CN1857242A - Externally applied tamoxifen citrate microemulsion preparation and its preparing process - Google Patents
Externally applied tamoxifen citrate microemulsion preparation and its preparing process Download PDFInfo
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- CN1857242A CN1857242A CN 200610017526 CN200610017526A CN1857242A CN 1857242 A CN1857242 A CN 1857242A CN 200610017526 CN200610017526 CN 200610017526 CN 200610017526 A CN200610017526 A CN 200610017526A CN 1857242 A CN1857242 A CN 1857242A
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- microemulsion
- tamoxifen citrate
- tamoxifen
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- 229960003454 tamoxifen citrate Drugs 0.000 title claims abstract description 61
- FQZYTYWMLGAPFJ-OQKDUQJOSA-N tamoxifen citrate Chemical compound [H+].[H+].[H+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 FQZYTYWMLGAPFJ-OQKDUQJOSA-N 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims description 5
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 15
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- 239000007787 solid Substances 0.000 claims abstract description 6
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
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- 229920000053 polysorbate 80 Polymers 0.000 abstract description 7
- 229940068968 polysorbate 80 Drugs 0.000 abstract description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
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Abstract
The present invention relates to a kind of externally applied tamoxifen citrate microemulsion preparation and its preparation process. The externally applied tamoxifen citrate microemulsion preparation is liquid or semi-solid preparation with tamoxifen citrate as active component, supplementary material polysorbate-80, propylene glycol and oleic acid as well as water. It has the features of being transparent, thermodynamically stable, excellent transdermal effect, etc.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly, the present invention relates to a kind of citric acid tamoxifen microemulsion external preparation and preparation method thereof.
Background technology
Tamoxifen (Tamoxifen, TAM or TMX) claims tamoxifen (Triphenylethylene) again, and its chemical name is N, N-dimethyl-2-[4-(1,2-diphenyl-1-butylene base) phenoxy group]-2 amine, its molecular formula is: C
26H
29NO, molecular weight are 371.53.Tamoxifen belongs to non-steroid estrogen, and two kinds of isomers of Z type and E type are arranged, and faces at present should go up extensive use and have only citric acid tamoxifen (Tamoxifen Citrate) a kind of, is Z formula structure, and molecular formula is: C
26H
29NOC
6H
8O
7, molecular weight is: 563.65.
Tamoxifen is widely-used as antitumor drug clinically, and is all undertaken by oral administration.Along with the development of clinical practice, constantly find the new indication of tamoxifen, the telangiectasis that for example is used for the treatment of psoriasis, causes by corticosteroid ointment, children's's cutaneous hemangioma etc.The needs of these clinical practices require people to develop the novel form of tamoxifen external.
In recent years, the research of existing tamoxifen exterior-applied formulation.Be mixed with ointment or lotion (CPI 1996, (9607) B5,15) treatment psoriasis, life-time service non-evident effect with tamoxifen; Make carrier with carrier, manufacture experimently into percutaneous plaster (Gregorcet al.Adv Drug Delivery Rev 1996,18,349) and improve its bioavailability; Make ointment (Hong Li etc., Chinese pediatric surgery magazine, 1998 with tamoxifen; 19:46.) treat the acquisition of children's's cutaneous hemangioma than encouraging result.(2002,31 (6): 379) the facial telangiectasis that is caused by corticosteroid ointment of treatment can make face red spot obviously improve for Dai Xunyi, clinical department of dermatologry magazine with the tamoxifen cream.Tamoxifen medicine for external use treatment cystic hyperplasia of breast (CN 1539410A) etc.
Because the citric acid tamoxifen is almost insoluble in water, soluble,very slightly in chloroform, slightly soluble in ethanol or acetone.In the research of citric acid tamoxifen exterior-applied formulation, improve transdermal effect, intensifier target becomes the key of technology to effect.General exterior-applied formulation be with the citric acid tamoxifen directly and adjuvant be mixed with and form, because the dissolubility of medicine in preparation is lower, be difficult to form higher Concentraton gradient in the skin both sides, the diffusion and the infiltration of medicine have been limited, and be not easy to enter the skin corium of aqueous, so be difficult to reach ideal curative effect.
The present invention adopts microemulsion (Microemulsion) new technique, and the citric acid tamoxifen is prepared into microemulsion formulation, with traditional exterior-applied formulation such as ointment, Emulsion, gel etc. following outstanding advantage is arranged relatively:
1. microemulsion has good short transdermal effect, and its short transdermal mechanism mainly shows: microemulsion all has higher dissolubility to lipophilic or hydrophilic medicament, can produce higher Concentraton gradient after the administration and increase the flowability of medicine, thereby improve drug transdermal; Microemulsion can increase horny layer double-layer of lipoid flowability, destroys horny layer aqueous passage and with horny layer generation hydration etc., helps medicine to see through the natural cover for defense horny layer that external absorbs; The particle diameter of microemulsion is little and even, and the interactional chance of carrier and horny layer just increases, and the medicine Transdermal absorption is increased, and the complete structure of microemulsion also can be through the hair follicle Transdermal absorption.
2. microemulsion is isotropic transparency liquid, through pressure sterilizing or centrifugally can not make it layering, can filter, can long term store, belong to the thermodynamically metastable fixed system.
3. the structure of microemulsion can be isolated contacting of extraneous and medicine, prevents oxidation, the hydrolysis of medicine, improves stablely, can also cover bad smell.
4. not energy requirement or external force acting of the preparation process of microemulsion, simple to operate, do not need special installation.
5. microemulsion has slow release and targeting.
The citric acid tamoxifen is an insoluble drug, make microemulsion after, help improving dissolubility, make medicine enter skin corium easily, strengthen Transdermal absorption.Thus, it is little and be difficult to the problem of transdermal to have solved effective drug loading of tamoxifen external preparation.
Summary of the invention
The purpose of this invention is to provide a kind of externally applied tamoxifen citrate microemulsion preparation;
Another object of the present invention provides a kind of preparation method of externally applied tamoxifen citrate microemulsion preparation.
Externally applied tamoxifen citrate microemulsion preparation of the present invention, liquid or the semi-solid preparation formed by tamoxifen citrate microemulsion and acceptable auxiliary, wherein, rafter acid tamoxifen microemulsion is by as the Tamoxifen Citrate of active component, as the polyoxyethylene sorbitan monoleate of surfactant, as the cosurfactant propylene glycol, form as the oleic acid of oil phase with as the pure water or the distilled water of water; As acceptable auxiliary can be to be selected from sodium carboxymethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, carbopol and the poloxamer one or more.
In the externally applied tamoxifen citrate microemulsion preparation of the present invention, the percentage by weight of each composition in preparation can be Tamoxifen Citrate 0.1%-10%, preferred 0.5%-5%, more preferably 1%-2%; Polyoxyethylene sorbitan monoleate 1%-50%, preferred 5%-30%, more preferably 10%-20%; Propylene glycol 10%-60%, preferred 20%-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%; The percentage by weight of acceptable auxiliary in preparation can be 0-30%, preferred 0-20%, more preferably 0-10%.
Externally applied tamoxifen citrate microemulsion preparation of the present invention can prepare through the following steps:
A. microemulsion preparation: with Tamoxifen Citrate and mixed with propylene glycol, after the heating for dissolving, add polyoxyethylene sorbitan monoleate, oleic acid, stir, add pure water or distilled water again, stirring is transparency liquid, promptly gets tamoxifen citrate microemulsion.
B. substrate preparation: get acceptable auxiliary,, stir, promptly get external-use substrate with pure water or distilled water swelling.
C. exterior-applied formulation preparation: tamoxifen citrate microemulsion and external-use substrate are mixed, stir, behind the accent pH, supply full dose, make liquid or semi-solid preparation, and solution, spray, gel or liniment are made in packing according to the administration characteristics.
The method of above-mentioned external preparation, wherein, used acceptable auxiliary can be to be selected from sodium carboxymethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, carbopol and the poloxamer one or more in the substrate preparation.
The pH value scope of externally applied tamoxifen citrate microemulsion preparation of the present invention is 6-8.
The specific embodiment
Following embodiment further specifies 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 80 10-500g
Oleic acid 1-200g
Pure water or distilled water add to 1000g
Tamoxifen Citrate is added in the propylene glycol, and slight fever makes dissolving, adds polysorbate 80, oleic acid and an amount of pure water or distilled water again, stir, transfer pH to 6-8, add pure water or distilled water to 1000g, stir, promptly obtain the tamoxifen citrate microemulsion solution.
Embodiment 2
Tamoxifen Citrate 1-100g
Propylene glycol 100-600g
Polysorbate 80 10-500g
Oleic acid 1-200g
Acritamer 940 10-100g
Triethanolamine is an amount of
Pure water or distilled water add to 1000g
Tamoxifen Citrate is added in the propylene glycol, and slight fever makes dissolving, adds polysorbate 80, oleic acid and an amount of pure water or distilled water again, stirs, and makes tamoxifen citrate microemulsion; Acritamer 940 with an amount of pure water or distilled water swelling, is made external-use substrate; Mix tamoxifen citrate microemulsion and external-use substrate, stir,, add pure water or distilled water, promptly get the tamoxifen citrate microemulsion gel to 1000g with transferring triethanolamine pH to 6-8.
Embodiment 3
Tamoxifen Citrate 1-100g
Propylene glycol 100-600g
Polysorbate 80 10-500g
Oleic acid 1-200g
Polyvinyl alcohol 10-100g
Pure water or distilled water add to 1000g
Tamoxifen Citrate is added in the propylene glycol, and slight fever makes dissolving, adds polysorbate 80, oleic acid and an amount of pure water or distilled water again, stirs, and makes tamoxifen citrate microemulsion; Polyvinyl alcohol with an amount of pure water or distilled water swelling, is made external-use substrate; Mix tamoxifen citrate microemulsion and external-use substrate, stir, transfer pH to 6-8, add pure water or distilled water, promptly get the tamoxifen citrate microemulsion liniment to 1000g.
By following description of test beneficial effect of the present invention.
Test the experiment of 1 Thermodynamically stable
Tamoxifen citrate microemulsion of the present invention is a light yellow transparent liquid, through 3000r/min centrifugal 30 minutes, and not stratified, do not precipitate, be transparency liquid still, the tamoxifen citrate microemulsion that shows preparation is a thermodynamically stable dispersion.
Test the particle diameter and the envelop rate of 2 microemulsion
Tamoxifen citrate microemulsion of the present invention, its emulsion droplet size homogeneous, particle diameter is between 20～100nm.The envelop rate of medicine is more than 90%.
Test the transdermal test in vitro experiment of 3 microemulsion external preparation
Investigate the transdermal absorption factor of the different exterior-applied formulations of Tamoxifen Citrate.Prepare microemulsion, gel and the micro emulsion gels of Tamoxifen Citrate respectively, the Tamoxifen Citrate content of three 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 exterior-applied formulation
2.h) (n=4)
| Group | Gel | Microemulsion | Micro emulsion gels |
| 2h 6h 10h 14h 18h 24h | 1.3±0.5 10.8±1.2 14.5±1.6 19.7±1.6 25.6±2.0 30.2±2.5 | 1.9±0.3 16.2±3.2 21.3±4.0 29.9±4.3 41.6±4.6 50.8±5.4 | 2.3±0.5 19.4±4.7 26.7±4.4 39.0±5.2 47.7±4.7 58.5±6.9 |
| Q | 1.2033t+1.2822 | 0.0087t+2.1844 | 1.4130t+2.5016 |
| r | 0.9861 | 0.9922 | 0.9896 |
Through the t testing identity, relatively 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).
Test the stability experiment of 4 microemulsion external preparation
Carry out the such environmental effects experiment: the tamoxifen citrate microemulsion gel of packing is placed on respectively under 60 ℃ of high temperature, high humidity 92.5%, illumination 4500lx, 4 ℃ of conditions of low temperature deposited 10 days, examine its character, discriminating, pH value, related substance, content, microbial limit, skin irritation, result's every index before and after test has no significant change, and shows tamoxifen citrate microemulsion gel having good stability to the influence factor.
Associating accelerated tests: the tamoxifen citrate microemulsion gel of packing is placed in the environment of 40 ℃ of temperature and humidity 75% 6 months.Examine its character, discriminating, pH value, related substance, content, microbial limit, skin irritation, result's every index before and after test has no significant change, and shows having good stability of tamoxifen citrate microemulsion gel.
Test the skin irritation test of 5 microemulsion external preparation
Intact skin of observation animal and damaged skin repeatedly percutaneous contact the local excitation reaction that is produced behind the tamoxifen citrate microemulsion gel.Consubstantiality left and right sides self matching type is adopted in test.6 rabbit are divided into 2 groups at random, 3 every group, are respectively intact skin low dose, heavy dose and vehicle group; Damaged skin low dose, heavy dose and vehicle group.The depilation district is coated with each 1g of tamoxifen citrate microemulsion gel (8mg/g and 32mg/g) respectively in the animal left side; Depilation district, right side is coated with excipient 1g.Every kind is tried the thing application area is 50cm
2The trial zone, continuous 7 days.Behind the last coating 24h, tried thing with warm water cleaning, perusal and histopathologic examination, record is smeared the position and is had or not erythema and edema situation, and observe and to smear the position whether situations such as the thick early rough or epidermatic atrophy of pigmentation, petechia, skin are arranged, skin irritation intensity is estimated.
The tamoxifen citrate microemulsion gel to the rabbit intact skin and damaged skin irritant test result repeatedly, observing in a week during the administration and after the drug withdrawal, all show as nonirritant, there is not any other variation smearing the position, the average response value is nonirritant all less than 0.4.
Test the skin anaphylactic test of 6 microemulsion external preparation
After repeating contact and be subjected to the tamoxifen citrate microemulsion gel by animal skin, observe body immune system and be reflected at performance on the skin.Cavia porcellus is divided into 4 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 microemulsion gel group; The 4th group of positive sensitizer 2,4-dinitro-chloro-benzene group.Smear in depilation district, Cavia porcellus left side respectively and respectively tried thing 1g, and repeated to smear in the 7th day and the 14th day.After last administration sensitization 14 days, will respectively be tried the depilation district, right side that thing is coated in Cavia porcellus respectively, remove behind the 6h and tried thing, observe immediately, and in 24,48,72h observes skin allergy respectively.
Result of the test shows, positive drug 2, and the 4-dinitro-chloro-benzene 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 and tamoxifen citrate microemulsion gel group do not have other General Symptoms exciting the position not have erythema, no edema, and the sensitization rate is 0%.
Claims (7)
1. externally applied tamoxifen citrate microemulsion preparation, it is characterized in that liquid or the semi-solid preparation formed by tamoxifen citrate microemulsion and acceptable auxiliary, wherein, rafter acid tamoxifen microemulsion is by as the Tamoxifen Citrate of active component, as the polyoxyethylene sorbitan monoleate of surfactant, as the cosurfactant propylene glycol, form as the oleic acid of oil phase with as the pure water or the distilled water of water; As acceptable auxiliary can be to be selected from sodium carboxymethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, carbopol and the poloxamer one or more.
2. external preparation according to claim 1, it is characterized in that the percentage by weight of each composition in preparation can be Tamoxifen Citrate 0.1%-10% in the tamoxifen citrate microemulsion, polyoxyethylene sorbitan monoleate 1%-50%, propylene glycol 10%-60%, oleic acid 0.1%-20%, pure water or distilled water 20%-80%; The percentage by weight of acceptable auxiliary in preparation can be 0-30%.
3. external preparation according to claim 2, it is characterized in that the percentage by weight of each composition in preparation can be Tamoxifen Citrate 0.5%-5% in the tamoxifen citrate microemulsion, polyoxyethylene sorbitan monoleate 5%-30%, propylene glycol 20%-50%, oleic acid 0.5%-10%, pure water or distilled water 30%-60%; The percentage by weight of acceptable auxiliary in preparation can be 0-20%.
4. external preparation according to claim 3, it is characterized in that the percentage by weight of each composition in preparation can be Tamoxifen Citrate 1%-2% in the tamoxifen citrate microemulsion, polyoxyethylene sorbitan monoleate 10%-20%, propylene glycol 30%-40%, oleic acid 1%-5%, pure water or distilled water can be 40%-50%; The percentage by weight of acceptable auxiliary in preparation can be 0-10%.
5. a method for preparing the externally applied tamoxifen citrate microemulsion preparation of one of claim 1-4 comprises the following steps:
A. microemulsion preparation: with Tamoxifen Citrate and mixed with propylene glycol, after the heating for dissolving, add polyoxyethylene sorbitan monoleate, oleic acid, stir, add pure water or distilled water again, stirring is transparency liquid, promptly gets tamoxifen citrate microemulsion.
B. substrate preparation: get acceptable auxiliary,, stir, promptly get external-use substrate with pure water or distilled water swelling.
C. exterior-applied formulation preparation: tamoxifen citrate microemulsion and external-use substrate are mixed, stir, behind the accent pH, supply full dose, make liquid or semi-solid preparation, and solution, spray, gel or liniment are made in packing according to the administration characteristics.
6. the method for external preparation according to claim 5, wherein, used acceptable auxiliary can be to be selected from sodium carboxymethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, carbopol and the poloxamer one or more in the substrate preparation.
7. according to the described external preparation of claim 1-6, the pH value scope that it is characterized in that making liquid or semi-solid preparation is 6-8.
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| CN 200610017526 CN1857242A (en) | 2006-03-16 | 2006-03-16 | Externally applied tamoxifen citrate microemulsion preparation and its preparing process |
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| CN106924176A (en) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | A kind of TAM flexible nano-liposomes gel and preparation method thereof |
| CN108210484A (en) * | 2016-12-11 | 2018-06-29 | 复旦大学 | Tamoxifen gel emplastrum and preparation method thereof |
| CN109640958A (en) * | 2016-05-20 | 2019-04-16 | 蔚蓝生物技术股份有限公司 | Vaginal delivery systems comprising selective estrogen receptor modulators (SERMs) and uses thereof |
| EP4248948A4 (en) * | 2020-11-09 | 2025-01-08 | Fundação Oswaldo Cruz | Composition, pharmaceutical composition, use of a stable topical composition comprising a nanoemulsion and of at least one antileishmanial compound, and method for the treatment of cutaneous leishmaniasis |
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2006
- 2006-03-16 CN CN 200610017526 patent/CN1857242A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109640958A (en) * | 2016-05-20 | 2019-04-16 | 蔚蓝生物技术股份有限公司 | Vaginal delivery systems comprising selective estrogen receptor modulators (SERMs) and uses thereof |
| US10857127B2 (en) | 2016-05-20 | 2020-12-08 | Azure Biotech, Inc. | Vaginal delivery systems containing selective estrogen receptor modulator (SERM) and uses thereof |
| CN109640958B (en) * | 2016-05-20 | 2022-11-22 | 蔚蓝生物技术股份有限公司 | Vaginal delivery systems comprising selective estrogen receptor modulators (SERMs) and uses thereof |
| 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 patch and preparation method thereof |
| CN106924176A (en) * | 2017-03-20 | 2017-07-07 | 荆楚理工学院 | A kind of TAM flexible nano-liposomes gel and preparation method thereof |
| CN106924176B (en) * | 2017-03-20 | 2020-08-11 | 荆楚理工学院 | Tamoxifen flexible nano liposome gel and preparation method thereof |
| EP4248948A4 (en) * | 2020-11-09 | 2025-01-08 | Fundação Oswaldo Cruz | Composition, pharmaceutical composition, use of a stable topical composition comprising a nanoemulsion and of at least one antileishmanial compound, and method for the treatment of cutaneous leishmaniasis |
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