CN1074117A - The prescription of " Gaowujiasu " picking and method for making - Google Patents
The prescription of " Gaowujiasu " picking and method for making Download PDFInfo
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- CN1074117A CN1074117A CN 92100233 CN92100233A CN1074117A CN 1074117 A CN1074117 A CN 1074117A CN 92100233 CN92100233 CN 92100233 CN 92100233 A CN92100233 A CN 92100233A CN 1074117 A CN1074117 A CN 1074117A
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- sensitive adhesive
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- lappaconitine
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Abstract
The invention belongs to the prescription and the preparation technology of membrane controlled release type percutaneous drug administration preparation " Gaowujiasu " picking.Said preparation includes protective layer, pressure-sensitive adhesive layer, controlled release layer, drug storehouse storage glue-line and backing layer.After dispensing, can reach the blood drug level of effective treatment at short notice, produce the steady plasma-drug concentration that is similar to intravenous drip in the body because the drugs with function of controlled release (film) layer enters with constant speed subsequently.Offeing medicine, this patch formulation has equal effect with the lappaconitine injection in 12 hours.More remarkable to other intractable pain (rheumatalgia, headache) effect.Said preparation stability can be for 2 years.
Description
The invention belongs to lasting prescription and the preparation that discharges percutaneous drug administration preparation of membrane controlled release type, said preparation is particularly suitable for doing the usefulness of long-acting analgesic.
Because the development new drug needs costly, it is difficult day by day to go into operation, therefore from existing medicine by changing dosage form and route of administration to reach new therapeutic purposes, reduce the toxic and side effects of medicine, make it the even more ideal crucial problem of study of pharmacy that become of curative effect, this also is the another approach of new drug development.The transdermal therapeutic system that early sixties grows up (Transdermal Theropeatlc System is called for short TTS) is exactly a kind of new route of administration.Because this class preparation is superior than injection, tablet, have that drug release time is long, effect is lasting, constant speed release medicine and characteristics such as easy to use.Therefore development is very fast.Existing " nitroglycerin, clonidine " waits some transdermal controlled-release formulations to occur abroad, and domestic in recent years also have some similar preparations to occur, and all obtains satisfied effect through using.
The objective of the invention is to develop a kind of long-acting analgesic effect that has, need not again to inject or the prescription and preparation (work) method thereof of the " Gaowujiasu " picking of sustained release drug for oral administration.
For making " Gaowujiasu " picking of the present invention in use, can produce the steady plasma-drug concentration effect that is similar to intravenous drip, so the present invention has adopted the technical solution of the percutaneous drug administration preparation of release-controlled film, the control that makes controlled drug release film can constant speed enter in the body, keeping the blood drug level of stable state, thereby produce persistent analgesic activity.The present invention specifically comprises: " Gaowujiasu " picking formation, prescription, processing technology, and existing division is as follows:
One, " Gaowujiasu " picking of the present invention constitutes: 5 layers of structure, and wherein: (1) ground floor is a protective layer, adopts the silication separate paper, no pharmacological action tears off during use; (2) second layer is a pressure-sensitive adhesive layer, includes the lappaconitine medicine, and its effect is to stick on the skin, and makes wherein contained lappaconitine medicine can be rapidly see through that skin enter and the blood drug level that reaches effective treatment produces drug effect at short notice; The 3rd layer is controlled release layer (being release-controlled film), skinning controlled-release function.Just see through that skin enters and after reaching the blood drug level of effective treatment when the medicine in the pressure-sensitive adhesive layer, lappaconitine medicine in the drug storehouse storage glue-line below release-controlled film (layer) by this layer (release-controlled film) constant constant speed migrate to pressure-sensitive adhesive layer, enter blood through skin afterwards, be in relative plateau (being similar to the intravenous drip administration) to keep blood drug level; (4) the 4th layers is the drug storehouse storage glue-line, contains to keep the lappaconitine that steady blood drug level reaches the required dose of design natural law; (5) layer 5 is a backing layer, adopts aluminium foil, rises and supports no pharmacological action.
Two, " Gaowujiasu " picking prescription of the present invention comprises: the ratio of pressure-sensitive adhesive layer prescription, drug storehouse storage glue-line prescription and this two-layer middle lappaconitine amount.Wherein:
1, the lappaconitine content ratio is in pressure-sensitive adhesive layer and the drug storehouse storage glue-line:
Lappaconitine content in the pressure-sensitive adhesive layer: lappaconitine content=3～5 in the drug storehouse storage glue-line: 4～6.
2, the pressure-sensitive adhesive layer prescription is:
Low-polyisobutylene: height-polyisobutylene: mineral oil=7: 6: 11, lappaconitine consumption are 16.5～16.7% of substrate weight, and the enhancer of cutaneous penetration consumption is 7.9～8.0% of a substrate weight.
3, drug storehouse storage glue-line prescription is:
Low-polyisobutylene: height-polyisobutylene: mineral oil=4: 6: 10, lappaconitine consumption are 15% of substrate weight, and the enhancer of cutaneous penetration consumption is 8% of a substrate weight.
4, in above-mentioned each prescription: described substrate is meant by low-polyisobutylene, three kinds of substrate that become to be grouped into of height-polyisobutylene and mineral oil; Described enhancer of cutaneous penetration adopts azone or dimethyl sulfoxide or lower alcohols; Described mineral oil adopts liquid paraffin; Described low-polyisobutylene is that mean molecule quantity is 40000 polyisobutylene; Described height-polyisobutylene is that mean molecule quantity is 1270000 polyisobutylene.
Three, the present invention's preparation (work) process: this process comprises: technologies such as preparation (work) of pressure sensitive adhesive preparation, the preparation of drug storehouse storage glue, each layer of " Gaowujiasu " picking and crossed belt, and existing division is as follows:
1, pressure sensitive adhesive preparation:
(1), the amount of filling a prescription by above-mentioned pressure-sensitive adhesive layer, get a certain amount of low-polyisobutylene and height-polyisobutylene insert in the sealed container, and by these two kinds of polyisobutylene total amounts: the amount of chloroform=1: 10 adds an amount of chloroform, and sealing is stirred and is dipped to dissolving fully to make transparent pressure sensitive adhesive body fluid standby.
(2), the amount of filling a prescription by above-mentioned pressure-sensitive adhesive layer, getting an amount of lappaconitine is suspended in the distilled water, jolting, add consumption again: total consumption of chloroform when the amount of chloroform=1: 13～17 is determined three extractions by lappaconitine, and these chloroforms are divided into three extractions use, three times the extraction back adds an amount of anhydrous sodium sulfate to dewatering fully, and it is standby to merge three extracts.
(3), the amount by above-mentioned pressure-sensitive adhesive layer prescription adds an amount of mineral oil and an amount of enhancer of cutaneous penetration in three extracts of gained, be added to behind the mix homogeneously in the pressure sensitive adhesive colloidal solution of above-mentioned gained and go, viscosity is suitable when wherein adding an amount of chloroform with the assurance coating again, and sealing stirs and promptly makes pressure sensitive adhesive.
2, drug storehouse storage glue preparation:
Various raw material consumptions are all by the drug storehouse storage layer formula amount of getting.The chloroform consumption is in the ratio amount of getting in " pressure sensitive adhesive preparation " technology, and each road technology is identical with " pressure sensitive adhesive preparation " technology, makes drug storehouse storage glue at last.
3, the pressure-sensitive adhesive coating layer is neutralized sensitive tape:
Above-mentioned prepared pressure sensitive adhesive is uniformly coated on the silication separate paper to form thickness be the pressure-sensitive adhesive layer of 40～60 μ m, promptly makes pressure sensitive adhesive tape.
4, coating drug storehouse storage glue-line system drug storehouse storage adhesive tape.
It is the drug storehouse storage glue-line of 35～65 μ m that the above-mentioned drug storehouse storage glue that makes is uniformly coated on the last formation of aluminium foil (backing layer) thickness, promptly makes the drug storehouse storage adhesive tape.
5, system controlled release layer (being release-controlled film):
(1), get ethylene-vinyl acetate copolymer and add chloroform, and heat the widely different dissolving fully that flow to, the ethylene-vinyl acetate copolymer after the dissolving is made the ethylene-vinyl acetate copolymer film that film thickness is 30 μ m, i.e. release-controlled film.
(2), on the drug storehouse storage glue layer that sticks on the drug storehouse storage adhesive tape that the ethylene-vinyl acetate copolymer film (being release-controlled film) that makes is smooth.
6, crossed belt and film-making: have the one side of release-controlled film to stick mutually with on the one side of no silication separate paper on the pressure sensitive adhesive tape and the drug storehouse storage adhesive tape, make semi-finished product, make every subsides (sheet) again and contain the " Gaowujiasu " picking finished product that the lappaconitine amount is 12～15mg.
So far, the present invention has reached its intended purposes.The " Gaowujiasu " picking of making according to the technology of the present invention solution is the agent of a kind of skin absorbs film release-controlled skin-penetrating therapeutic.Through the provincial hospital, Fujian Province, the unit clinical verifications of totally 259 examples such as attached Concord Hospital of Fujian Medical College and Fuzhou Hospital of the Air Army, PLA, its result shows that the medicine in the " Gaowujiasu " picking enters blood through the skin absorption and reaches valid density, medicine is under the effect of release-controlled film after the process regular hour, enter the steady plasma-drug concentration that produces similar intravenous drip in the body with constant speed, " Gaowujiasu " picking preparation and lappaconitine injection have equal effect in dispensing 12 hours, " Gaowujiasu " picking reaches 90～92.7% total effective rates that obviously are better than the lappaconitine injection only 35% to the improvement of pain intensity and analgesic total effective rate in 12 hours to 72 hours, and this illustrates that " Gaowujiasu " picking of the present invention has the characteristics of long-acting analgesic.And learn in the result of above-mentioned clinical verification: to the postoperative pain produce effects is 42.2%, and total effective rate is 87.8%; To relaxing tumor pain produce effects 36.8%, total effective rate is 89.5%; Other pain is as produce effects 56.1% such as headaches, and total effective rate is 92.7%.No addiction and obviously pair effect.Special centering, minor operation, relaxing tumor pain have better long-acting analgesic effect, and the muscular soreness that cold, fever is caused and other intractable pain for example analgesic activity of rheumatalgia, headache etc. are more remarkable." Gaowujiasu " picking of the present invention is through stability test: it has stability preferably illumination, air, low humidity, humidity, room temperature storage test and the evidence of low-temperature study method.Through the sample of low-temperature study after three months, do not detect decomposed substance with the check of book layer chromatography, this principal agent material that shows " Gaowujiasu " picking of the present invention is stable.According to U.S. FDA, through aforementioned stable investigation method, medicine is no change in three months, can think that " Gaowujiasu " picking of the present invention was stable in 3 years.
Accompanying drawing is that " Gaowujiasu " picking of the present invention constitutes sketch map; " 1 " expression protective layer (silication separate paper) wherein, " 2 " expression pressure-sensitive adhesive layer, " 3 " expression controlled release layer (release-controlled film); " 4 " expression drug storehouse storage glue-line, " 5 " expression backing layer (aluminium foil).
Embodiment 1, this example contain the embodiment that lappaconitine is the " Gaowujiasu " picking of 12mg for every subsides (sheet), and its prescription is implemented by (table 1 :), and its preparation method is implemented by above-mentioned technical solution, make 1000 and paste (sheet), the about 3.8cm of every subsides
2, containing the lappaconitine amount is that 12mg/ pastes (sheet).
| (table 1 :) | Pressure-sensitive adhesive layer | The drug storehouse storage glue-line |
| Lappaconitine is low-polyisobutylene height-polyisobutylene saxol azone | 6.86 restrain 12.0 grams, 10.29 grams, 18.87 grams, 3.25 grams | 5.14 restrain 6.85 grams, 10.28 grams, 17.13 grams, 2.74 grams |
| (table 2 :) | Pressure-sensitive adhesive layer | The drug storehouse storage glue-line |
| Lappaconitine is low-polyisobutylene height-polyisobutylene saxol dimethyl sulfoxine | 8.57 restrain 15.0 grams, 12.86 grams, 23.57 grams, 4.06 grams | 6.43 restrain 8.57 grams, 12.86 grams, 21.43 grams, 3.43 grams |
It is as follows that " Gaowujiasu " picking that the foregoing description 1,2 is made and lappaconitine injection carry out the clinical practice contrast:
(1), test group 1: " Gaowujiasu " picking 15mg/ pastes (being embodiment 2) two and pastes; Test group 2: " Gaowujiasu " picking 12mg/ pastes (being embodiment 1) two and pastes.It is affixed on acomia place behind two ears, and single-dose kept 72 hours, 2 milliliters of the normal saline of intramuscular injection simultaneously.
(2), matched group: the blank paster two of no lappaconitine is affixed on acomia place behind two ears, keeps while intramuscular injection lappaconitine injection 2ml: 4mg 72 hours.
Learn through the test of above-mentioned test group and matched group clinical comparison: in 0～12,24～48,72 hour three time section, 24mg/ (being embodiment 1 two subsides) and 30mg/ time (being embodiment 2 two subsides) two kinds of dosage of " Gaowujiasu " picking dosage do not have significant difference to the analgesia obvious effective rate and the total effective rate of postoperative pain, two various dose groups (test group 1,2) its analgesia total effective rate and matched group in 0～12 hour do not have significant difference more yet, illustrate that test group that percutaneous absorbs back two kinds of dosage all can reach the equal effect of injection.To 72 hours, the improvement of 1,2 pairs of pain intensities of two test group and analgesia total effective rate were that 90.57～92.86% to be better than injection (matched group) total effective rate be 41.16～45.1%, illustrate that two test group 1,2 have long-acting characteristics after 12 hours.Wherein 24mg/ time (embodiment 1) group and 30mg/ time (embodiment 2) group analgesic onset time were respectively 1.58 ± 0.49 hours, and 1.62 ± 0.51 hours, effect was held time and is respectively 71.41 ± 0.63 hours, 70.13 ± 0.49 hours.
Claims (6)
1, a kind of membrane controlled release type percutaneous drug administration preparation; it is characterized in that said preparation is the " Gaowujiasu " picking of 5 layers of structure; it is made the controlled release layer of release-controlled film, the drug storehouse storage glue-line that includes the lappaconitine medicine and aluminium foil backing layer and is constituted by silication separate paper protective layer, the pressure-sensitive adhesive layer that includes the lappaconitine medicine, employing ethylene-vinyl acetate copolymer film, and it is 12～15mg that every subsides (sheet) preparation contains lappaconitine.
2, be used to prepare the prescription of the described " Gaowujiasu " picking of claim 1, it is characterized in that this prescription comprises: pressure-sensitive adhesive layer prescription, drug storehouse storage glue-line prescription and this two-layer middle lappaconitine content ratio, wherein:
2,1, the lappaconitine content ratio is lappaconitine content in the pressure-sensitive adhesive layer in described pressure-sensitive adhesive layer and the drug storehouse storage glue-line: lappaconitine content=3～5 in the drug storehouse storage glue-line: 4～6,
2,2, described pressure-sensitive adhesive layer prescription is, low-polyisobutylene: height-polyisobutylene: mineral oil=7: 6: 11, lappaconitine consumption are 16.5～16.7% of substrate weight, the enhancer of cutaneous penetration consumption is 7.9～8.0% of a substrate weight,
2,3, described drug storehouse storage glue-line prescription is, low-polyisobutylene: height-polyisobutylene: mineral oil=4: 6: 10, lappaconitine consumption are 15% of substrate weight, the enhancer of cutaneous penetration consumption is 8% of a substrate weight,
2,4, the substrate described in the above-mentioned various prescriptions is meant the substrate of being made up of low-polyisobutylene, height-polyisobutylene and three kinds of compositions of mineral oil.
3, the process that is used for preparation (work) claim 1 and the described " Gaowujiasu " picking of claim 2, it is characterized in that this process comprises: the pressure sensitive adhesive preparation, the preparation of drug storehouse storage glue, each layer of " Gaowujiasu " picking (pressure-sensitive adhesive layer, drug storehouse storage glue-line, controlled release layer) preparation (work), system band and crossed belt, film-making technology, wherein:
3,1, said pressure sensitive adhesive preparing process is:
A), the amount of filling a prescription by above-mentioned pressure-sensitive adhesive layer, getting an amount of low-polyisobutylene and height-polyisobutylene inserts in the sealed container, and by these two kinds of polyisobutylene total amounts: the amount of chloroform=1: 10 adds an amount of chloroform, and sealing is stirred and is dipped to dissolving fully and makes transparent pressure sensitive adhesive colloidal solution
B), the amount of filling a prescription by above-mentioned pressure-sensitive adhesive layer, getting an amount of lappaconitine is suspended in the distilled water, jolting, add consumption again: total consumption of chloroform when the amount of chloroform=1: 13～17 is determined three extractions by lappaconitine, carry out three extractions with chloroform, the extraction back adds an amount of anhydrous sodium sulfate to dewatering fully, merges three times extract.
C), the amount by above-mentioned pressure-sensitive adhesive layer prescription adds an amount of mineral oil and an amount of enhancer of cutaneous penetration in three extracts of gained, be added to behind the mix homogeneously in the pressure sensitive adhesive colloidal solution of above-mentioned gained and go, viscosity is suitable when wherein adding an amount of chloroform with the assurance coating again, sealing stirs and makes pressure sensitive adhesive
3,2, said drug storehouse storage glue preparing process is: various raw material consumptions are all by the above-mentioned drug storehouse storage glue-line prescription amount of getting, the chloroform consumption is by the corresponding proportion amount of getting in above-mentioned " pressure sensitive adhesive preparing process ", drug storehouse storage glue preparing process adopts the technology preparation identical with above-mentioned " pressure sensitive adhesive preparing process "
3,3, preparation (work) technology of said pressure-sensitive adhesive layer and pressure sensitive adhesive tape is: above-mentioned prepared pressure sensitive adhesive is uniformly coated on to form thickness on the silication separate paper be the pressure-sensitive adhesive layer of 40～60 μ m, promptly makes pressure sensitive adhesive tape,
3,4, preparation (work) technology of said drug storehouse storage glue-line and drug storehouse storage adhesive tape is: above-mentioned prepared drug storehouse storage glue is uniformly coated on to form thickness on the aluminium foil backing layer be the drug storehouse storage glue-line of 35～65 μ m, promptly makes the drug storehouse storage adhesive tape,
3,5, preparation (work) technology of said controlled release layer is:
A), get ethylene-vinyl acetate copolymer and add chloroform, and heat the widely different dissolving fully that flow to, dissolved ethylene-vinyl acetate copolymer is made the ethylene-vinyl acetate copolymer film that film thickness is 30 μ m,
B), on the drug storehouse storage glue layer that sticks on the drug storehouse storage adhesive tape that the ethylene-vinyl acetate copolymer film that makes is smooth,
3,6, said crossed belt, film-making technology be: have the one side of release-controlled film to stick mutually with on the one side of no silication separate paper on the pressure sensitive adhesive tape and the drug storehouse storage adhesive tape, make that to contain the lappaconitine amount be that 12～15mg/ pastes the finished product of (sheet) again.
4, according to the prescription of the " Gaowujiasu " picking of claim 1 and claim 2, it is characterized in that described low-polyisobutylene is that mean molecule quantity is 40000 polyisobutylene, height-polyisobutylene is that mean molecule quantity is 1270000 polyisobutylene.
5, according to the prescription of the " Gaowujiasu " picking of claim 1 and claim 2, it is characterized in that described enhancer of cutaneous penetration can adopt azone or dimethyl sulfoxide or lower alcohols.
6, according to the prescription of the " Gaowujiasu " picking of claim 1 and claim 2, it is characterized in that described mineral oil can adopt liquid paraffin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92100233 CN1074117A (en) | 1992-01-10 | 1992-01-10 | The prescription of " Gaowujiasu " picking and method for making |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92100233 CN1074117A (en) | 1992-01-10 | 1992-01-10 | The prescription of " Gaowujiasu " picking and method for making |
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| Publication Number | Publication Date |
|---|---|
| CN1074117A true CN1074117A (en) | 1993-07-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 92100233 Pending CN1074117A (en) | 1992-01-10 | 1992-01-10 | The prescription of " Gaowujiasu " picking and method for making |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6896898B1 (en) | 1999-11-19 | 2005-05-24 | Xel Herbaceuticals, Inc. | Transdermal delivery system for alkaloids of aconitum species |
| CN100406012C (en) * | 2005-04-19 | 2008-07-30 | 北京正大绿洲医药科技有限公司 | Hydrobromic acid high tortoiseshell component drip pill and its preparation method |
| CN100417376C (en) * | 2006-11-03 | 2008-09-10 | 昆明制药集团股份有限公司 | Cataplasma of bulleyaconitine A |
| CN100457105C (en) * | 2002-12-14 | 2009-02-04 | 昆明制药集团股份有限公司 | Bulley aconitne transdermal paster |
| US8011195B2 (en) | 2006-09-18 | 2011-09-06 | Lg Electronics Inc. | Kimchi refrigerator and control method of the same |
-
1992
- 1992-01-10 CN CN 92100233 patent/CN1074117A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6896898B1 (en) | 1999-11-19 | 2005-05-24 | Xel Herbaceuticals, Inc. | Transdermal delivery system for alkaloids of aconitum species |
| CN100457105C (en) * | 2002-12-14 | 2009-02-04 | 昆明制药集团股份有限公司 | Bulley aconitne transdermal paster |
| CN100406012C (en) * | 2005-04-19 | 2008-07-30 | 北京正大绿洲医药科技有限公司 | Hydrobromic acid high tortoiseshell component drip pill and its preparation method |
| US8011195B2 (en) | 2006-09-18 | 2011-09-06 | Lg Electronics Inc. | Kimchi refrigerator and control method of the same |
| CN100417376C (en) * | 2006-11-03 | 2008-09-10 | 昆明制药集团股份有限公司 | Cataplasma of bulleyaconitine A |
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