CN101711754A - Tamoxifen citrate emplastrum and preparation method thereof - Google Patents
Tamoxifen citrate emplastrum and preparation method thereof Download PDFInfo
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- CN101711754A CN101711754A CN200910172504A CN200910172504A CN101711754A CN 101711754 A CN101711754 A CN 101711754A CN 200910172504 A CN200910172504 A CN 200910172504A CN 200910172504 A CN200910172504 A CN 200910172504A CN 101711754 A CN101711754 A CN 101711754A
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- tamoxifen citrate
- emplastrum
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Abstract
The invention relates to a tamoxifen citrate emplastrum and a preparation method thereof. A tamoxifen citrate micro emulsion is prepared into a transdermal emplastrum, and the transdermal emplastrum is divided into four layers: an anti-adhesion layer, a viscose layer, a back lining layer and a medicine storage layer. The tamoxifen citrate micro emulsion is used as a drug effect ingredient and comprises tamoxifen citrate used as an active ingredient, polysorbate 80 used as a surfactant, propylene glycol used as a cosurfactant, pure water or distilled water, and the like. Besides the drug effect ingredient, some non-polar polymers, a plasticizer, a tackifier, transdermal enhancer and an antioxidant are also added to the emplastrum. Compared with the traditional dosage forms such as tablets, solutions, oral cavity disintegrants, dispersants and external micro emulsion preparations, the tamoxifen citrate emplastrum has the prominent advantages of safety, low toxicity, convenient and simple use and accurate drug dosage.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of Tamoxifen Citrate plaster preparation and preparation method thereof.
Background technology
In " externally applied tamoxifen citrate microemulsion preparation and preparation method thereof " patent (application number 200610017526.6), we disclose the preparation method of externally applied tamoxifen citrate microemulsion preparation.This microemulsion formulation has improved the dissolubility of Tamoxifen Citrate, have good transdermal effect and slow release, targeting, simultaneously, the structure of microemulsion has been isolated contacting of extraneous and medicine, can prevent oxidation of drug and hydrolysis, improves stable, cover bad smell, holding time prolongs, and preparation technology is simple, does not need special installation.
But, the agents area of externally applied tamoxifen citrate microemulsion preparation is a breast, as everyone knows, external preparation needs long administration time, if the open-assembly time of agents area is long, then unfavorable to the protection individual privacy, the open-assembly time of agents area is too short, and then transdermal effect may not reach requirement, covers with medicated clothing, then easily wipe medicine, pollution clothes; Meanwhile, the dosage of microemulsion formulation also is difficult to control.This is the deficiency of aforementioned patent.
In order to keep the advantage of aforementioned patent, overcome its deficiency, on the basis of aforementioned patent, introduce plaster (Microemulsion) new technique, develop into tamoxifen citrate microemulsion plaster preparation.
Summary of the invention
The purpose of this invention is to provide a kind of Tamoxifen Citrate plaster preparation.
Another object of the present invention provides a kind of preparation method of Tamoxifen Citrate plaster preparation.
The present invention makes the percutaneous sticking plaster agent with tamoxifen citrate microemulsion, and this transdermal patch is divided into four layers, adherent layer, adhesive-layer, backing layer and drug storing layer.Active ingredient is a tamoxifen citrate microemulsion, by as the Tamoxifen Citrate of active component, as the polysorbate 80 of surfactant, form as cosurfactant propylene glycol and pure water or distilled water etc., the percentage by weight of each composition in preparation can be Tamoxifen Citrate 0.1%-10%, preferred 0.5%-5%, more preferably 1%-2%; Polysorbate 80 1%-50%, preferred 5%-30%, more preferably 10%-20%; Propylene glycol 10%-60%, preferred 2%-50%, more preferably 30%-40%; Oleic acid 0.1%-20%, preferred 0.5%-10%, more preferably 1%-5%; Pure water or distilled water 20%-80%, preferred 30%-60%, more preferably 40%-50%.
Except that above-mentioned active ingredient, also add some non-polar polymers, plasticizer, viscosifier, transdermal enhancer and antioxidant in the plaster preparation of the present invention.Non-polar polymer can be one or more in polyisobutylene, polystyrene, polyisoprene, polybutadiene, polyhexene-butylene, polyethylene-propylene, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, natural rubber, the butyl rubber; Plasticizer can be one or more in liquid paraffin, vaseline, the long-chain fatty acid phthalate ester; Viscosifier can be one or more in resinae, rosin based, esterase, the hydrogenated ester; Transdermal enhancer can be one or more in fatty acid, aliphatic alcohol, fatty acid ester, alkyl sulfoxide class, azone class, pyrrolidinone compounds, surfactant, carbamide class, limonene and other the fat-soluble transdermal enhancers; Antioxidant can be 2, one or more in 6-di-t-butyl Pyrogentisinic Acid, antrancine 12, the vitamin E.
Tamoxifen Citrate emplastrum of the present invention can prepare through the following steps:
With Tamoxifen Citrate and mixed with propylene glycol, after the heating for dissolving, add polysorbate 80, oleic acid, stir, add pure water or distilled water again, be stirred to transparency liquid, the tamoxifen citrate microemulsion that obtains is standby.The acceptable auxiliary composition is heated to 140-160 ℃ of fusion, cool the temperature to after 90-100 ℃ and to add bonding force reinforcing agent and standby tamoxifen citrate microemulsion, mixing, again with mixture while hot to stripping film (release paper), lid layer stripping film more above, the two sides pressurization makes film forming.Above-mentioned film is to be cooled to room temperature, and top one deck stripping film is peeled off, non-woven fabrics is covered pressurization forms on adhesive phase.
Positive effect of the present invention is, with existing dosage form such as tablet, solution, Orally-disintegrating tablet, dispersant and comprise that the described exterior-applied formulation of aforementioned patent compares, has following outstanding advantage:
1. can keep metastable local blood drug level, bring into play persistent drug effect, 24 hours accumulative total of main component transdermal amount surpasses 70%, can keep constant relatively blood drug level in a long time in the part, not only avoided the peak valley phenomenon of the caused blood drug level of whole body administration, also can reduce administration number of times, help treatment of diseases.
2. effective ingredient directly acts on diseased region in skin enters body, can effectively avoid the influence to non-target organ of " first pass effect ", gastrointestinal reaction and the medicine of oral administration, has reduced the toxicity of medicine, has improved the safety of medication.
3. easy to use, simple, there are not issuable difficulty of other dosage forms and misery, improved patient's adaptability.
4. adopt the form of emplastrum, not only dosage is accurate, farthest shortens the time that privacy exposes, pollution clothes not, and it is in good time to occur in the part, removes plaster at any time, reduces the incidence rate of medicine toxicity.
5. the production technology of emplastrum is simple, is easy to grasp, and both can also can be convenient to realize the production automation and sterile working in hospital preparation chamber limited production in factory's painting machine mass production.Preparation process does not have dust simultaneously, becomes the cream material few than other preparation consumptions, helps saving, and helps environmental conservation and labor protection.
6. the emplastrum volume is little, in light weight, packs, stores and transports, carries all more convenient.
7. when adopting different one-tenth cream materials, can make the emplastrum of different drug release rates and the emplastrum of multilamellar pastille, help solving the incompatibility that may occur between medicine.
The specific embodiment
Following examples can further specify the present invention.But, be to be understood that the present invention is limited to these examples never in any form.
Embodiment 1.
Tamoxifen Citrate 1-100g
Propylene glycol 100-600g
Polysorbate 10-500g
Oleic acid 1-200g
Pure water or distilled water add to 1000g
Use this prescription, it is standby to make tamoxifen citrate microemulsion.The acceptable auxiliary composition is heated to 140-160 ℃ of fusion, temperature fallen after 90-100 ℃ add bonding force reinforcing agent and standby tamoxifen citrate microemulsion, mixing, again with mixture while hot to stripping film (release paper), lid layer stripping film more above, the two sides pressurization makes film forming.Above-mentioned film is to be cooled to room temperature, and top one deck stripping film is peeled off, non-woven fabrics is covered pressurization forms on adhesive phase.
Embodiment 2.
Tamoxifen Citrate 1-100g
Propylene glycol 100-600g
Polysorbate 10-500g
Oleic acid 1-200g
Acritamer 940 10-100g
Pure water or distilled water add to 1000g
Use this prescription, it is standby to make tamoxifen citrate microemulsion.The acceptable auxiliary composition is heated to 140-160 ℃ of fusion, cool the temperature to after 90-100 ℃ and to add bonding force reinforcing agent and standby tamoxifen citrate microemulsion, mixing, again with mixture while hot to stripping film (release paper), lid layer stripping film more above, the two sides pressurization makes film forming.Above-mentioned film is to be cooled to room temperature, and top one deck stripping film is peeled off, non-woven fabrics is covered pressurization forms on adhesive phase.
Embodiment 3.
Tamoxifen Citrate 1-100g
Propylene glycol 100-600g
Polysorbate 10-500g
Oleic acid 1-200g
Polyvinyl alcohol 10-100g
Pure water or distilled water add to 1000g
Use this prescription, it is standby to make tamoxifen citrate microemulsion.The acceptable auxiliary composition is heated to 140-160 ℃ of fusion, cool the temperature to after 90-100 ℃ and to add bonding force reinforcing agent and standby tamoxifen citrate microemulsion, mixing, again with mixture while hot to stripping film (release paper), lid layer stripping film more above, the two sides pressurization makes film forming.Above-mentioned film is to be cooled to room temperature, and top one deck stripping film is peeled off, non-woven fabrics is covered pressurization forms on adhesive phase.
Beneficial effect of the present invention can pass through following description of test:
Test the experiment of 1 Thermodynamically stable
The active ingredient of Tamoxifen Citrate emplastrum of the present invention is a microemulsion, through 3000r/min centrifugal 30 minutes, and not stratified, do not precipitate, be transparence still, the tamoxifen citrate microemulsion that shows preparation is a thermodynamically stable dispersion.
Test the particle diameter and the envelop rate of 2 active ingredient
Tamoxifen Citrate emplastrum of the present invention, the particle diameter of active ingredient are between 20-100nm, and the envelop rate of medicine is more than 90%.
Test the transdermal test in vitro experiment of 3 emplastrumes
Investigate the transdermal absorption factor of the different exterior-applied formulations of Tamoxifen Citrate.The emplastrum, microemulsion, gel and the micro emulsion gels that prepare Tamoxifen Citrate respectively.The Tamoxifen Citrate content of four kinds of dosage forms is 1.52%.Adopt Franz transdermal diffusion instrument, the rat skin of abdomen, 37 ℃ of normal saline are acceptable solution, respectively at the transdermal accumulative total infiltration capacity of measuring different time, as following table.
Transdermal absorption factor (the μ g/cm of table Tamoxifen Citrate plaster dosage form
2.h) (n=4)
Through the t testing identity, the transdermal penetration effect of microemulsion and micro emulsion gels does not have significant difference (P＞0.05) between the two; The transdermal penetration effect of microemulsion and micro emulsion gels is significantly higher than gel (P＜0.05); The transdermal penetration effect of emplastrum is significantly higher than micro emulsion gels, microemulsion and gel (P＜0.05).
Test the stability experiment of 4 emplastrumes
Carry out the such environmental effects experiment: the Tamoxifen Citrate emplastrum of packing is placed on respectively under 60 ℃ of high temperature, high humidity 92.5%, illumination 45001x, 4 ℃ of conditions of low temperature deposited 10 days, investigate its character, discriminating, pH value, related substance, content, microbial limit, skin irritation, result's every index before and after experiment has no significant change, and shows Tamoxifen Citrate plaster preparation having good stability to the influence factor.
Associating accelerated tests: the Tamoxifen Citrate plaster preparation of packing is placed in the environment of 40 ℃ of temperature and humidity 75% 6 months.Investigate its character, discriminating, pH value, related substance, content, microbial limit, skin irritation, result's every index before and after experiment has no significant change, and shows that Tamoxifen Citrate plaster stability of formulation is good.
Test the skin irritation test of 5 plaster preparations
Intact skin and the damaged skin of observing animal repeatedly contact the local excitation reaction that is produced behind the Tamoxifen Citrate plaster.Consubstantiality left and right sides self matching type is adopted in test.9 rabbit are divided into 3 groups at random, 3 every group, are respectively intact skin low dose, heavy dose and vehicle group.The depilation district pastes Tamoxifen Citrate emplastrum (8mg/g and 32mg/g) and each 1g of plaster respectively in the animal left side; Excipient 1g is pasted in depilation district, right side.Every kind is tried thing plaster area is 50cm
2The trial zone, continuous 7 days.Behind the last administration 24h, tried thing with warm water cleaning, perusal and histopathologic examination, record plaster position has or not erythema and edema situation, and observe the plaster position whether situations such as pigmentation, petechia, pachylosis or epidermatic atrophy are arranged, skin irritation intensity is estimated.
The Tamoxifen Citrate plaster observing in a week during the administration or after the drug withdrawal, all shows as nonirritant to rabbit intact skin and damaged skin irritant test result repeatedly, does not have any other variation at the plaster position, and the average response value is nonirritant less than 0.4.
Test the skin anaphylactic test of 6 plaster preparations
After repeating to contact the Tamoxifen Citrate plaster by animal skin, observe body immune system and be reflected at performance on the skin.Cavia porcellus is divided into five groups at random, 10 every group, male and female half and half.First group is the blank group; Second group is vehicle group; The 3rd group is Tamoxifen Citrate emplastrum group; The 4th group is the plaster in the Tamoxifen Citrate emplastrum, the 5th group of positive sensitizer 2,4-dinitro-chloro-benzene phenol.Paste in Cavia porcellus left side depilation district respectively and respectively tried thing 1g, and repeated to apply ointment or plaster, after last administration sensitization 14 days in the 7th day and 14 days, applied ointment or plaster respectively in depilation district, the right side of Cavia porcellus respectively trying thing, remove behind the 6h and tried thing, observe immediately, and in 24,48,72h observes anaphylaxis respectively.
Result of the test shows, positive drug 2, and 4-dinitro-chloro-benzene phenol makes animal anaphylaxis occur, is subjected to the examination district that obvious erythema and Mild edema are arranged, and all reaches 100% in 6h, 24h sensitization rate, is the extreme sensitization.Blank group, vehicle group, Tamoxifen Citrate emplastrum group and Tamoxifen Citrate plaster group are exciting the position not have erythema, no edema, and no General Symptoms, the sensitization rate is 0%.
Claims (4)
1. Tamoxifen Citrate plaster preparation, it is characterized in that: it is made up of tamoxifen citrate microemulsion and acceptable auxiliary, be divided into and be adherent layer, adhered layer, drug storing layer and four parts of backing layer, drug storing layer is a tamoxifen citrate microemulsion, adherent layer, adhered layer and backing layer three parts are to be prepared by acceptable auxiliary, emplastrum adjuvant commonly used is made up of non-polar polymer and plasticizer, also can contain viscosifier, transdermal enhancer and antioxidant.
2. the emplastrum that absorbs through skin according to claim 1, wherein the active ingredient microemulsion is by as the Tamoxifen Citrate of active component, as the polysorbate 80 of surfactant, as the cosurfactant propylene glycol, form as the oleic acid of cosolvent and Acritamer 940 and pure water or distilled water etc.
3. plaster preparation according to claim 1, as non-polar polymer can be in polyisobutylene, polystyrene, polyisoprene, polybutadiene, polyhexene-butylene, polyethylene-propylene, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, natural rubber, the butyl rubber one or more.
4. plaster preparation according to claim 1, plasticizer can be wherein one or more such as liquid paraffin, vaseline, long-chain fatty acid phthalate ester; Viscosifier can be wherein one or more of resinae, rosin based, esterase, hydrogenated ester; Transdermal enhancer can be one or more in fatty acid, aliphatic alcohol, fatty acid ester, alkyl sulfoxide class, azone class, pyrrolidinone compounds, surfactant, carbamide class, limonene and other the fat-soluble transdermal enhancers; Antioxidant can be 2, one or more in 6-di-t-butyl Pyrogentisinic Acid, antrancine 12 and the vitamin E.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910172504A CN101711754A (en) | 2009-11-06 | 2009-11-06 | Tamoxifen citrate emplastrum and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910172504A CN101711754A (en) | 2009-11-06 | 2009-11-06 | Tamoxifen citrate emplastrum and preparation method thereof |
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| CN101711754A true CN101711754A (en) | 2010-05-26 |
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| CN200910172504A Pending CN101711754A (en) | 2009-11-06 | 2009-11-06 | Tamoxifen citrate emplastrum and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102559111A (en) * | 2012-02-02 | 2012-07-11 | 大连理工大学 | Styrene-series hot-melt pressure-sensitive adhesive and preparation method |
| CN108210484A (en) * | 2016-12-11 | 2018-06-29 | 复旦大学 | Tamoxifen gel emplastrum and preparation method thereof |
-
2009
- 2009-11-06 CN CN200910172504A patent/CN101711754A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102559111A (en) * | 2012-02-02 | 2012-07-11 | 大连理工大学 | Styrene-series hot-melt pressure-sensitive adhesive and preparation method |
| CN108210484A (en) * | 2016-12-11 | 2018-06-29 | 复旦大学 | Tamoxifen gel emplastrum and preparation method thereof |
| CN108210484B (en) * | 2016-12-11 | 2021-06-25 | 复旦大学 | Tamoxifen gel plaster and preparation method thereof |
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Application publication date: 20100526 |