CN101618011A - Sinomenine hydrochloride controlled release patch and preparation method thereof - Google Patents
Sinomenine hydrochloride controlled release patch and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a sinomenine hydrochloride controlled release patch, a preparation method thereof and application thereof in treating arthritis, pain relief and the like. The patch comprises sinomenine hydrochloride, a framework material, plasticizing agent, crosslinking agent, antioxidant and solvent. The preparation method can release medicament to local focus parts at a control rate and ensures that the medicament maintains daylong therapeutic effect with little adverse reaction.
Description
Technical field
The present invention relates to Sinomenine hydrochloride controlled release patch and preparation method thereof, this paster has effects such as treatment rheumatic arthritis and analgesia.
Background technology
Rheumatism, rheumatoid arthritis are frequently-occurring disease, are mainly in person between twenty and fifty, and the cause of disease is not clear and definite as yet so far.Modern medicine thinks that the rheumatic arthritis pilosity is born in rheumatism, and it is a kind of with intraarticular synovial membrane inflammation onset, the prolonged synovial membrane that more do not cause thickens, pannus forms, and cartilage and subchondral bone destroy, and joint distortion and tetanic chronic systemic autoimmune disease finally take place.Rheumatoid arthritis belongs to a kind of autoimmune disease more, is the inflammatory lesion that each system organization of a kind of whole body all has varying degree, and wherein the pathological changes in joint shows the most outstandingly.Primary disease involves the little joint of brothers more, and elbow, knee joint is the easiest gets involved, and is very big to human health risk.
Sinomenine is to separate a kind of main alkaloid monomer of purifying, medicinal its hydrochlorate that mostly is, i.e. sinomenine hydrochloride (Sinomenone Hydrochloride) from the Caulis Sinomenii rhizome.On chemical constitution, it is made up of hydrogen phenanthrene nucleus and ethamine bridge, the similar morphine.Pharmacodynamics test and clinical research result show that sinomenine has pharmacological actions such as antiinflammatory, immunosuppressant, analgesia, blood pressure lowering, arrhythmia.Sinomenine hydrochloride is mainly used in diseases such as treatment rheumatism, rheumatoid arthritis, arthralgia, numbness of the skin clinically.At present preparations such as domestic existing ZHENGQINGFENGTONGNING PIAN, sinomenine hydrochloride injection, hair Sinomenium acutum total alkali sheet, sinomenine hydrochloride enteric coatel tablets are applied to clinically, are obtaining better curative effect aspect various rheumatisms such as treatment rheumatoid arthritis and the arrhythmia.
During oral the and drug administration by injection of sinomenine hydrochloride, adverse reaction rate is higher, has limited its clinical practice to a certain extent.(article sees Li Le for details to Li Le etc., Zhang Cailing, Song Biwei " pharmacological research of sinomenine and clinical practice ", new Chinese medicine and clinical pharmacology, 2006,17 (4), 310-3) biological half-life of report sinomenine own is shorter, and clinical treatment generally needs oral for a long time, and dosage is bigger than normal; By promoting that histamine release causes clinical adverse such as erythra, gastrointestinal tract.Compare with oral, injection type, external preparation can reduce medicine gastrointestinal is stimulated, and reduces adverse reaction rate.
CN 200410021120.6 discloses a kind of sinomenine hydrochloride cataplasma and preparation method thereof, the employing of this dosage form, improved the drug level of sinomenine hydrochloride at the inflammatory local joint, its analgesia, antiinflammatory action have been strengthened, reduce the fluctuation of sinomenine hydrochloride blood drug level, reduced drug-induced untoward reaction.But the shortcoming that exists of some cataplasmas mainly is that mastic and skin adherence are bad at present, when sticking easily from the landing of skin affected part, the bigger joint part of activity particularly; Preparation is after long-time the placement, and mastic hardens because of dehydration, or absorption skin perspiration loses stickiness when sticking.CN 03134370.8 discloses sinomenine hydrochloride spray and preparation method thereof, but there is tangible defective in skin with spray, be that easy the flowing of vaporific solution makes administration be difficult for accurately location, easy and contact with clothing need just can make drug effect better bring into play with the hands massage treatment.Control-released plaster is the local skin medication, and is easy to use, can stop medication at any time, thereby improve the compliance of patient's medication, in addition, it is site-specific delivery of drugs accurately, processing such as need not give the massage does not almost have influence to medicated clothing, can overcome many drawbacks of spray administration; The more important thing is that the speed that control-released plaster adopts technology such as skeleton that medicine is discharged is slowed down from substrate, prolong and keep pharmaceutical release time, can be corresponding prolong drug action time, thereby reduce administration number of times, improve patient's compliance.In addition, this technology can obtain the local effect that discharges, and makes medicine reach target site easily, reduces blood drug level simultaneously, thereby reduces systemic side effects.
Summary of the invention
The objective of the invention is to, a kind of Sinomenine hydrochloride controlled release patch is provided.
The present invention also provides a kind of preparation method of Sinomenine hydrochloride controlled release patch.
The present invention also further provides the purposes of a kind of Sinomenine hydrochloride controlled release patch treatment rheumatic arthritis and pains and other diseases.
In order to realize purpose of the present invention, adopt following technical scheme:
Control release paster of the present invention with sinomenine hydrochloride as active component.This control release paster is the matrix type control release paster.Typical framework material comprises polyacrylate polymers or polyisobutylene base polymer and their derivant, optimization polypropylene esters of gallic acid polymer Eudragit E100.
Framework material amount ranges of the present invention is 30～95%, and preferable range is 40～80%.
Cross-linking agent of the present invention is succinic acid, malic acid or fumaric acid and their mixture.Preferably apple acid.
Plasticizer of the present invention is dibutyl sebacate, triethyl citrate, ethyl sebacate or diethyl phthalate and their lake mixture.Preferred ethyl sebacate.
Antioxidant of the present invention comprises sodium sulfite, sodium pyrosulfite, cysteine, thiourea, arabo-ascorbic acid, BHT, vitamin E, disodium edetate, or its mixture, wherein preferably sulfuric acid hydrogen sodium, sodium pyrosulfite, cysteine, thiourea, or its mixture.
According to the present invention, be benchmark with the framework material, the amount ranges of the corresponding cross-linking agent of per 1 gram framework material is 2.2-5.0%, and the plasticizer dosage scope is 35-60%, and ethanol is 2-10ml, and the drug loading of sinomenine hydrochloride is 0.1-0.6mg/cm
2Preferred dosage of crosslinking agent is 4.8%, and plasticizer consumption is 30%, and the ethanol consumption is 4ml, and the drug loading of sinomenine hydrochloride is 0.3mg/cm
2
To achieve the object of the present invention, the present invention has carried out the test of caused by dimethylbenzene xylene Mus ear swelling, the swollen test of rat granuloma and the test of rat immunity adjuvant arthritis.
As mentioned above, the present invention has not only solved the compliance of patient's medication, also greatly reduces side effect.
Description of drawings
Accompanying drawing 1 is blood drug level-time graph in the different Sinomenine hydrocloride preparation rat bodies
Following examples are used to further describe the present invention, but limit the scope of the present invention anything but.
The specific embodiment
Embodiment 1:
Sinomenine hydrochloride 1.0g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Succinic acid 3.2g
Triethyl citrate 40.0g
Sodium sulfite 0.15g
Ethanol 6ml
Sinomenine hydrochloride 2.0g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Malic acid 4.8g
Ethyl sebacate 30.0g
Sodium pyrosulfite 0.20g
Ethanol 4ml
Embodiment 3
Sinomenine hydrochloride 4.0g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Fumaric acid 3.3g
Diethyl phthalate 50.0g
Thiourea 0.10g
Ethanol 6ml
Embodiment 4
Sinomenine hydrochloride 6.0g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Fumaric acid 2.6g
Dibutyl sebacate 60.0g
Cysteine 0.25g
Ethanol 10ml
Sinomenine hydrochloride 0.5g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Malic acid 2.2g
Triethyl citrate 45.0g
Sodium pyrosulfite 0.20g
Ethanol 2ml
Sinomenine hydrochloride 3.0g
Acrylic ester type pressure sensitive adhesive (Eudragit E100) 100.0g
Fumaric acid 4.6g
Dibutyl sebacate 55.0g
Thiourea 0.20g
Ethanol 5ml
The preparation method of above embodiment is all as follows:
(1) takes by weighing sinomenine hydrochloride, adhesive, cross-linking agent, plasticizer, antioxidant and solvent;
(2) adhesive, cross-linking agent, plasticizer are mixed, add solvent, left standstill after stirring 24 hours, make the abundant swelling of adhesive;
(3) in (2) gained mixture, add sinomenine hydrochloride and antioxidant, leave standstill a few hours; Behind the abundant stirring and evenly mixing, ultrasonic degas;
(4) (3) gained pastille mixture is coated on the separate paper, drying adds backing layer, cutting, promptly.
Test example 1 pharmacodynamic experiment
1. the influence of Sinomenine hydrochloride controlled release patch Dichlorodiphenyl Acetate induced mice writhing response
Method:
According to embodiment 2 preparation sinomenine hydrochloride patches, add respectively sinomenine hydrochloride in 4,6,10g: the ratio of 100g Eudragit E100 prepares patch, be respectively low, in and high dose group, be used for following experiment.
Get test and use 50 of mices, male, body weight 20g-22g, be divided into 5 groups at random, be model control group, positive controls and embodiment 2 basic, normal, high dosage groups, 10 every group, each organizes mouse back with the about 2cm * 3cm of 8% sodium sulfide solution depilation, begin administration behind the depilation 24h, model control group gives blank patch 5cm in its depilation district, back
2/ only, embodiment 2 basic, normal, high dosage groups give the Sinomenine hydrochloride controlled release patch 5cm of basic, normal, high dosage respectively in its depilation district, back
2/ only, be administered once every day, uses fixedly 6h of medical rubber cream after the medication, successive administration 3 days, and positive controls only is administered once, and 60min before the lumbar injection acetum irritates stomach and gives 4% aspirin 0.2ml/10g.Each organize mice respectively at the last administration after 60min, lumbar injection 0.6% acetum 0.2ml/ only, the number of times of mice generation writhing response is as the quantitative target of pain in record injection back mouse writhing response latency (time of body occurring turning round for the first time) and the 15min, and the mice incubation period that writhing response do not occur is by 15min.
The result: each is organized mice and occur writhing response (abdominal part indent in succession behind the lumbar injection acetum, trunk and hind leg are upheld, behavior reactions such as hips up), positive controls mouse writhing reaction quantity obviously is less than model control group, and there is the part mice writhing response in 15min, not occur, among the embodiment 2, turn round the body number in the high dose group mice 15min and obviously be less than model control group, p＜0.01, low dose group mouse writhing stoichiometric number is compared with matched group does not have significant difference, among the embodiment 2, the high dose group mouse writhing response latency increases to some extent, does not have significant difference but compare with matched group.The results are shown in Table 3.
The influence of table 3. sinomenine control-released plaster Dichlorodiphenyl Acetate induced mice writhing response
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Sinomenine hydrochloride controlled release patch xylol induced mice ear swelling influence
Method: get test and use 50 of mices, male, body weight 20g-22g, be divided into 5 groups at random, it is model control group, positive controls and embodiment 2 are low, in, high dose group, every group 10, each organizes mouse back with the about 2cm * 3cm of 8% sodium sulfide solution depilation, begin administration behind the depilation 24h, model control group only gives normal saline 0.2ml/ in its depilation district, back, positive controls only gives fluocinonide ointment 0.1g/ in its depilation district, back, embodiment 2 is low, in, high dose group gives low in its depilation district, back respectively, in, the Sinomenine hydrochloride controlled release patch 5cm of high dose
2/ only, be administered once every day, successive administration 3 days.Each organize mice respectively at administration in afternoon on the 3rd after 60min, dimethylbenzene 0.03ml is applied to two sides, mouse right ear front and back causes inflammation, left side ear is not done any processing, put to death mice behind the 30min, two ears about the neat basal part of the ear is cut are laid former auricle at same position respectively with the 8mm card punch, weigh, every Mus auris dextra sheet weight deducts left auricle weight and is the swelling degree, the difference between comparative control group, embodiment 2 and the model control group.
The result: positive controls mice ear degree is starkly lower than model control group, and embodiment 2 basic, normal, high dosage group mice ear degree are starkly lower than model control group, p＜0.01, but do not see dose dependent, the results are shown in Table 4.
The influence of table 4. sinomenine control-released plaster xylol induced mice ear swelling
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
3. the Sinomenine hydrochloride controlled release patch is to the bullate influence of rat granuloma
Method: get 32 of the male wistar rats of body weight 140-160g, be divided into 5 groups at random, i.e. model control group, positive controls and embodiment 2 basic, normal, high dosage groups, 6～7 every group, each organizes rat back with the about 20cm of 8% sodium sulfide solution depilation
2Depilation in per 3 days once in the experimentation, under the ether light anaesthesia, the back median incision, expand subcutaneous tissue with vascular forceps, with two sterilization cotton balls (30 ± 1mg, autoclaving, 60 ℃ of oven dry) implant the rat back both sides respectively, implant cotton balls and began administration the same day, model control group only gives normal saline 0.5ml/ in its depilation district, back, positive controls only gives fluocinonide ointment 0.2g/ in its depilation district, back, and embodiment 2 basic, normal, high dosage groups give the Sinomenine hydrochloride controlled release patch 15cm of basic, normal, high dosage respectively in its depilation district, back
2/, be administered once every day, and successive administration 7 is big, puts to death animal on the 8th day, dissects and takes out cotton balls, picks most muscle, fatty tissue, 60 ℃ of oven dry, weighs, and it is heavy to deduct cotton balls, is granuloma and weighs, and respectively organizes granuloma weight, and calculates suppression ratio.
The result: positive controls granuloma weight is starkly lower than model control group, and embodiment 2 middle and high dosage group granuloma weight are starkly lower than model control group, and p＜0.001 the results are shown in Table 5.
Table 5. Sinomenine hydrochloride controlled release patch is to the bullate x ± s (mg) that influences of rat granuloma
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
4. the Sinomenine hydrochloride controlled release patch is to the influence of rat immunity adjuvant-induced arthritis
Method: get 50 of the male wistar rats of body weight 160-200g, be divided into 5 groups at random, i.e. model control group, positive controls and embodiment 2 basic, normal, high dosage groups, 10 every group, each organizes rat back with the about 20cm of 8% sodium sulfide solution depilation
2, behind the depilation 24h, model control group gives blank patch 15cm
2/ only, positive controls filling stomach gives prednisone 6mg/kg, and (1.5mg/ml, 4ml/kg), embodiment 2 basic, normal, high dosage groups give the Sinomenine hydrochloride controlled release patch 15cm of basic, normal, high dosage respectively in its unhairing district, back
2/ only, be administered once every day, successive administration 22 days, and behind the first administration 1h, 0.1ml causes inflammation with the right back toes intradermal injection Freund ' of every Mus s Freund's complete adjuvant.Observe following index in the process of the test: the general situation of (1) rat; (2) body weight writes down rat body weight weekly after the administration; (3) right back sufficient girth, cause scorching before and cause scorching back 20h, begin to observe the right back sufficient girth of rat, record at any time in the test is until off-test; (4) left back sufficient girth, cause scorching before and cause scorching back 14 days, 19,21, the left back sufficient girth of observation rat; (5) arthritis index is causing scorching (during off-test) in back 21 days, record rat arthritis index.
The result: cause and respectively organize rat after the inflammation and right back foot swelling occurs, occur in succession asthenia, movable minimizing, bradykinesia, left back foot and before foot swelling, afterbody the arthritis brief summary appears, phenomenons such as swelling appear in nose, meet the performance of adjuvant-induced arthritis.With model control group relatively, the above symptom of the basic, normal, high dosage group of Sinomenine hydrochloride controlled release patch all has alleviating in various degree.The results are shown in Table 6-table 9.
Table 6 Sinomenine hydrochloride controlled release patch is to the influence of rat body weight
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 7 Sinomenine hydrochloride controlled release patch is to the influence of the right back sufficient girth of rat
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 8 Sinomenine hydrochloride controlled release patch is to the influence of the left back sufficient girth of rat
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 9 Sinomenine hydrochloride controlled release patch is to the exponential influence of rat arthritis
Compare with model control group:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Test example 4 safety experiments
1. Sinomenine hydrochloride controlled release patch single-dose skin irritation test
Method: get test and use 6 of rabbit, 24h loses hair or feathers animal spinal column both sides with 8% sodium sulfide solution before administration, each 60cm of every side
2, after the depilation animal being divided into two groups, i.e. intact skin group and damaged skin group, damaged skin group are scratched with No. 16 syringe needles of disinfectant district's skin that will lose hair or feathers before administration, are divided into the intersecting parallels cut, the degree of being with the oozing of blood, left and right sides skin injury degree basically identical.Medication: the contrast of consubstantiality left and right sides self is adopted in test, and left side depilation district (being coated with medicament region) gives embodiment 2 60cm
2, depilation district in right side gives blank patch 60cm
2, with medical rubber cream sealing, fixing.Every animal sub-cage rearing behind the administration 24h, removes covering, cleans left drug with warm water, and smear the position respectively at observation behind 1h, 24h, 48h and the 72h and have or not situations such as erythema and edema, and the recovery situation of above-mentioned variation and time.
The result: in above-mentioned observing time, 6 rabbit left and right sides smear zones there is no erythema and edema formation, and scoring is 0 (the results are shown in Table 10).Show that embodiment 2 single medications are to animal subject skin nonirritant.
Table 10 Sinomenine hydrochloride controlled release patch single-dose rabbit skin S R bonds fruit
2. Sinomenine hydrochloride controlled release patch multiple dosing skin irritation test
Method: get test and use 6 of rabbit, depilation, grouping, the same single-dose of skin injury method gave embodiment 2 and normal saline respectively 7 days by above-mentioned medication, and 23h removes left drug after each administration, observe behind the 1h and smear the position and have or not situations such as erythema and edema, and repeat to be administered once.Behind last administration 24h, remove covering, clean left drug, smear the position respectively at observation behind 1h, 24h, 48h and the 72h and have or not situations such as erythema and edema with warm water, and the recovery situation of above-mentioned variation and time, go forward side by side to assassinate by the scoring of table 11, table 12 and swash intensity evaluation.Whether the position is smeared in observation simultaneously situations such as pigmentation, petechia, pachylosis or epidermatic atrophy.
The result: during the administration, observe 6 rabbit left and right sides smear zones every day and there is no erythema and edema formation, administration is observed to 72h after finishing, and 6 rabbit left and right sides smear zones there is no erythema and edema formation, and scoring is 0 (the results are shown in Table 13); Also situations such as non-pigment calmness, petechia, pachylosis or epidermatic atrophy take place.Show that more than 2 medication of embodiment is to animal subject skin nonirritant.
Table 11 skin irritation reaction standards of grading
Table 12 skin irritation intensity evaluation
Table 13 embodiment 2 multiple dosing rabbit skin S R bonds fruit
3. Sinomenine hydrochloride controlled release patch skin anaphylactic test
Method: get test and use 30 of Cavia porcelluss, with the depilation of animal spinal column both sides, the every side of depilation area is 3 * 3cm to 24h with 8% sodium sulfide solution before administration
2, after the depilation animal is divided into 3 groups, i.e. medicine group, negative control group and positive thing matched group.The medicine group gives embodiment 2, and negative control group gives blank patch, and positive thing matched group gives positive sensitizer 2,4-dinitro-chloro-benzene.
Sensitization contact: depilation district, each treated animal left side is coated with 2 of medicine, normal saline and 1% respectively, and 4-dinitro-chloro-benzene 0.2ml covers with one deck oilpaper and two-layer gauze after the administration, reuse medical rubber cream sealing, fixing.Behind the administration 6h, remove covering, clean left drug with warm water.The the 7th and the 14th day, respectively repeat once with same method.
Excite contact: after the last sensitization contact 14 days, with 2 of medicine, normal saline and 0.5%, 4-dinitro-chloro-benzene 0.2ml was applied to each depilation district, treated animal right side respectively, cover as stated above after the administration, fix, behind the administration 6h, remove covering, clean left drug with warm water.At once observe, then in 24h, 48h, 72h observe the skin allergy situation once more, calculate mean scores and sensitization rate (the sensitization rate is observed with four times and skin erythema or the maximum once calculating of edema animal example number are occurred).
The result: 10 Cavia porcelluss of positive thing matched group are removed and are tried to observe at once behind the thing, and erythema in various degree all appears in skin, edema do not occur, and the sensitization rate is 100%, after this alleviate gradually, recover normal to 72h skin is most; Erythema or edema do not appear in negative control group, medicine group Cavia porcellus in the observation period, the sensitization rate is 0%.The results are shown in Table 14.
Table 14 embodiment 2 administration skin allergy mean scores and sensitization rate
Annotate: the sensitization rate is four the highest results that observe
The experiment of test example 5 pharmacokineticss
Method: get 12 of SD male rats, body weight 150～180g is divided into 2 groups at random, and 6 every group, press rat body weight 4mg/100g for one group and calculate, irritate stomach and give sinomenine hydrochloride solution; Another group gives embodiment 2, and method is: with the rat back depilation, press rat body weight 4mg/100g and calculate, give the patch of proper area.Adopt the eye socket rear vein beard to get blood, respectively at after the administration 0.25,0.5,0.75,1,2,4,6,9,13,18h gets the about 0.8mL of blood, and is centrifugal, gets serum 450 μ L, extracts sample introduction, mensuration blood drug level in accordance with the law.With the blood drug level meansigma methodss of 6 rats of each time point blood drug level value as this time point.
Result's (seeing accompanying drawing 1) shows, with the administration of Sinomenine hydrochloride controlled release patch, it is very low to enter systemic blood concentration, far below the concentration of gastric infusion, illustrate that the general action that causes with the control-released plaster administration is very low, so its untoward reaction is also very low.
Invention has been described though utilized above-mentioned specific embodiment, it should be understood that those skilled in the art can also carry out various improvement or change, and they also should be in the scope of the invention that limits as claims.
Claims (8)
1, a kind of control release paster that is used for transdermal administration, it contains sinomenine hydrochloride, framework material, plasticizer, cross-linking agent, antioxidant, solvent and other pharmaceutically acceptable auxiliaries.
2, control release paster as claimed in claim 1 is characterized in that, is benchmark with the framework material, the amount ranges of the corresponding cross-linking agent of per 1 gram framework material is 2.2-5.0%, the plasticizer dosage scope is 35～60%, and ethanol is 2-10ml, and the drug loading of sinomenine hydrochloride is 0.1-0.6mg/cm
2
3, control release paster as claimed in claim 1, framework material wherein are selected from acrylate base polymer or polyisobutylene base polymer and their derivant, can select one or more chemical compounds for use.
4, control release paster as claimed in claim 2, the amount ranges of framework material wherein are 30～95% (g/ml).
5, control release paster as claimed in claim 1, cross-linking agent wherein are succinic acid, malic acid or fumaric acid and their mixture.
6, control release paster as claimed in claim 1, plasticizer wherein are dibutyl sebacate, triethyl citrate, ethyl sebacate or diethyl phthalate and their mixture.
7, control release paster as claimed in claim 1, antioxidant wherein comprises sodium sulfite, sodium pyrosulfite, cysteine, thiourea, arabo-ascorbic acid, BHT, vitamin E, disodium edetate, or its mixture.
8, the preparation method of control release paster as claimed in claim 1 is characterized in that, comprises following processing step:
(1) takes by weighing sinomenine hydrochloride, adhesive, cross-linking agent, plasticizer, antioxidant and solvent;
(2) adhesive, cross-linking agent, plasticizer are mixed, add solvent, left standstill after stirring 24 hours, make the abundant swelling of adhesive;
(3) in (2) gained mixture, add sinomenine hydrochloride and antioxidant, leave standstill a few hours; Behind the abundant stirring and evenly mixing, ultrasonic degas;
(4) (3) gained pastille mixture is coated on the separate paper, drying adds backing layer, cutting, promptly.
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| CN102399187A (en) * | 2011-11-15 | 2012-04-04 | 湖南正清制药集团股份有限公司 | Preparation method of sinomenine |
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| CN103211758B (en) * | 2013-03-19 | 2014-08-13 | 广东医学院 | Liquid crystal nanoparticle transdermal agent and preparation method thereof |
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| CN114748529A (en) * | 2021-07-05 | 2022-07-15 | 海南艾斯卓普科技有限公司 | Biodegradable sports contusion health-care patch and preparation method thereof |
| CN114748529B (en) * | 2021-07-05 | 2023-08-29 | 海南艾斯卓普科技有限公司 | Biodegradable sport contusion health care patch and preparation method thereof |
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Application publication date: 20100106 |