CN1075372C - Indomethacin adhesive plaster - Google Patents
Indomethacin adhesive plaster Download PDFInfo
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- CN1075372C CN1075372C CN95102534A CN95102534A CN1075372C CN 1075372 C CN1075372 C CN 1075372C CN 95102534 A CN95102534 A CN 95102534A CN 95102534 A CN95102534 A CN 95102534A CN 1075372 C CN1075372 C CN 1075372C
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- indomethacin
- adhesive plaster
- plaster
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Abstract
The present invention discloses a technology of an indomethacin adhesive plaster. An indomethacin adhesive plaster is a novel transdermal therapeutic system prepared from indomethacin used as main medicine, a transdermic accelerating agent, cosolvent, adhesive, etc. In the system, the indomethacin used as main medicine can penetrate through the skin to directly act on the affected region, and medicine can be released for a long time in substrate. The indomethacin adhesive plaster has the controlled release function, and after the indomethacin adhesive plaster is pasted on the part of the skin, no stimulation, or hypersensitivity, or exfoliation reaction occurs. The technology of an indomethacin adhesive plaster has obvious social benefits. The indomethacin adhesive plaster prepared according to the technology has the broad market, and therefore, the indomethacin adhesive plaster has obvious economic benefits.
Description
The invention discloses the systems technology of the Indomethacin adhesive plaster of the novel skin-penetrating therapeutic that a class is made up of the short agent of principal agent indomethacin and transdermal, cosolvent, pressure sensing adhesive agent etc., it belongs to the pharmaceutics technical field, also belong to technical field of polymer materials, its International Classification of Patents code is respectively A61, C08.
Indomethacin (Indomethacin, IND) be potent NSAID (non-steroidal anti-inflammatory drug) commonly used clinically, has good anti-inflammatory pain-stopping effect, for treatment of diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitiss, effect is remarkable, and its mechanism of action mainly is suppress the pro-inflammatory cytokine prostaglandin synthetic.
But NSAID (non-steroidal anti-inflammatory drug) is indomethacin particularly, and when with tablet, during the capsule oral administration, existing with gastrointestinal tract disorder (as to GI irritation, bringing out gastric ulcer etc.) is main untoward reaction.Its incidence rate is about 36.5%, and the patient of oral this medicine more than 20% therapy discontinued of having to because of toxicity is arranged approximately.In order to reduce these toxicities, the pharmacy work person attempts the mode with suppository rectally and injection drug administration by injection.
Though rectally has avoided medicine to pass through the oral shortcoming that gastrointestinal tract causes gastrointestinal side effect that directly acts on, indomethacin must have enough amounts to enter blood circulation arrival site of action (affected part) competence exertion therapeutic effect.Because higher blood drug level, thus still there is certain untoward reaction, as central nervous system's toxicity: headache, dizziness etc.In addition, suppository is very inconvenient in the use, and rectum is also very irregular to the absorption of medicine, and individual variation is big, and is acceptable poor.Therefore be subjected to certain restriction in the use.The indomethacin injection type also has many research reports at home and abroad, and because of it is insoluble in water, not only to add solubilizing agent, but also will regulate below the pH value to 7.0, thereby most poor stability, injection artifact availability is low, is difficult to promote the use of.
In recent years, in order to overcome above-mentioned shortcoming, it is the externally applied transdermal preparation of effective ingredient that people are are researching and developing with the indomethacin, makes indomethacin can see through skin, directly act on affected part, the drug level that arrives local organization (affected part) is higher than the drug level that enters in the blood far away.Both reach therapeutic effect, avoided the generation of untoward reaction simultaneously again.Indomethacin liniment, ointment promptly are like this.But liniment, outer time spent of ointment are easily wiped by clothes, and action time is short, and in ointment, indomethacin must be with a spot of alkali (as NaHCO in addition
3) dissolving, cause the indomethacin instability, hydrolyzate be parachlorobenzoic-acid and 5-methoxyl group-2-methyl-3-indoleacetic acid (Yi-Hung Tsai et al. " Int.J.pharm. " 1986,28:47-58).Thus, people to expect developing with the indomethacin be that the rubber mass plaster of principal agent is comparatively suitable.
With rubber is the Indomethacin adhesive plaster of substrate, under the condition that has absorption enhancer propylene glycol and carbamide to exist, obviously is longer than ointment and liniment action time, also is difficult for wiping for clothes.But in the production process of rubber mass plaster, be solvent, not only consumed industrial well sold and in short supply goods and materials, also can cause environmental pollution, introduced unsafe factor in process of production simultaneously with gasoline, because of the gasoline highly volatile, inflammable and explosive.More unsatisfactoryly be,, be affixed on affected part, anaphylaxis can take place because of containing vegetable protein in the rubber; For strengthening rubber plaster viscosity and preventing viscosifier and the age resistor that ageing of rubber adds, can produce zest to skin; Because extremely strong easily the causing of rubber mass viscosity peeled off reaction.Rubber is easily aging, places and just loses viscosity in 1 year, and above-mentioned problems are the good solution of neither one so far.So developing new is not the emplastrum of the substrate person's that becomes the pharmacy work one of the objective of the struggle with rubber.
The objective of the invention is: inventor of the present invention is for addressing the above problem, intending research and development is effective ingredient with the indomethacin, with the acrylate copolymer pressure sensitive adhesive is substrate, with ethanol, propylene glycol, glycerol, PEG400 etc. are cosolvent, with azone, high-grade aliphatic ester, DMSO, DMF etc. are the transdermal therapeutic system of transdermal enhancer, to expect that this plaster directly is affixed on affected part, indomethacin can absorb by percutaneous, topica is dense far above blood drug level, long action time, nonirritant, no anaphylaxis does not have and peels off reaction, does not also have the novel skin-permeable and control-released plaster of GI irritation and central nervous system's untoward reaction.
Its horny layer of human body skin is to be main component with the keratin, and contains liposoluble constituents such as a large amount of fat, wax, cholesterol, and it has the external environment of adaptation and changes the function that composition escapes in the foreign body intrusion of resisting, control volume.So, medicine is difficult to the percutaneous absorption.The present invention is intended to prepare a kind of novel transdermal therapeutic system, and this system's Chinese medicine can see through keratodermatitis, directly acts on affected part, makes the dense blood drug level that is higher than of topica far away.Adopt new hydrophilic high molecular material and transdermal enhancer in this transdermal therapeutic system.This transdermal therapeutic system nonirritant, no anaphylaxis, nothing are peeled off reaction.Make the good anti-inflammatory pain-stopping effect of the existing indomethacin of this transdermal therapeutic system, have no adverse reaction again.
Be the technical measures that realize that the object of the invention is taked:
The present invention is a novel percutaneous controlled-release therapy system.
The main component that can produce anti-inflammatory pain-stopping effect among the present invention is an indomethacin, and indomethacin is the potent NSAID (non-steroidal anti-inflammatory drug) of life-time service clinically.In transdermal therapeutic system of the present invention, the consumption of indomethacin is 0.1～30.0%.
Among the present invention, it is substrate that this transdermal therapeutic system adopts hydrophilic macromolecular material, is the best with the acrylate polymer pressure sensitive adhesive especially.The acrylate polymer pressure sensitive adhesive just is used to prepare medical adhesive tape from the sixties.Itself is minimum to skin irritation, need not add viscosifier, antioxidant, seldom causes allergic reaction, and the acrylate polymer pressure sensitive adhesive of possess hydrophilic property also has the characteristics of poisture-penetrability.Used acrylate polymer pressure sensitive adhesive among the present invention, its standard has been recorded the pharmaceutic adjuvant handbook into the U.S., has very high safety.Acrylate polymer presses the consumption of sour glue comparatively suitable with 50.0～90.0% among the present invention.
Among the present invention, indomethacin is for producing the main component of drug effect.Indomethacin dissolves in acetone, and is molten in methanol, ethanol, chloroform or ether part omitted, slightly soluble in benzene, and soluble,very slightly in toluene, almost insoluble in water, molecular weight is 357.8, mp is 158～162 ℃.In order to guarantee the indomethacin dissolving, be easy to Transdermal absorption, it is cosolvent that the present invention has designed with ethanol, glycerol, propylene glycol, Liquid Macrogol, PEG400 etc., these alcohols materials mix with high molecular weight acrylic ester polymer pressure sensitive adhesive and indomethacin, after the coating drying, indomethacin is molecular dispersion, becomes the solid dispersion of transparent fully indomethacin-acrylate polymer.The consumption of alcohols materials such as glycerol, ethanol, propylene glycol, PEG-300, PEG-400 is 2.0～20.0%.Available one or more cosolvents and usefulness among the present invention.
The main component indomethacin must absorb through skin among the present invention, directly acts on affected part, and the human body skin horny layer is that medicine sees through the natural cover for defense that skin enters human body, and generally speaking, medicine is difficult to see through skin.Add commercially available Percutaneous absorption enhancer such as carbamide, senior fat intestinal acid esters, dimethyl formamide, dimethyl sulfoxide (DMSO), azone etc. in the transdermal therapeutic system of the present invention, can improve the percutaneous absorbtivity of medicine greatly, produce excellent curative.Transdermal enhancer is good with azone especially among the present invention.Among the present invention, the consumption of transdermal enhancer is 0.5～10.0%.
Among the present invention, the principal agent composition indomethacin of indomethacin transdermal therapeutic system, cosolvent such as glycerol, ethanol, PEG300, PEG400 etc., substrate such as acrylate polymer are pressed sour glue, transdermal enhancer such as carbamide, azone etc. be mix homogeneously fully, be applied on the base paper with the coating machine stand then,, use the PVC thin film then through 70 ℃～150 ℃ dryings, perhaps non-woven fabrics etc. is mounted the backing material, transitivity is compound, is die-cut into a certain size and specification, promptly gets indomethacin percutaneous controlled-release system.
The method for preparing the percutaneous controlled-release system among the present invention is the transitivity composite algorithm, and the production temperature is 70 ℃～150 ℃.
Among the present invention, mounting the backing material is PVC thin film or non-woven fabrics.
The present invention adopts above-mentioned material and above-mentioned prepared indomethacin controlled release plaster.
Compared with the prior art the technique effect that has reached than the present invention:
The indomethacin transdermal therapeutic system of the present invention's preparation has good anti-inflammatory pain-stopping effect, and has no adverse reaction.Its pharmacokinetics (medicine percutaneous absorption test), pharmacodynamics, and clinical test results is as follows.A. pharmacokinetics (medicine percutaneous absorption test)
Get 6 of the healthy rabbits of the about 2.5～3.0kg of body weight, the depilation of ridge both sides, each 50cm of area
2, meet rabbit body weight 20mg/kg and prepare plaster, losing hair or feathers was affixed on back depilation place after 24 hours.After administration 0.5,1,2,3,4,8,12,24, got blood by ear vein in 36 hours, measure blood drug level, see Table 1 (detecting of HPLC instrument is limited to 0.1 μ g/mL)
Blood drug level time (hr) 0.5 1234 blood concentrations (μ g/ml) 0.20 ± 0.11 0.32 ± 0.18 0.68 ± 0.27 0.86 ± 0.40 1.05 ± 0.44 time (hr) 8 12 24 36 blood concentrations (μ g/ml) 0.81 ± 0.42 0.91 ± 0.37 0.63 ± 0.16 0.15 ± 0.05 of table 1 Indomethacin adhesive plaster percutaneous absorption test
The same method is got 6 of healthy rabbits after administration 6 hours, takes out and sticks position muscle, measures that indomethacin content is 42.72 ± 17.9 μ g/g (n=6) in the muscle
The percutaneous absorption test shows: the drug level in the partial musculature is about 40 times of blood level, and reaches 24 hours action time, has controlled release and long-acting.B. the test of pesticide effectiveness B.1. indomethacin percutaneous controlled-release system on Carrageenan bring out the therapeutical effect of rat toes edema
Method by volumes such as Xu Shuyun " pharmacological testing methodology " nineteen eighty-two version P525 record is tested.Get 16 of male SD rats, body weight 140 ± 10g is divided into two groups at random, and 8 every group, experiment is preceding with the volumetric values below every the right back ankle of rat joint of volumetric method mensuration.The right back toe position of the every Mus of I group sticks blank plaster, as negative control, the II group sticks indomethacin percutaneous controlled-release plaster, after the administration 4 hours, peel off plaster, at the carrageenin of the right back toes of every Mus middle part subcutaneous injection 0.05ml1.0%, behind the Yu Zhiyan 1, tested each following volumetric values in rat ankle joint in 3,5 hours, calculate swelling degree and suppression ratio according to formula (1) and formula (2).
The swelling degree
V in the formula (1)
nAnd v
tRepresentative causes the swelling value of scorching front and back respectively.
Suppression ratio
E in the formula (2)
tAnd E
cRepresent the average swelling degree of administration group and blank group respectively.
The therapeutical effect of the rat toes edema that table 2 Indomethacin adhesive plaster on Carrageenan is brought out
Group time (hr) index 135
Blank group (n=8) swelling degree (ml 0.29 ± 0.07 0.28 ± 0.09 0.33 ± 0.07 of x ± s)
Plaster group (n=8) swelling degree (ml 0.23 ± 0.06 of x ± s)
*0.22 ± 0.07* 0.58 ± 0.08
*
Suppression ratio (%) 52.38 67.21 30.95
*P＜0.05
**P＜0.01
The result shows that Indomethacin adhesive plaster can significantly suppress the rat paw inflammation that carrageenin brings out.B.2. the therapeutical effect of Indomethacin adhesive plaster rat arthritis that Freund's complete adjuvant is brought out
Press the method test that Xu Shuyun etc. compiles " pharmacological experimental methodology " nineteen eighty-two version P534 record, getting SD is rat was all measured the following normal foot pawl in left and right hind leg ankle joint with volumetric method before medication displacement.After injection Freund's complete adjuvant 0.1ml causes scorching 30min in the right back sufficient sole of the foot of every Mus afterwards, stick and contain medicine plaster, dosage is 30mg/kg.wt, immobilization with adhesive tape, and each group causes scorching back 1,2,3 days, in kind changed dressings once with dosage every day, after causing scorching back 18 hours and 3 days, measure right back sufficient displacement with volumetric method, observe the influence of Indomethacin adhesive plaster the constitutional inflammation.The dosage that continues in a week to use the same method with identical after causing inflammation sticked confession reagent thing 7 days to every group of rat, promptly cause scorching back and measured the swelling value of left and right metapedes on the 14th day, observe the influence of Indomethacin adhesive plaster to secondary inflammation, after causing scorching 19 days, change dressings once with said method and dosage, continuous use 7 days, observe the therapeutical effect of Indomethacin adhesive plaster, calculate swelling degree and suppression ratio by formula (1) and formula (2) to secondary inflammation.
Table III Indomethacin adhesive plaster is to the influence of constitutional pathological changes
After causing scorching 3 days after causing scorching 18 hours
Swelling degree suppression ratio swelling degree suppression ratio
(the ml % of x ± s) (the blank group of ml % I (n=10) 0.28 ± 0.08 0.47 ± 0.14 II Indomethacin adhesive plaster (n=10) 0.24 ± 0.05 of x ± s)
*62.34 0.22 ± 0.07 89.30
*P＜0.05
*P＜0.01 (comparing) with the blank group
Table IV Indomethacin adhesive plaster is to the influence (causing scorching back 14 days) of Secondary cases pathological changes
Group number of animals swelling degree suppression ratio swelling degree suppression ratio after causing scorching 3 days after causing scorching 18 hours
((x ± s) the blank group of ml % I 10 0.35 ± 0.17 0.64 ± 0.11 II contain medicine plaster 10 0.23 ± 0.08 to the ml % of x ± s)
*77.78 0.27 ± 0.11
*81.24
P＜0.01 (comparing) with the blank group
Table V Indomethacin adhesive plaster is to the therapeutical effect (after causing scorching 26 days) of Secondary cases pathological changes
Group number of animals swelling degree suppression ratio swelling degree suppression ratio after causing scorching 3 days after causing scorching 18 hours
((x ± s) the blank group of ml % I 10 0.28 ± 0.1 0.57 ± 0.09 II contain medicine plaster 10 0.22 ± 0.09 to the ml % of x ± s)
*64.34 0.26 ± 0.09
*82.58
*P＜0.05 **P＜0.01
Above-mentioned test shows that the prepared percutaneous controlled-release system of the present invention can obviously suppress the rat arthritis that Freund's complete adjuvant brings out.C. clinical test results
The Indomethacin adhesive plaster of Fa Benming preparation is through hospital of Tongji University, People's Hospital, Hubei Province, the clinical trial of attached institute of Hubei College Of Traditional Chinese Medicine, this product is 87.66% to the total effective rate of scapulohumeral periarthritis, osteoarthritis, rheumatoid arthritis treatment, and with the total effective rate of indometacin enteric-coated tablet be 62.66%, two group have significant difference (P＜0.05) and the Indomethacin adhesive plaster adverse reaction rate extremely low.
Embodiment:
R: indomethacin 25g
1,2-propylene glycol 25g
Azone 10g
Acrylic copolymer pressure sensitive adhesive 500g
Make 1000 of plaster altogether
With indomethacin, 1,2-propylene glycol, azone, the abundant mix homogeneously of acrylate copolymer pressure sensitive adhesive are applied on the base paper with the coating machine stand, and dry then, transitivity is compound to be mounted on the backing material PVC, receives and changes, promptly die-cut.
Claims (4)
1. Indomethacin adhesive plaster, it is to be principal agent with the indomethacin, it is characterized in that: this card cream be with PVC or non-woven fabrics for mounting the backing material, the compatibility of plaster is:
Indomethacin 0.1-30%;
Pressure sensitive adhesive 50.0-90.0%;
Cosolvent 2.0-20%;
Promoter 0.5-10.0%.
2. by the described Indomethacin adhesive plaster of claim 1, it is characterized in that: described pressure sensitive adhesive is the acrylate polymer pressure sensitive adhesive.
3. by the described Indomethacin adhesive plaster of claim 1, it is characterized in that: described cosolvent is one or more the mixture in ethanol, propylene glycol, PEG-400, PEG-300, the glycerol.
4. by the described Indomethacin adhesive plaster of claim 1, it is characterized in that: described promoter is azone, carbamide, DMSO or DMF.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95102534A CN1075372C (en) | 1995-05-18 | 1995-05-18 | Indomethacin adhesive plaster |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95102534A CN1075372C (en) | 1995-05-18 | 1995-05-18 | Indomethacin adhesive plaster |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1144655A CN1144655A (en) | 1997-03-12 |
| CN1075372C true CN1075372C (en) | 2001-11-28 |
Family
ID=5074365
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95102534A Expired - Fee Related CN1075372C (en) | 1995-05-18 | 1995-05-18 | Indomethacin adhesive plaster |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1075372C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526001B (en) * | 2011-12-30 | 2013-09-25 | 沈阳药科大学 | Indomethacin salt transdermal patch and preparation method thereof |
| CN106333937B (en) * | 2016-08-30 | 2020-04-28 | 蔡玉安 | Plaster matrix with large drug loading and high sustained viscosity |
| CN107412286B (en) * | 2017-06-26 | 2021-05-25 | 杭州仁德医药有限公司 | Preparation method of external plaster for treating arthralgia |
-
1995
- 1995-05-18 CN CN95102534A patent/CN1075372C/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| 《医药工业》1986,17(2) 1986.1.1 * |
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| Publication number | Publication date |
|---|---|
| CN1144655A (en) | 1997-03-12 |
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