CN101618030A - Triptolide transdermal patch and preparation method thereof - Google Patents
Triptolide transdermal patch and preparation method thereof Download PDFInfo
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- CN101618030A CN101618030A CN200910013027A CN200910013027A CN101618030A CN 101618030 A CN101618030 A CN 101618030A CN 200910013027 A CN200910013027 A CN 200910013027A CN 200910013027 A CN200910013027 A CN 200910013027A CN 101618030 A CN101618030 A CN 101618030A
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- Prior art keywords
- triptolide
- sensitive adhesive
- patch
- pressure sensitive
- transdermal
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- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 30
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- 150000002596 lactones Chemical class 0.000 claims description 40
- 239000007788 liquid Substances 0.000 claims description 13
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 7
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims description 7
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 6
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- NOOLISFMXDJSKH-UHFFFAOYSA-N p-menthan-3-ol Chemical compound CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 6
- -1 siloxanes Chemical class 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000003655 absorption accelerator Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 235000010603 pastilles Nutrition 0.000 claims description 5
- 238000004026 adhesive bonding Methods 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 230000001464 adherent effect Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 9
- 230000007794 irritation Effects 0.000 abstract description 2
- 239000003961 penetration enhancing agent Substances 0.000 abstract 1
- 239000002674 ointment Substances 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 230000008961 swelling Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000000149 penetrating effect Effects 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 3
- 208000009386 Experimental Arthritis Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000035617 depilation Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 210000000544 articulatio talocruralis Anatomy 0.000 description 2
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 2
- 239000004568 cement Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 108010084652 homeobox protein PITX1 Proteins 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
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- 231100000027 toxicology Toxicity 0.000 description 2
- 229940126680 traditional chinese medicines Drugs 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000545405 Tripterygium Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 231100000293 acute skin toxicity Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000000454 fifth toe Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
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- 210000004994 reproductive system Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- JNYIQRMXGCWKOU-UHFFFAOYSA-M sodium methanol chloride Chemical compound [Na+].[Cl-].OC JNYIQRMXGCWKOU-UHFFFAOYSA-M 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
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- 210000002268 wool Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a triptolide transdermal patch, which is prepared by a therapeutically effective amount of triptolide, polyvinylpyrrolidone, a certain amount of pressure-sensitive adhesive, tackifier and penetration enhancer, and the triptolide transdermal patch has the advantages of high transdermal absorption rate and small local irritation on skin, thereby being an ideal triptolide preparation.
Description
Technical field
The present invention relates to a kind of transdermal patch, be specifically related to a kind of transdermal patch that contains the active component Radix Tripterygii Wilfordii lactone alcohol, belong to field of pharmaceutical preparations.
Background technology
Radix Tripterygii Wilfordii lactone alcohol claims triptolide again, be a kind of white crystal, water insoluble, be dissolved in dimethyl sulfoxide, acetone, organic solvents such as ethanol, Radix Tripterygii Wilfordii lactone alcohol is an isolating diterpenic lactone from the tripterygium plant Radix Tripterygii Wilfordii, it is one of main effective ingredient of Radix Tripterygii Wilfordii, chemical property is stable in vivo, physiologically active is strong, the high 100-200 of its relevant potency ratio Radix Tripterygii Wilfordii total glycosides doubly studies show that Radix Tripterygii Wilfordii lactone alcohol has antitumor, antiinflammatory, effects such as immunosuppressant, be used for the treatment of psoriasis clinically, rheumatoid arthritis and leukemia etc. have obtained curative effect preferably.
Triptolide is taken for a long time, can show many untoward reaction clinically, mainly show digestive system, skin and mucosa, urinary system and reproductive system etc., wherein dyspepsia reaction incidence rate can be up to 34%, Triptolide alcohol formulations toxicity test proves, the LD50=0.8mg/kg of mouse mainline, the LD50=0.9mg/kg of lumbar injection; Subacute toxicity test shows, dog, and 20ug/kg, injection every day once continuous 7 days, heart, hemopoietic system and gastrointestinal reversibility toxic reaction then occur respectively.Because many toxic and side effects of Triptolide, therefore application clinically has been subjected to bigger restriction.
Radix Tripterygii Wilfordii lactone alcohol is because its slightly solubility when making transdermal absorption formulation, often needs to solve the problem of raising transdermal absorption factor, to realize its ideal therapeutic effect.Radix Tripterygii Wilfordii lactone alcohol ointment in the prior art preparation, be intended to reduce in the body toxicity to reach more directly therapeutic effect by topical, but because its composition is insoluble in water, molecular weight is also relatively large, effective ingredient tissue permeability in the preparation is poor, transdermal absorption factor is low, thereby influence therapeutic effect, and in the process of using, the local irritation incidence rate is higher, can reach 32.34% (Shanghai City Radix Tripterygii Wilfordii lactone alcohol Ointment in Treatment psoriasis cooperative groups. Radix Tripterygii Wilfordii lactone alcohol Ointment in Treatment psoriasis. Chinese journal of dermatology [J], 1988,21 (6): 381-382).And because this preparation still is a kind of externally applied liniment, its application is subjected to multiple effects limit, such as after the usefulness preferably not with contact with clothing, avoid agents area to contact water, antiperspirant etc., also there is inconvenience in the time spent.Chinese patent CN100431547 discloses a kind of Radix Tripterygii Wilfordii lactone alcohol compound preparation of intra-articular injection therapy osteoarthritis, is Radix Tripterygii Wilfordii lactone alcohol and hyaluronic acid or chitosan are made preparation in a kind of articular cavity.Though this preparation can directly arrive focus, when using, it need under medical personnel's help, inject, and be not easy to the patient and independently use at any time.And Thunder God aches the extremely scorching reaction that the lactone injection also can be certain together, (effect of triptolide on local stimulation such as Lin Jianfeng, China's clinical pharmacology and therapeutics, 2000,5 (2): studies show that 131-133) Radix Tripterygii Wilfordii lactone alcohol rat paw subcutaneous injection can cause tangible inflammatory reaction, shows as the redness of rat paw, also can cause pain reaction, pain time can be kept 10min.
Summary of the invention
The inventor is in order to address the above problem, carried out extensive studies, find, with Radix Tripterygii Wilfordii lactone alcohol and polyvinylpyrrolidone and a certain amount of short ooze absorbent such as Mentholum or azone and mix after, unite and join in a kind of pressure-sensitive adhesive such as acrylate pressure sensitive adhesive or the siloxanes pressure sensitive adhesive, make a kind of transdermal patch of hydrophobic type, wherein Radix Tripterygii Wilfordii lactone alcohol is a kind of stable dissolved state in patch.The transdermal patch that the present invention makes identical painful lactone alcohol ointment more of the prior art is compared, and can show better release performance and Transdermal absorption performance, and have persistent action effect, and it is littler to the zest of skin to be affixed on the affected part.
The object of the present invention is to provide a kind of transdermal absorption factor height, little to the local skin zest, stick triptolide transdermal patch easily.
Triptolide transdermal patch of the present invention, comprise backing layer, the gluing casing play of pastille and imitative adhesion coating, wherein the gluing casing play of pastille mainly is 0.1%～5% active component Radix Tripterygii Wilfordii lactone alcohol by percentage by weight, the pressure sensitive adhesive of 50%-90%, the transdermal absorption accelerator of 1%-10% is formed, the viscosifier of 5%-30% and the polyvinylpyrrolidone of 1%-10%, wherein said pressure sensitive adhesive is acrylate pressure sensitive adhesive or siloxanes pressure sensitive adhesive, described viscosifier are the rosin tree lipidol, many obedient resins or Petropols, described transdermal absorption accelerator are Mentholum, azone, ethanol, in the propylene glycol any one or two kinds.
Among the present invention, viscosifier are preferably the rosin tree lipidol, have especially preferably removed the low rosin tree lipidol that boils partly and carried out hydrogenization; Percutaneous absorption enhancer is preferably Mentholum or azone.
Among the present invention, also can at random contain antioxidant, wetting agent, plasticizer and an amount of filler.
As mentioned above, triptolide transdermal patch provided by the present invention is a kind of patch of hydrophobic type, is substantially free of water.
The present invention also aims to provide a kind of method for preparing Radix Tripterygii Wilfordii lactone alcohol of the present invention, comprising: get the pressure sensitive adhesive of recipe quantity, with dissolve with ethanol, standby; Other gets polyvinylpyrrolidone, viscosifier, Percutaneous absorption enhancer and the medicine Triptolide of recipe quantity, join in the above-mentioned pressure-sensitive ethanol liquid, stir, make medicine-containing gel liquid, the ultrasonic degas bubble, then routinely on the coating machine it being coated on the backing layer material, preparation drug-reservoir layer, under 60-90 ℃ of condition dry 2-5 hour, make its drying after, cover adherent layer again, be die-cut into patch at last.Die-cut patch can be regulated size as required.
Specific embodiment
Below by embodiment the present invention is described in more detail, cited embodiment should not be construed as and the present invention will be limited to this.
Embodiment 1 to 3
In each embodiment, the pressure sensitive adhesive (acrylate pressure sensitive adhesive or siloxanes pressure sensitive adhesive) with recipe quantity joins in the dehydrated alcohol, fully stirs and makes dissolving; Other gets the ingredient Radix Tripterygii Wilfordii lactone alcohol of recipe quantity, with anhydrous alcohol solution, viscosifier, Percutaneous absorption enhancer (azone or Mentholum) with recipe quantity join in the above-mentioned pastille alcoholic solution, stir to make abundant dissolving, make glue, mix with above-mentioned pressure sensitive adhesive ethanol liquid, stir, and ultrasonic 30 minutes de-bubbled, at this moment, rubber cement liquid should be as clear as crystal.Then with rubber cement liquid on the coating machine it being coated on the backing layer material, preparation drug-reservoir layer, under 60 ± 5 ℃ of conditions dry 2-3 hour, make its drying after, cover adherent layer again, be die-cut into the paster of required size at last, promptly get the Radix Tripterygii Wilfordii lactone alcohol patch.
Table 1 embodiment 1-3 write out a prescription (percentage by weight %)
The part of removing when * being in the end dry
Fixedly Radix Tripterygii Wilfordii lactone alcohol content is, acrylate pressure sensitive adhesive is, the rosin tree lipidol is, the amount of polyvinylpyrrolidone, for the penetrating agent that adds not commensurability (accounting for the weight percentage of total prescription) (azone: 0%, 1%, 3%, 5%, 7%), to determine to add the optimised quantity of penetrating agent.
Fixedly Radix Tripterygii Wilfordii lactone alcohol content is, acrylate pressure sensitive adhesive is, the rosin tree lipidol is, the amount of penetrating agent azone, for the polyvinylpyrrolidone (0%, 3%, 5%, 7%, 10%, 12%) that adds not commensurability (accounting for the weight percentage of total prescription), to determine to add the optimised quantity of penetrating agent.
Measure by the Triptolide percentage composition that percutaneous in its 24 hours is seen through, we find, when polyvinylpyrrolidone and penetrating agent all do not join in the transdermal patch, in the transdermal patch of making in the Radix Tripterygii Wilfordii lactone alcohol 24 hours the percutaneous transmitance low; When adding penetrating agent, its percutaneous transmitance increases, but works as after the penetrating agent that is added is higher than 5%, and instead the percutaneous transmitance in 24 hours reduces, and has stoped the further release of effective ingredient.Add the transdermal patch of polyvinylpyrrolidone, can make Radix Tripterygii Wilfordii lactone alcohol present a kind of more stable dissolved state in patch, its addition is that 1～5 times of active constituents of medicine is advisable.
Embodiment 4 pharmacological toxicology embodiment
Below test from pharmacological toxicology and to verify safety of the present invention and effectiveness.
In order to estimate its safety, for the Secure Application of this medicine provides foundation, we have carried out relevant toxicity research to triptolide transdermal paster provided by the invention.
The test of one acute dermal toxicity
Select 10 of healthy adult Wistar rats for use, male and female half and half, body weight 220-250g adopts the method for once limiting the quantity of, 24h before on-test cuts off the quilt hair that the contamination zone is intended at animal trunk back, and unhairing is to answer extreme care, can not injured skin in order to avoid cutaneous permeability, press 100mg/kg dosage, the clip content of dispersion is attached to back part of animal depilation district (scope 3-4cm greater than the Triptolide transdermal patch that 10mg/ pastes
2), cover with two-layer template, seal fixedly 24h with the nonirritant adhesive plaster, take out behind the 24h and tried thing, observe animal poisoning sign, 7 days observation periods, to weigh once in the 7th day, off-test is put to death animal and is observed general pathology and changes.
The result shows that the sign of poisoning does not appear in animal, the observation period animal do not have death, triptolide transdermal patch is actual nontoxic to the rat skin acute toxicity.
8 of healthy White Rabbits are selected in two acute skin irritation tests for use, male and female are regardless of, be divided into two groups, (Fujian Pacific Pharmacy Co.,Ltd produces to be respectively patch group of the present invention and Radix Tripterygii Wilfordii lactone alcohol ointment group, the accurate word H35021241 of traditional Chinese medicines), test and back part of animal spinal column diamond wool cut in preceding 24 hours, can not damage epidermis during cropping, unhairing scope left and right sides Ge Yue 2cm * 3cm.During test; get triptolide transdermal patch of the present invention and Radix Tripterygii Wilfordii lactone alcohol ointment; about 0.05mg (in the amount of Radix Tripterygii Wilfordii lactone alcohol) is attached to depilation district, right side; (2.5cm * 2.5cm) and one deck template cover; the sealing of reuse nonirritant adhesive plaster, fixing 4h; depilation district in left side is contrast, remove 1h, 24h behind the triptolide transdermal patch of the present invention, 48h and 72h observation and are tried the side dermoreaction to use two layers of gauze then.Equally, get Radix Tripterygii Wilfordii lactone alcohol ointment (every rabbit is smeared consumption for containing Radix Tripterygii Wilfordii lactone alcohol 0.02mg), observational technique ketone patch group.
The result shows: after removing triptolide transdermal patch, animal is tried position skin and erythema, edema are not occurred, and 24h, 48h, 72h top average are 0 grade, and triptolide transdermal patch of the present invention is a nonirritant to the rabbit acute skin irritation; And Radix Tripterygii Wilfordii lactone alcohol ointment group as seen, and animal is tried the position and the fraction erythema occurs, and with among a small circle edema, the top average is 1 grade.From last result as can be seen, triptolide transdermal patch of the present invention is less than existing Radix Tripterygii Wilfordii lactone alcohol ointment aspect skin irritation.
Three, transdermal penetration test
Do not have a hair rat (body weight 200g) with pentobarbital anesthesia, remove ventral seta after, downcut the skin of abdomen sample, the dermatological specimens that each is such places a kind of Franz diffusion cell (effective infiltrating area: 2.83cm
2, pool volume: 16ml), and with triptolide transdermal patch of the present invention (area 2.5cm
2, be followed successively by and contain Radix Tripterygii Wilfordii lactone alcohol 0.005mg, 0.02mg, 0.05mg, be i.e. three kinds of patches of embodiment 3,2,1) be attached on the dermatological specimens; Other gets Radix Tripterygii Wilfordii lactone alcohol ointment, and (Fujian Pacific Pharmacy Co.,Ltd produces, the accurate word H35021241 of traditional Chinese medicines) 0.02mg (in the amount of effective ingredient Radix Tripterygii Wilfordii lactone alcohol) places in the supply chamber, attaching receipts liquid is 50% methanol sodium chloride solution in the pond, note bubble in the emptying pond, making between the contacting of skin and reception liquid does not have bubble.Subsequently, in 37 ℃ of following heated at constant temperature cells, stir the liquid of accepter in this pond by a kind of magnetic stirrer, with constant interval (4,8,12,16,20,24h), repeatedly to the accepter liquid (0.5ml that partly takes a sample, replenish the fresh liquid of respective volume simultaneously), and measure the content of this liquid part Radix Tripterygii Wilfordii lactone alcohol.
The results are shown in Table 2
The percutaneous of each time point of table 2 Radix Tripterygii Wilfordii lactone alcohol patch sees through percentage composition (%)
From last table result as can be seen, under the identical situation of consumption, triptolide transdermal patch is at a variant time point accumulative total excessive all obvious unnecessary Radix Tripterygii Wilfordii lactone alcohol ointment, utilization rate of active components is higher than ointment formulation, and the accumulative total transmitance of patch increases with component content in the patch and increases.
Four, to the therapeutical effect of adjuvant-induced arthritis
Animal: the SD rat, be male, body weight 220-250g purchases in Shenyang Pharmaceutical University experimental animal center.
Reagent: bacillus calmette-guerin vaccine (Chinese biological goods evaluating center), lanoline (Shenyang Pu Ruixing Fine Chemical Co., Ltd), liquid paraffin (Shenyang Chemical Co., Ltd.'s product).
The preparation of adjuvant: with liquid paraffin and lanoline in 2: 1 ratio in 70 ℃ of abundant mixings of following heat supply, it is even that autoclaving, every then ml add the abundant ground and mixed of bacillus calmette-guerin vaccine 6mg, makes Freund's complete adjuvant.
The foundation of arthritis model: every above-mentioned adjuvant 0.1ml of the right back sufficient plantar subcutaneous injection of rat, induce arthritic generation, every other day observe once, be completed into until arthritis, the lasting swelling 4 days of the injection adjuvant one parapodum sole of the foot from first day, then begin detumescence, continued swelling once more in the 8th day, peaked in the 16th day, afterbody, ear's secondary response was in generation in the 12nd day, mainly show as injection adjuvant offside (left hind) pedal swelling, afterbody, the also swelling in various degree of ear and forelimb joint is marked to each group rat left hind lesion degree by following standard: 0 minute: do not have red and swollen; 1 minute: the little toe arthroncus; 2 minutes: toe joint and pedal swelling; 3 minutes: ankle joint sufficient pawl swelling once; 4 minutes: comprise the whole sufficient pawl swelling of ankle joint.
Grouping and administration: behind the injection adjuvant the 19th day, the rats with arthritis secondary response tended towards stability, and the whole body pathological changes is also more obvious.Above-mentioned rat is divided into 5 groups at random, every group 10, first group is the substrate matched group, sticks the patch that does not contain medicine, second group is Radix Tripterygii Wilfordii lactone alcohol ointment group, touch deposited ointment, the 3-5 group is patch group of the present invention (substrate of embodiment 2, sticking dosage is 5,20,50 μ g/kg), coating every day or replacing patch are once, continuous 7 days, measured left back sufficient sole of the foot thickness in the 7th day, the results are shown in Table 3.
Table 3 Triptolide transdermal patch to the influence of the left back foot swelling of adjuvant-induced arthritis (x ± s, n=10)
Compare with matched group:
*P＜0.05,
*P＜0.01; Compare with the ointment group:
#P＜0.05.
Last table result shows, left back foot swelling improves significantly to adjuvant-induced arthritis for Radix Tripterygii Wilfordii lactone alcohol ointment and transdermal patch, difference has significance good (P＜0.05), the middle and high dosage group of transdermal patch wherein of the present invention difference more remarkable (P＜0.01); The middle and high dosage group of the present invention is compared with the ointment group, and its improvement effect obviously is better than ointment group (P＜0.05).
Claims (3)
1, a kind of triptolide transdermal patch, described patch comprises backing layer, the gluing casing play of pastille and imitative adhesion coating, it is characterized in that: the gluing casing play of pastille mainly is 0.1%～5% active component Radix Tripterygii Wilfordii lactone alcohol by percentage by weight, the pressure sensitive adhesive of 50%-90%, the transdermal absorption accelerator of 1%-10% is formed, the viscosifier of 5%-30% and the polyvinylpyrrolidone of 1%-10%, wherein said pressure sensitive adhesive is acrylate pressure sensitive adhesive or siloxanes pressure sensitive adhesive, described viscosifier are the rosin tree lipidol, many obedient resins or Petropols, described transdermal absorption accelerator are Mentholum, azone, ethanol, in the propylene glycol any one or two kinds.
2, Radix Tripterygii Wilfordii lactone alcohol patch according to claim 1 is characterized in that described viscosifier are the rosin tree lipidol, and described transdermal absorption accelerator is Mentholum or azone.
3, a kind of method for preparing claim 1 or 2 described triptolide transdermal patch comprises: get the pressure sensitive adhesive of recipe quantity, and with dissolve with ethanol, standby; Other gets polyvinylpyrrolidone, viscosifier, transdermal enhancer and the medicine Triptolide of recipe quantity, join in the above-mentioned pressure-sensitive ethanol liquid, stir, make medicine-containing gel liquid, the ultrasonic degas bubble, then routinely on the coating machine it being coated on the backing layer material, preparation drug-reservoir layer, under 60-90 ℃ of condition dry 2-5 hour, make its drying after, cover adherent layer again, be die-cut into patch at last.
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| CN2009100130273A CN101618030B (en) | 2009-08-10 | 2009-08-10 | Triptolide transdermal patch and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670565A (en) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | Percutaneous absorption patch containing natural medicaments |
| CN102670624A (en) * | 2011-03-14 | 2012-09-19 | 福建省医学科学研究院 | Patch for treating rheumatic arthritis and preparation method thereof |
| CN109125733A (en) * | 2018-10-30 | 2019-01-04 | 成都先手生物科技有限公司 | A kind of composition for the treatment of of arthritis and its application |
| CN111000888A (en) * | 2019-12-27 | 2020-04-14 | 浙江中医药大学 | Tripterygium wilfordii residue patch and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US7691404B2 (en) * | 2000-11-06 | 2010-04-06 | Samyang Corporation | Transdermal delivery system of diclofenac with improved water absorbability and adhesion properties |
-
2009
- 2009-08-10 CN CN2009100130273A patent/CN101618030B/en not_active Withdrawn - After Issue
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670565A (en) * | 2011-03-14 | 2012-09-19 | 苏州博创园生物医药科技有限公司 | Percutaneous absorption patch containing natural medicaments |
| CN102670624A (en) * | 2011-03-14 | 2012-09-19 | 福建省医学科学研究院 | Patch for treating rheumatic arthritis and preparation method thereof |
| CN102670624B (en) * | 2011-03-14 | 2015-04-15 | 福建省医学科学研究院 | Patch for treating rheumatic arthritis and preparation method thereof |
| CN109125733A (en) * | 2018-10-30 | 2019-01-04 | 成都先手生物科技有限公司 | A kind of composition for the treatment of of arthritis and its application |
| CN111000888A (en) * | 2019-12-27 | 2020-04-14 | 浙江中医药大学 | Tripterygium wilfordii residue patch and preparation method thereof |
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| CN101618030B (en) | 2010-12-29 |
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