the year in use among the people, its significant curative effect and safety have obtained the checking of a large amount of patient.The safety testings such as the acute toxicity test that we carry out, long term toxicity test, sensitivity test and relevant pharmacodynamics test, clinical trial scientifically demonstrate that it is evident in efficacy and have the feature of safety further.The significant curative effect of its intimate mystery reflected in use among the people, clinical trial obtains affirmative and the support of Yunnan various circles of society.
The present invention updates and perfect on prior art basis, we preferably 65 ~ 70% ethanol make the Extraction solvent of this externally-applied medicinal composition, after carrying out seepage pressure effects effective ingredient, by screening, the optimization of therapeutic dose, obtain the medicine that swells and ache of therapeutic dose; Again through a large amount of preparation process research and perfect, successfully have developed the gel ointment that swells and ache.Therefore, the present invention continues gel ointment disclosing this externally-applied medicinal composition and preparation method thereof on Chinese patent 200510010901.X basis.
Gel ointment system is by medicine dissolution or be mixed in natural in synthesizing water-solubility macromolecular material substrate, and spread onto on back lining materials, for the external preparation sticked in skin, play general action or local action through Transdermal absorption, also belong to Percutaneously administrable preparation, its original shape is " poultice ".Due to developing rapidly of the field such as Modern Fine Chemical Industry and polymer material science, for pharmaceutics provides the adjuvant of more superior performances.Therefore, first gel ointment was succeeded in developing by Japan in the seventies in last century.A large amount of gel ointment is had to go on the market in the developed country such as American-European-Japanese by now, the dark favorable comment by doctor and patient.China started to study this dosage form in the eighties in last century, but its development is comparatively slow, only has the product of minute quantity to appear on the market till now.
Gel ointment is the world today's a kind of high in technological content, applied range, Novel external emplastrum easy to use, at the seventies initial stage, the state such as Japanese, European has started to develop medical gel unguentum, along with the development of 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, by there being the medicine of more than 30% that percutaneous drug administration preparation will be made into, the new upsurge of an inner disease outer treat will be started.Compared with traditional external plaster, gel ointment has the following advantages: good to the biocompatibility of skin, affinity, breathability, absorption of perspiration, and is not easy allergy; Owing to adopting water-soluble macromolecule bio-matrix, use rear noresidue, not pollution clothes; Because performance of keeping humidity is good, skin keratinocytes aquation can be made very soon, be conducive to the Transdermal absorption of medicine, there is rapid-action advantage, because permeability is good, use comfortable; To no skin irritation and sensitization; Repeatedly can take off subsides, not affect the treatment.Gel ointment is as a kind of Novel external preparation, flexible, convenient owing to using, and acts on feature fast, external analgesic is praised highly and likes.
Summary of the invention
Object of the present invention aims to provide a kind of safe, effective, side effect is little, compliance is good gel ointment and preparation method thereof that swells and ache.
The present invention's gel ointment that swells and ache is for traumatic injury, rheumatic arthritis, scapulohumeral periarthritis, gouty arthritis, a kind of external preparation product of the treatment such as cyclomastopathy exploitation.The present invention swells and ache gel ointment to treat the externally-applied medicinal composition that swells and ache for raw material, through effective component extracting, make drug gel or solid dispersion (i.e. the medicine that swells and ache of the present invention), then be aided with carbomer (940p), the auxiliaries such as polyacrylic acid (NP700), dihydroxyaluminum aminoacetate, glycerol, tartaric acid, polyvidone (K90) that is neutralized of part forms.
The present invention swells and ache the one pure Chinese medicine Novel external gel ointment that gel ointment system develops based on " externally-applied medicinal composition that treatment is swollen and ache ".The present invention is on the basis of " externally-applied medicinal composition that treatment is swollen and ache ", and preferably the Extraction solvent of this externally-applied medicinal composition made by 65 ~ 70% ethanol, obtains the medicine that swells and ache of the present invention after carrying out the technological operations such as seepage pressure effects; Medicine percolate of the present invention is the extracting solution of 65 ~ 70% ethanol, directly uses cohesiveness and the adhesion that can change gel cream because concentration of alcohol is higher, gel ointment hold tack is reduced, easily comes off, cannot make gel ointment.By conventional heating, concentrated or dry removing ethanol can make drug precipitation or precipitation, causes the curative effect of medicine to reduce, by lyophilization or cryogenic vacuum Drying Time of Vertical Spray Dryer long, production cost is high, and is difficult to find suitable dissolution with solvents medicine.After medicine percolate and gel-type vehicle or solid dispersion host material are made gel or solid dispersion by the present invention, because macromolecular material is to effects such as the solubilisings of medicine, volatilization remove portion ethanol (ingredient can not be caused to precipitate or separate out) can be heated, both the effect of ethanol to gel cream can have been reduced, avoid weakening of adhesion, can make again to swell and ache medicine in gel cream with molecularity distribution simultaneously, be conducive to the swell and ache chemical stability of medicine in gel ointment and the curative effect of product.
Gel-type vehicle of the present invention can be one or more in carbomer, polyvinyl alcohol, polyacrylic acid and sodium salt thereof etc.
Solid dispersion substrate of the present invention can be one or more in polyvinylpyrrolidone, Polyethylene Glycol, methylcellulose and carboxymethyl cellulose and sodium salt, hydroxypropyl emthylcellulose etc.
The present invention's medicine that swells and ache has significant antiinflammatory, analgesia, improves microcirculation, suppresses gouty arthritis and suppresses the effect of cyclomastopathy etc.
The gel ointment that swells and ache of the present invention is the gel ointment described in " Chinese Pharmacopoeia " version in 2010 that swell and ache medicine and the pharmaceutics by therapeutic dose allows the pharmaceutic adjuvant added to make.
The present invention's gel ointment that swells and ache is made up of backing layer, ointment-containing body and lid lining (protecting film) three part.Ointment-containing body contains the medicine that swells and ache of therapeutic dose, with one or more pharmaceutic adjuvants, comprise one or more in basic polymer, cross-linking agent, organic acid, excipient, wetting agent, binding agent, purified water, solvent, antiseptic and the material such as antioxidant, surfactant; The back lining materials that backing layer uses can be the one in cotton, spun rayon cloth, non-woven fabrics, flannel; The lid lining material that lid lining protecting film uses can be the one in separate paper, polypropylene film, polyethylene film, cellophane, polyester, aluminium foil-polyethylene composite film.The swell and ache specification of gel ointment of the present invention is the specification of conventional emplastrum; According to different specifications, often the amount of pasting containing the medicine that swells and ache in the gel ointment that swells and ache is 1.0 grams ~ 8.0 grams, and often the preferred amounts of pasting containing the medicine that swells and ache in the gel ointment that swells and ache is 2.0 grams ~ 4.0 grams.
Of the present inventionly swell and ache gel ointment by weight percentage, consist of the following composition:
Wherein, the medicine that swells and ache is obtained by following methods: take raw material Borneolum Syntheticum 6 parts by weight ratio, Mentholum 6 parts, 0.08 part, Moschus adds appropriate amount of ethanol to be made it to dissolve, all the other Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae)s 18 parts, Delavay ampelopsis root 18 parts, Folium Craibiodendri Yunnanensis 18 parts, Herba Veratri Taliensis 18 parts, Radix Psammosilenes 18 parts, Radix Aconiti Brachypodi (Radix Aconiti Szechenyiani) 18 parts, Radix Aconiti Kusnezoffii 18 parts, colguhoumia root 18 parts, Herba Erigerontis 18 parts, Radix Notoginseng 18 parts, Radix et Rhizoma Dysosmatis 18 parts, Rhizoma Paridis 18 parts, Fructus Gardeniae 18 parts, Pseudobulbus Bletillae (Rhizoma Bletillae) 18 parts, the Radix Angelicae Dahuricae 18 parts, 6 parts, Radix Glycyrrhizae is ground into coarse powder, mixing, according to the percolation (Chinese Pharmacopoeia version in 2010 annex I 0) under fluid extract and extractum item, with 65 ~ 70% ethanol as solvent, carry out percolation, collect percolate 1000 parts, cold preservation 48 hours, filter, for subsequent use.Get gel-type vehicle or solid dispersion substrate appropriate, add above-mentioned percolate for subsequent use, abundant stirring and dissolving, heating volatilization remove portion ethanol in water-bath, when being chilled to 40 DEG C, add the alcoholic solution such as Borneolum Syntheticum, stir, must swell and ache medicine 750 parts.
Medicine of the present invention has Repercusion analgesia, blood circulation promoting and blood stasis dispelling, relaxing muscles and tendons and removing obstructionfrom meridians, effect of eliminating mass and relieving fullness eliminating stagnation, is used for the treatment of the class disease that swells and ache, therefore is named as the medicine that swells and ache; Dosage form is gel ointment, therefore is named as the gel ointment that swells and ache.
The preparation method of the gel ointment that swells and ache of the present invention is:
(1) wetting agent is fully mixed with basic polymeric matrix, cross-linking agent, excipient etc., add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) 2. the suitable quantity of water such as binding agent, organic acid is dissolved;
(3) 2. will join 1., and fully be uniformly mixed under vacuum, obtain ointment-containing body through cross-linking reaction, ointment-containing body is coated with.
Its preparation process is as follows:
Its preparation principle is as follows:
Basic polymer fully mixes with cross-linking agent (microsolubility polyvalent metal compounds is as aluminium compound) and medicine etc., add organic acid slowly to dissolve cross-linking agent and discharge metal ion (as aluminium ion), basic polymer and metal ion (as aluminium ion) are cross-linked to form gel.By controlling gel formation speed, thus make crosslinked and coating process etc. easier.
Basic polymer of the present invention can be the polyacrylic acid that degree of neutralization does not wait, carbomer, carboxymethyl cellulose and sodium salt thereof, one or more in polyvinyl alcohol etc.The polyacrylic acid that degree of neutralization does not wait comprises: sodium polyacrylate, F-500, NP-600, NP-700, NP-800 etc.Carbomer comprises: Carbopol 934, Carbopol 940, Carbopol 97l etc.
Cross-linking agent of the present invention can be aluminium hydroxide, dihydroxyaluminum aminoacetate, aluminum chloride, one or more in disodiumedetate (EDTA) etc.
Organic acid of the present invention can be lactic acid, tartaric acid, one or more in citric acid etc.
Wetting agent of the present invention can be glycerol, propylene glycol, Polyethylene Glycol, one or more in sorbitol etc.
Sticker of the present invention can be sodium alginate, methylcellulose, one or more in sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, degree of neutralization polyacrylic acid not etc. etc.Polyvinylpyrrolidone comprises: PVPK-30, PVPK-90 etc.Sticker of the present invention can be used for preventing drug crystallization from separating out and as drug stabilizing agent.
Excipient of the present invention can be carboxymethyl cellulose (CMC), carbopol (CVP), one or more in crospolyvinylpyrrolidone (PVPP) etc.Solvent and/or wetting agent can be retained in gel by excipient of the present invention, are easy to gel coating in addition and prevent the advantage of contraction of gel structure.
Also one or more in the material such as antiseptic and antioxidant, surfactant, filler, metal-chelator can be added in present component composition; Common cooperation reaches solubilize drugs and promotes drug osmotic and reduce the effects such as bubble formation.
Gel ointment of the present invention compared with prior art possesses following characteristics:
1. the biocompatibility of pair skin, affinity, breathability, absorption of perspiration are good, and are not easy allergy;
2. performance of keeping humidity is good, can make skin keratinocytes aquation very soon, be conducive to the Transdermal absorption of medicine, have rapid-action advantage,
3. permeability is good, uses comfortable;
4. pair no skin irritation and sensitization, be not easy allergy; And this gel ointment is subsides every day one, therefore every patch amount is less, and skin malaise symptoms occurs less.
Product of the present invention is through pharmacodynamics test, and its exercising result in antiinflammatory, analgesia etc. is as follows:
One, immune inflammation
To the effect of rat assist agent arthritis
Get 150 ~ 200g male rat 80, be divided at random blank group, model control group, indometacin, gel ointment matrix group, the gel ointment that swells and ache (low, high, in) group, often organize 10, except indometacin group every day according to dosage gastric infusion 1 time, all the other each treated animals equal every days according to dosage in the following coating in right back ankle joint (pure water), continuous 6 days.Before last coating, first measure left and right sufficient normal volume, after coating 30 minutes, in every Rat Right metapedes plantar subcutaneous injection Freund ' s Freund's complete adjuvant 0.1ml, except blank group.To cause after inflammation coating 26 days continuously again.And after Yu Zhiyan 2h, 24h, 3d and later separated in time measure the sufficient volume in left and right, note simultaneously observation cause scorching 8 days after foot swelling and tail, ear's erythema situation and body weight change before rat, and press document
[1]standard scores to every Mus delayed hypersensitivity, until cause scorching latter 28 days.28th day, measure and cause inflammation foot swelling rate all around, compare the significance of indices group difference.Result is as follows:
Result shows: the high, medium and low dosage group of the gel ointment that swells and ache all can suppress foot swelling caused by adjuvant arthritis rats, and can reduce the arthritis index of adjuvant arthritis rats.Result points out the gel ointment that swells and ache to have inhibitory action to adjuvanticity rat arthritis.
Table 1 is on the impact (mL of adjuvant arthritis rats paw swelling; N=10;
)
Note: with blank group ratio: * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with model group:
△p < 005,
△ △p < 001,
△ △ △p < 0001; Compare with bare substrate group:
▲p < 0.05
Table 2 is on the impact (n=10 of adjuvant arthritis rats arthritis index;
)
Note: with blank group ratio: * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with model group:
△p < 005,
△ △p < 001; Compare with bare substrate group:
▲p < 0.05
Two, to the effect of gouty arthritis
1. on the impact of Monosodium urate induced rat gouty arthritis
80 male rats, are divided into 8 groups at random, often organize 10.According to dosage administration every day of each treated animal, for three days on end; After last administration 30 minutes, except blank group rat is except right sufficient pad portion injecting normal saline 0.05ml, all the other respectively organized rat at right sufficient pad portion injection Monosodium urate normal saline suspension 0.05ml, the generation of induction gouty arthritis.Respectively with vernier caliper measurement cause scorching before and cause scorching after the thickness in 1h, 2h, 4h, 6h and 8h Rat Right foot pad portion so that scorching before and after difference as the swelling of gouty arthritis, take the mean and to compare with model control group, carry out statistical test.
Table 3 swell and ache gel ointment on the impact of rat gouty arthritis (
n=10)
Note: compare with blank group: * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with solvent group:
△p < 0.05,
△ △p < 0.01,
△ △ △p < 0.001
Result of the test display (see table 3): after Monosodium urate modeling, model group compares with blank group significant difference (P < 0.01), proves the rat gouty arthritis model success that Monosodium urate is induced.The high, medium and low dosage of the gel ointment that swells and ache all has significant inhibitory action at different time to the rat paw edema that urate is induced, and wherein low dosage 1h after modeling has demonstrated significant inhibitory action.The gel ointment that swells and ache is pointed out to have significant antagonism to rat gouty arthritis.
2. on the impact of Monosodium urate inducing mouse gouty arthritis
60 male mices, grouping and medication see the following form, after last administration 30 minutes, except blank group mice is except right sufficient pad portion injecting normal saline 0.05ml, all the other respectively organize mice at right sufficient pad portion injection Monosodium urate normal saline suspension 0.05ml, the generation of induction gouty arthritis.Respectively with vernier caliper measurement cause scorching before and cause scorching after the diameter at 0.5cm place under 1h, 2h, 4h and 6h mouse ankle joint so that the difference of scorching front and back is as the swelling of gouty arthritis, takes the mean to compare with model control group, carries out statistical test.
Table 4 swell and ache gel ointment on the impact of mice gouty arthritis (
n=10)
Note: compare with blank group: * P < 0.05, * * P < 0.01, compares with solvent group:
△p < 0.05,
△ △p < 0.01,
△ △ △p < 0.001
Result of the test display (see table 4): the basic, normal, high dosage of the gel ointment that swells and ache all has remarkable inhibitory action at different time to the mice foot swelling that urate is induced, and especially low, middle dosage 1h, 2h, 4h after modeling have the inhibitory action of highly significant.The gel ointment that swells and ache is pointed out to have significant antagonism to mice gouty arthritis.
Three, antiinflammatory action
1. on the impact of rat carrageenan foot swelling
80 male rats, are divided into 8 groups at random, often organize 10.According to dosage administration every day of each treated animal, for three days on end; After last administration 30 minutes, the carrageenin normal saline suspension 0.1ml of right sufficient pad portion subcutaneous injection 1%.With vernier caliper measurement measure respectively cause scorching before and cause scorching after the thickness in the right sufficient pad portion of 0.5h, 1h, 2h, 3h, 4h so that scorching before and after the difference of thickness as swelling, take the mean and to compare with model control group, carry out statistical test.The results are shown in Table 5
Table 5 swell and ache gel ointment on the swollen impact of rat carrageenan foot (
n=10)
Compare with blank group:
△p < 0.05,
△ △p < 0.01.Compare with model group:
*p < 0.05,
*p < 0.01.Compare with solvent group:
▲p < 0.05,
▲ ▲p < 0.01
Result of the test shows: after carrageenin modeling, model group compares with blank group significant difference (P < 0.01), proves model success.Gel ointment 3 dosage that swell and ache all can significantly suppress rat carrageenan foot swollen, particularly, low dosage causing scorching after the inhibitory action highly significant of 2,3 hours.The gel ointment that swells and ache is pointed out to have significant antiinflammatory action to rat carrageenan foot is swollen.
2. Oleum Tiglii is caused to the impact of mice auricle swelling
Get 18 ~ 22g mice 72, male and female half and half, be divided at random blank group, indometacin, gel ointment matrix group, the gel ointment that swells and ache (basic, normal, high) group, often organize 12.Except indometacin group every day according to dosage gastric infusion 1 time, each treated animal according to dosage auris dextra coating (Matrix controls) every day, continuous 5 days, last administration was after 45 minutes, and every Mus auris dextra two sides uniform application 0.05ml Oleum Tiglii causes inflammation, cause inflammation and repaste medicine 1 time in latter 30 minutes, put to death animal on time after causing scorching latter 60 minutes, with the card punch of diameter 6mm, ears are cut with position homalographic, weigh, using the difference of two auricle weight as swelling, calculate inhibitory rate of intumesce.Result is as follows:
Table 6 gel ointment that swells and ache causes the impact of mice auricle swelling on Oleum Tiglii
Note: compare with blank group:
*p < 0.05,
*p < 0.01; Compare with bare substrate group:
△p < 0.05,
△ △p < 0.01,
△ △ △p < 0.001
Result shows: the basic, normal, high dosage group of the gel ointment that swells and ache has inhibitory action to Oleum Tiglii induced mice auricle edema, there is significant difference (P < 0.05 compared with blank group, P < 0.05, P < 0.01), suppression ratio is respectively: 27.69%, 32.79%, 37.02%.Compared with bare substrate group, the basic, normal, high dosage group of the gel ointment that swells and ache has inhibitory action (P < 0.05, P < 0.05, P < 0.01) to Oleum Tiglii induced mice auricle edema.Result points out the acute inflammation of gel ointment to Oleum Tiglii induced mice auricle edema that swell and ache to have inhibitory action.
3. on the impact of mice granuloma induced by implantation of cotton pellets
Get 23-25g male mice 72, be divided into 6 groups at random, often organize 12, grouping and administration, except indometacin group every day according to dosage gastric infusion 1 time, each group mouse web portion unhairing coating (Matrix controls).Each Mus sterilizing cotton balls that subcutaneous each implantation 6mg is heavy in hind leg footpath portion, left and right under aseptic condition.From performing the operation the same day, each treated animal according to dosage left and right hind leg footpath every day portion coating 1 time, successive administration 13 days.Put to death mice after within 14th day, weighing, open former otch, cotton balls is taken out together with surrounding connective tissue, reject fatty tissue, in 70 DEG C of drying in oven, weigh, calculate each group of granuloma weight and granulation coefficient.The results are shown in Table 7
Table 7 swells and ache the impact of gel ointment on mice granuloma induced by implantation of cotton pellets
Note: compare with blank group: * P < 0.05, * * P < 0.01, compares with bare substrate group:
△p < 0.05,
△ △p < 0.01,
△ △ △p < 0.001
Result shows: compare with blank group, the minimizing tool of the basic, normal, high dosage group of the gel ointment that swells and ache to mice granuloma induced by implantation of cotton pellets has a significant effect (P < 0.05, P < 0.05, P < 0.01); Compare with bare substrate group, the minimizing tool of the basic, normal, high dosage group of the gel ointment that swells and ache to mice granuloma induced by implantation of cotton pellets has a significant effect (P < 0.05, P < 0.01, P < 0.001) point out the gel ointment that swells and ache to have inhibitory action to the chronic inflammatory disease caused by mice granuloma induced by implantation of cotton pellets.
Four, analgesic activity
1. the impact of Dichlorodiphenyl Acetate induced mice writhing pain
Get 18 ~ 22g mice 72, male and female half and half, be divided at random blank group, aspirin, gel ointment matrix group, the gel ointment that swells and ache (high, medium and low) group, often organize 12.Except aspirin group every day according to dosage gastric infusion 1 time, each group of mouse web portion unhairing coating (Matrix controls), continuous 4 days, in last administration after 30 minutes, the glacial acetic acid 0.2ml/ of every Mus lumbar injection 0.6% only, the writhing number of times of mice pain in observed and recorded 15 minutes, and calculate analgesia suppression ratio.Result is as follows:
Table 8 swell and ache gel ointment Dichlorodiphenyl Acetate cause mouse writhing reaction impact
Note: with blank group ratio: * P < 0.05, * * P < 0.01; Compare with bare substrate group:
△p < 0.05,
△ △p < 0.01 result shows: the gel ointment that swells and ache basic, normal, high dosage group Dichlorodiphenyl Acetate causes mice pain writhing inhibitory action, there is significant difference (P < 0.05 compared with blank group, P < 0.01, P < 0.05), suppression ratio is respectively: 49.17%, 54.70%, 48.45%; Compared with bare substrate group, the gel ointment that swells and ache basic, normal, high dosage group Dichlorodiphenyl Acetate causes mice pain writhing inhibitory action (P < 0.05, P < 0.01, P < 0.05).The writhing that result points out the gel ointment Dichlorodiphenyl Acetate that swells and ache to cause mice pain has inhibitory action.
2. on the impact of mouse hot-plate induced pain reaction
Select 18-22 female mice, on hot plate dolorimeter, measure pain threshold 3 times (to occur licking metapedes reaction for observation index) before experiment, select 3 the qualified mices 70 of pain threshold in 5s-30s, be divided into 7 groups at random, often organize 10.Each treated animal every day according to dosage at foot coating, for three days on end; After last administration, 15min, 30min, 60min lick sufficient incubation period with stopwatch record mice respectively and make pain threshold, take the mean to compare with matched group, carry out statistical test.
Table 9 swell and ache impact that gel ointment reacts mouse hot-plate induced pain (
n=10)
Compare with model group:
*p < 0.05,
*p < 0.01.Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01
Result of the test (see table 9) shows: gel ointment three dosage that swell and ache all can incubation period of significant prolongation mouse hot-plate induced pain reaction, and in its analgesic activity, low dosage still has the feature of effect long action time.
Five, pain relieving capsule is on the microcirculatory impact of Mice Auricle
Get 17.5-20g mice 50, male and female half and half, be divided into blank group at random, bare substrate group, isopropyl kidney group, the gel ointment that swells and ache (basic, normal, high dosage group) often organize 10.Laboratory temperature remains on 25 ± 1 DEG C.Each treated animal is according to dosage administered once every day, continuous three days.After last administration 30min, with pentobarbital sodium 60mg/kg body weight intraperitoneal injection of anesthesia animal, fixing auricle, under being placed in the microcirculation microscope of amplification 50 times, with suitable blood vessel (boundary clear, spy is tremulous pulse very obviously, vein blood vessel) be the object of observation, experimental microcirculation disturbance is caused to mouse peritoneal injection isoprenaline by the dosage of 0.1mg/kg, (for ensureing the picture quality gathered before gathering moulding respectively, according to preliminary experiment, before modeling, image 5min after anesthesia gathers, modeling immediately after collection), after moulding 5, 10 and 15min time image, following four indexs of observation: 1. (fluidised form divides 5 grades to blood fluidised form (simultaneously carrying out with image acquisition): stagnation is 0 point, grain stream is 1 point, and grain linear flow is 2 points, and line grain stream is 3 points, and linear flow is 4 points), 2. arteriole caliber (A
3), 3. venule diamater (V
3), 4. capillary network counting.Observe and record the situation of change of indices before and after administration, to judge that medicine is to microcirculatory improvement situation.(for ensureing the objectivity of experimental result and reducing personal error in test, Animal Anesthesia, auricle are fixed, image acquisition, the scoring of blood fluidised form, blood vessels caliber measurement etc. easily affect the step of experimental result, by by preliminary experiment training, the personnel of energy skilled operation operate) the results are shown in Table 10,11,12
Table 10 swell and ache gel ointment on the impact of Mice Auricle arteriole caliber (
um, n=12)
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01
Table 11 swell and ache gel ointment on the impact of Mice Auricle venule diamater (
um, n=12)
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01
Table 12 swell and ache gel ointment on the impact of Mice Auricle capillary open number (
um, n=12)
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01
Table 13 swell and ache gel ointment on the impact of Mice Auricle hemorheology (
um, n=12)
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01
Experimental result shows: the gel ointment that swells and ache obviously can improve the hemorheology index of rat acute Blood stasis model caused by adrenal gland; The arteriole of experimental microcirculation disturbance mice caused by obvious increase epinephrine, venule diamater and capillary open number.Six, on the impact of rat mammary gland cyclomastopathy pathological model
Get rat some, every day axillary fossa subcutaneous injection estradiol benzoate 0.5mg/kg, continuous 25d, changes note Progesterone 1mg/kg, continuous 5d afterwards.After drug withdrawal, next day rejects the rat that breast increases not obvious (substrate < 3mm), then randomly draw 10 rats to put to death, every only select the breast obviously increased to make histopathological examination, increase with mammary gland alveolus expansions, lumen of gland hydrops, glandular cell increase the positive glandular cell of hypertrophy, glandular tissue estrogen receptor positive glandular cell and progesterone receptor and all account for microscopic field whole glandular cell more than 20% person for successful hyperplasia of mammary lobule change.The breast tissue pathological examination of 10 rats has more than 8 rat breasts to meet this pathological change for this batch of rat mammary gland cyclomastopathy model success.It starts to be not later than 3d after inactive Progesterone for subsequent experimental.Normal group and model group are fed with pure water.Medicine feed 50 days, after last medicine feed 5h, with the change of vernier caliper measurement rat second pair of breast diameter; Carry out statistical test.
Table 14 is on the impact of rat mammary gland cyclomastopathy pathological model
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with matrix group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01, compares with model group:
△p < 0.05,
△ △p < 0.01,
△ △ △p < 0.01
Table 15 is on the impact of rat uterus weight
Compare with blank group, * P < 0.05, * * P < 0.01, * * * P < 0.001; Compare with model group:
▲p < 0.05,
▲ ▲p < 0.01,
▲ ▲ ▲p < 0.01,
In experiment, after modeling, the estrogen of rat raises, progestogen reduce, and the diameter of its breast is also from little change large (P < 0.01), after using the treatment of mammary gland health, the breast diameter of rat is down to from expansion and normally (is compared with normal group, P > 0.05), obviously can alleviate the cyclomastopathy lesion degree of rat caused by diethylstilbestrol; Also obvious inhibitory action is had to the increase of modeling uterus weight.
Seven, on the impact of DNF inducing mouse delayed hypersensitivity
Select 18 ~ 22g mice 108, male and female half and half, be divided into 9 groups at random by sex and body weight, often organize each 6 of male and female, grouping and administrations are in table 7.Each treated animal every day according to dosage gastric infusion 1 time, continuous 9 days, matched group such as to gavage at the capacity pure water, and positive control prednisolone acetate group and each administration group give prednisolone acetate 10mg/kg in administration the 1st, 3,5,7,9 days gavages, and each group gavage volume is 20ml/kg body weight.Except blank group, all the other each treated animals 1h after first administration, in skin of abdomen uniform application 1%DNFB mixed liquor 50ul/ sensitization, and respectively to strengthen 1 time in the 2nd, 3 day.Administration the 9th day, attack in each Mus auris dextra two sides uniform application 1%DNFB mixed liquor with the volume of every ear 10ul, left ear is coated with equivalent acetone: oily mixed liquor in contrast, excite rear 16h to take off cervical vertebra and put to death animal, with the card punch of diameter 6mm, ears are cut with position homalographic, get auricle to weigh, using the difference of left and right two auricle weight and swelling as delayed hypersensitivity value.
Table 16 swells and ache the impact of gel ointment on DNF inducing mouse delayed hypersensitivity
Compared with matched group: * p < 0.05, compared with model group: △ p < 0.05
Experimental result shows, gel ointment administration 9 days of swelling and ache, can increase the delayed hypersensitivity being caused immunologic hypofunction mice by prednisolone acetate in various degree.There is immunoregulation effect.
Product of the present invention is through safety testing, and its result is as follows:
Acute toxicity testing: exempt from intact skin and the administration of damaged skin succession through family, has no high and low dose treated animal destructive skin wound and produces slight erythema, but do not find that epiderm skin and corium have any pathological changes; Have no the outward appearance of animal, behavioral activity, hair luster, eye and mucosa, breathing and central nervous system and occur that overt toxicity reacts.
Long term toxicity test: exempt from intact skin with quantity 25 times and 50 multiple doses to family and damaged skin successive administration just occurred slight skin wound repair after 16 days.
Skin allergy is tested: to guinea pig skin without anaphylaxis.
Gel ointment of the present invention compared with prior art possesses following characteristics:
1. the biocompatibility of pair skin, affinity, breathability, absorption of perspiration are good, have refrigerant sense, to no skin irritation and sensitization, are not easy allergy, use comfortable, use rear noresidue, not pollution clothes, repeatedly can take off subsides, not affect the treatment.
2. performance of keeping humidity is good, can make skin keratinocytes aquation very soon, be conducive to the Transdermal absorption of medicine, in addition, because Borneolum Syntheticum, Mentholum, Moschus etc. can make cutaneous vasodilation, promotes that other medicines absorb fast.Therefore, there is rapid-action advantage.
3. can directly act on sufferer place, avoid degraded and the liver first-pass effect of intestines and stomach, drug effect is rapid and reduce untoward reaction, and avoid the infringement of medicine to Liver and kidney function, security performance is high.
4. paste every day one, can maintain long-time release, reduce times for spraying, easy to use, patient compliance is high, is applicable to long-term prescription.
Product trial volunteer trial effect of the present invention
50 trial volunteers are tried out molding and to be swollen and ache gel ointment, to film residual, skin tracing ability, comfort, skin malaise symptoms, take off and pull pain etc. and evaluate, the results are shown in following table:
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, repeatedly can take off and pull and apply ointment or plaster.It is good to the biocompatibility of skin, affinity, breathability, absorption of perspiration that result points out the present invention to produce product, and be not easy allergy.
Detailed description of the invention
The following examples are further illustrating invention, but it is not meaned to any restriction to invention.
Embodiment 1
Backing layer: non-woven fabrics
Lid lining: embossing polyester film
Ointment-containing body layer component forms as follows by weight percentage:
Preparation method:
(1) glycerol (wetting agent) is taken by recipe quantity, polyacrylic acid NP-700 (basic polymer), the dihydroxyaluminum aminoacetate (cross-linking agent) of recipe quantity is added successively in glycerol, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the tartaric acid (organic acid) of recipe quantity, polyvinylpyrrolidone-K90 (binding agent) are dissolved in water and obtain 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 2.0 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 2.5 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 3.0 grams), dry, packaging, namely swell and ache gel ointment finished product.
Embodiment 2
Backing layer: non-woven fabrics
Lid lining: aluminium foil-polyethylene composite film
Ointment-containing body layer component forms as follows by weight:
Preparation method:
(1) glycerol (wetting agent) is taken by recipe quantity, polyacrylic acid NP-600 (basic polymer), the aluminium hydroxide (cross-linking agent) of recipe quantity is added successively in glycerol, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the lactic acid (organic acid) of recipe quantity, sodium carboxymethyl cellulose (binding agent) are dissolved in water and obtain 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 1.0 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 1.3 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 1.5 grams), dry, packaging, namely swell and ache gel ointment finished product.
Embodiment 3
Backing layer: non-woven fabrics
Lid lining: embossing polyethylene film
Preparation method:
(1) glycerol (wetting agent) is taken by recipe quantity, polyacrylic acid F-500 (basic polymer), the dihydroxyaluminum aminoacetate (cross-linking agent) of recipe quantity is added successively in glycerol, abundant mixing, adds the medicine that swells and ache, and is fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the tartaric acid (organic acid) of recipe quantity is dissolved in water and obtains 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 5.2 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 6.6 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 8.0 grams), dry, packaging, namely swell and ache gel ointment finished product.
Embodiment 4
Backing layer: non-woven fabrics
Lid lining: separate paper
Ointment-containing body layer component forms as follows by weight:
Preparation method:
(1) glycerol and propylene glycol (wetting agent) is taken by recipe quantity, polyacrylic acid NP-800 (basic polymer), crospolyvinylpyrrolidone, the aluminium hydroxide (cross-linking agent) of recipe quantity is added successively in glycerol and propylene glycol, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the lactic acid (organic acid) of recipe quantity, polyvinylpyrrolidone-K30 (binding agent) are dissolved in water and obtain 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 1.5 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 1.8 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 2.3 grams), dry, packaging, namely swell and ache gel ointment finished product.
Embodiment 5
Backing layer: artificial cloth
Lid lining: polypropylene film
Ointment-containing body layer component forms as follows by weight:
Preparation method:
(1) glycerol (wetting agent) is taken by recipe quantity, polyacrylic acid NP-700 (basic polymer), the dihydroxyaluminum aminoacetate (cross-linking agent) of recipe quantity is added successively in glycerol, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the tartaric acid (organic acid) of recipe quantity, polyvinylpyrrolidone-K90 (binding agent) are dissolved in water and obtain 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 1.8 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 2.3 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 2.7 grams), dry, packaging, namely swell and ache gel ointment finished product.
Embodiment 6
Backing layer: non-woven fabrics
Lid lining: embossing polypropylene film
Ointment-containing body layer component forms as follows by weight:
Preparation method:
(1) glycerol (wetting agent) is taken by recipe quantity, polyacrylic acid NP-700 (basic polymer), the dihydroxyaluminum aminoacetate (cross-linking agent) of recipe quantity is added successively in glycerol, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) take purified water by recipe quantity, the tartaric acid (organic acid) of recipe quantity, polyvinylpyrrolidone-K90 (binding agent) are dissolved in water and obtain 2.;
(3) will 2. join 1., fully stir under vacuum, ointment-containing body is obtained through cross-linking reaction, ointment-containing body is coated with (controlling ointment-containing body layer thickness at about 1.0mm), the specification being cut into conventional emplastrum (as: often pastes long 9cm × wide 6cm, the amount of often pasting containing the medicine that swells and ache is 2.6 grams, or be cut into and often paste long 10cm × wide 6.8cm, the amount of often pasting containing the medicine that swells and ache is 3.3 grams, or be cut into and often paste long 11cm × wide 7.5cm, the amount of often pasting containing the medicine that swells and ache is 4.0 grams), dry, packaging, namely swell and ache gel ointment finished product.
Claims (4)
1. the gel ointment that swells and ache, it is characterized in that ointment-containing body in gel ointment is by medicine 20% ~ 50% and the pharmaceutic adjuvant of swelling and ache: basic polymer 3 ~ 10%, cross-linking agent 0.1 ~ 1%, organic acid 0.1 ~ 0.6%, excipient 0 ~ 10%, wetting agent 20 ~ 40%, sticker 0 ~ 10%, purified water 15 ~ 50% is made, the described medicine that swells and ache is obtained by following methods: take raw material Borneolum Syntheticum 6 by weight ratio, Mentholum 6, Moschus 0.08 adds appropriate amount of ethanol to be made it to dissolve, all the other Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae)s 18, Delavay ampelopsis root 18, Folium Craibiodendri Yunnanensis 18, Herba Veratri Taliensis 18, Radix Psammosilenes 18, Radix Aconiti Brachypodi (Radix Aconiti Szechenyiani) 18, Radix Aconiti Kusnezoffii 18, colguhoumia root 18, Herba Erigerontis 18, Radix Notoginseng 18, Radix et Rhizoma Dysosmatis 18, Rhizoma Paridis 18, Fructus Gardeniae 18, Pseudobulbus Bletillae (Rhizoma Bletillae) 18, the Radix Angelicae Dahuricae 18, Radix Glycyrrhizae 6 is ground into coarse powder, mixing, according to the percolation (Chinese Pharmacopoeia version in 2010 annex I O) under fluid extract and extractum item, with 65 ~ 70% ethanol as solvent, carry out percolation, collect percolate 1000, cold preservation 48 hours, filter, for subsequent use, get gel-type vehicle or solid dispersion substrate appropriate, add above-mentioned percolate for subsequent use, abundant stirring and dissolving, heating volatilization remove portion ethanol in water-bath, when being chilled to 40 DEG C, add the alcoholic solution such as Borneolum Syntheticum, stir, must swell and ache medicine 750, wherein said pharmaceutic adjuvant comprises: basic polymer, be selected from the polyacrylic acid that degree of neutralization does not wait, carbomer, carboxymethyl cellulose and sodium salt thereof, one or more in polyvinyl alcohol, the polyacrylic acid that wherein degree of neutralization does not wait is sodium polyacrylate, F-500, NP-600, NP-700 or NP-800, and carbomer is selected from Carbopol934, Carbopol940 or Carbopol971, cross-linking agent, is selected from one or more in aluminium hydroxide, dihydroxyaluminum aminoacetate, aluminum chloride, disodiumedetate, organic acid, is selected from one or more in lactic acid, tartaric acid, citric acid, excipient, is selected from one or more in carboxymethyl cellulose, carbopol or crospolyvinylpyrrolidone, wetting agent, is selected from one or more in glycerol, propylene glycol, Polyethylene Glycol, sorbitol, sticker, be selected from one or more in sodium alginate, methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, degree of neutralization polyacrylic acid not etc., wherein polyvinylpyrrolidone is selected from PVPK-30, PVPK-90, gel-type vehicle is selected from one or more in carbomer, polyvinyl alcohol, polyacrylic acid and sodium salt thereof etc., and solid dispersion substrate is selected from one or more in polyvinylpyrrolidone, Polyethylene Glycol, methylcellulose and carboxymethyl cellulose and sodium salt, hydroxypropyl emthylcellulose etc.
2. the gel ointment that swells and ache according to claim 1, it is characterized in that often pasting ointment-containing body in gel ointment containing the amount of the medicine that swells and ache is 1.0 grams ~ 8.0 grams.
3. the gel ointment that swells and ache according to claim 1 and 2, it is characterized in that often pasting ointment-containing body in gel ointment containing the amount of the medicine that swells and ache is 2.0 grams ~ 4.0 grams.
4. the preparation method of the gel ointment that swells and ache according to claim 1, it is characterized in that the described gel ointment that swells and ache is obtained by following methods: (1) is grouped into by the one-tenth of ointment-containing body and takes wetting agent, basic polymer, excipient, cross-linking agent is added successively in wetting agent, abundant mixing, add the medicine that swells and ache, be fully uniformly mixed 1. under vacuum;
(2) be grouped into by the one-tenth of ointment-containing body and take purified water, organic acid, sticker, organic acid, sticker are dissolved in water and obtain 2.;
(3) 2. will join 1., and fully stir under vacuum, obtain ointment-containing body through cross-linking reaction, and ointment-containing body be coated with, be cut into the specification of conventional emplastrum, dry, packaging, must swell and ache gel ointment finished product.
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| CN103341135B (en) * | 2013-05-31 | 2015-04-22 | 广州花海药业股份有限公司 | Gel agent for treating arthralgia and preparing method thereof |
| CN103272028B (en) * | 2013-06-22 | 2015-10-07 | 昆明赛诺制药有限公司 | A kind of medicine for the treatment of traumatic injury and rheumatic arthralgia |
| CN103830514A (en) * | 2014-03-27 | 2014-06-04 | 贵州维康药业有限公司 | Externally-used patch for treating gout and preparation method thereof |
| CN107157806B (en) * | 2017-05-27 | 2020-05-26 | 南方医科大学 | Gel matrix suitable for 3D printing mask and preparation method and application thereof |
| CN108641104A (en) * | 2018-04-11 | 2018-10-12 | 中国人民解放军第七医院 | A kind of water base cross-linked polymer and its preparation method and application |
| CN108653245B (en) * | 2018-07-06 | 2021-05-11 | 张文涛 | Hydrogel transdermal patch containing various pure plant extract oils and preparation method thereof |
| CN109820955A (en) * | 2019-04-12 | 2019-05-31 | 尤刚 | A kind of dissolving blood stasis and detoxication cream and preparation method thereof |
| CN114533805B (en) * | 2022-03-18 | 2024-02-02 | 南岛南药健康产业投资(海南)有限公司 | External prescription for cervical vertebra and lumbar vertebra diseases |
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| CN101879250A (en) * | 2010-06-25 | 2010-11-10 | 安舒贴(天津)外用制剂科技有限公司 | Arthralgia relief gel paste and preparation method |
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| CN101879250A (en) * | 2010-06-25 | 2010-11-10 | 安舒贴(天津)外用制剂科技有限公司 | Arthralgia relief gel paste and preparation method |
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Application publication date: 20120411 Assignee: Yunnan Baiyao Group Co.,Ltd. Assignor: YUNNAN INSTITUTE OF MATERIA MEDICA Contract record no.: X2022530000005 Denomination of invention: A swelling and pain gel plaster and its preparation method Granted publication date: 20150121 License type: Common License Record date: 20220624 |
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