CN100434068C - Bexarotene gel and its preparation method - Google Patents
Bexarotene gel and its preparation method Download PDFInfo
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- CN100434068C CN100434068C CNB200410094094XA CN200410094094A CN100434068C CN 100434068 C CN100434068 C CN 100434068C CN B200410094094X A CNB200410094094X A CN B200410094094XA CN 200410094094 A CN200410094094 A CN 200410094094A CN 100434068 C CN100434068 C CN 100434068C
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- bexarotene
- gel
- glycerol
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- organic amine
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Abstract
The present invention discloses a preparation of external application of bexarotene, particularly a gelling agent and a preparing method thereof, which is used for treating skin T-cell lymph tumors. The gelling agent is composed of 0.1 to 1 weight percentage of bexarotene, 0.5 to 5 weight percentages of carbonyl ethene polymers, 0.5 to 5 weight percentages of organic amine, 1 to 20 weight percentages of glycerol, 5 to 50 weight percentages of low-grade ethanol and water. The bexarotene gelling agent provided by the present invention uses partial skin administration for enabling the medicine to directly act on a sick part. The effect is rapid, the blood medical level of the whole body is decreased, and the toxic reaction of the whole body administration is avoided. Compared with the toxicity exposed by oral administration, the partial skin administration is safe and reliable.
Description
Technical field
The present invention relates to the medical technical field relevant with external used medicine, in particular, is a kind of exterior-applied formulation one gel of treatment skin T-cell lymphoma medicine bexarotene and preparation method thereof.
Background technology
T-cell lymphoma skin symptom curative bexarotene (Bexarotene gel) is synthetic retinoic acid analog, and skin T-cell lymphoma is had the good curing effect.Chemical name: 4-[1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl-2-naphthyl) vinyl] benzoic acid.
The bexarotene crude drug is an off-white color, little yellow crystal, and is water insoluble, is slightly soluble in vegetable oil, ethanol.
The toxicity that bexarotene exposed mainly contains blood fat, transaminase's content slightly raises, hepatic tissue hypertrophy, HDL, LDL and cholesterol reduction and serium inorganic phosphorus, triglyceride (rising).Also can make the rat cruor time extending, the cataract incidence rate increases.Reproductive toxicity test discovers that bexarotene can make tire Os Mus bone aberration rate increase, and vigor descends (absorbing increases), tire Mus weight loss, and variation and teratogenesis rate increase (as cleft palate, celophthalmia, microphthalmia etc.).
System's degree of exposure of bexarotene topical is significantly less than oral administration.Local skin administration bexarotene blood drug level is very low, and 93.2% blood sample blood drug level is lower than 5ng/ml.Oral bexarotene capsule (300mg/m
2QD), its mean Cmax approximately is 200 times of percutaneous drug delivery, and its percutaneous drug delivery accumulates very low in human body.So, to compare than the toxicity that drug oral exposed, the local skin medication is safer reliable.
Summary of the invention
The object of the present invention is to provide a kind of lesions position that directly acts on, therapeutic effect is obvious, and is little to systemic side effects, safely and effectively external application preparation one gel of T-cell lymphoma skin symptom curative bexarotene and preparation method thereof.
Gel of the present invention is a kind of transparent gluey glop, and medicine dissolution has smooth in appearance, transparent exquisiteness, is easy to coating in substrate, easy cleaning, pollution clothes not, good stability, characteristics such as preparation technology is simple.
Technology contents of the present invention is implemented by following scheme:
Bexarotene gel is characterized in that, is made up of bexarotene, carbonyl ethylene polymer, organic amine, glycerol, rudimentary alcohol and water, and the percentage by weight of each constituent content is:
Bexarotene 0.1-1.0%
Carbonyl ethylene polymer 0.5-5.0%
Organic amine 0.5-5.0%
Glycerol 1-20%
Lower alcohol 5-50%
Distilled water surplus.
The carbonyl ethylene polymer that the present invention relates to is an interlinkage acrylate copolymer, and molecular weight ranges is greatly about 1000000 to 3000000.The carbonyl ethylene polymer that the present invention uses is a carbomer 910,934,940,1342.The carbonyl ethylene polymer can be with generating gel with regulating in the alkaline matter.
The nertralizer of described alkaline matter is selected from organic amine, and consumption is the 0.5%-5.0% of gel weight, is preferably 0.5%-3.0%, and that best is 0.5%-2.0%.
The organic amine that the present invention relates to is the rudimentary hydramine of monobasic as a carbinolamine, monoethanolamine, monopropylene glycol amine, an isopropanolamine; The rudimentary hydramine of binary as: dimethanolamine, diethanolamine, dipropanolamine, diisopropanolamine (DIPA), two butanolamines, two isobutyl hydramine, di-secondary butanolamine; The rudimentary hydramine of ternary is as trimethanolamine, triethanolamine, tripropanol amine, triisopropanolamine, three butanolamines, three isobutyl hydramine, three sec-butyl alcohol amine; One amine such as methylamine, ethamine, propylamine, 2-aminopropane.; Diamidogen is as dimethylamine, diethylamine, di-n-propylamine, diisopropylamine; Triamine is as trimethylamine, triethylamine; Be preferably triethanolamine, diisopropanolamine (DIPA), ethamine, two butanolamines or the like.These amine can use separately also can unite use, mixed liquor of triethanolamine, ethamine or the like for example, and its consumption is as the criterion finally to make gel PH scope 6.0-9.0.
Characteristics of the present invention be the organic amine that uses than in and carbonyl ethylene polymer requirement more, institute's consumption is preferably 7.5-9.0 finally to make gel PH scope 6.0-9.0.
Institute of the present invention glycerol adding amount is the 1%-20% of gel weight, is preferably 2%-10%, and that best is 4%-8%.
Because the dissolubility of bexarotene in water be very little, even almost be water insoluble, so preparation technology's of the present invention key is bexarotene is made a kind of stabilized uniform solution, solution of the present invention is to adopt lower alcohol that bexarotene is dissolved; Described lower alcohol comprises methanol, ethanol, dehydrated alcohol, propanol, isopropyl alcohol, is preferably methanol, dehydrated alcohol, isopropyl alcohol.The consumption of lower alcohol is gel weight 5%-50%, is preferably 10%-40%.The solution that adopts the method to make has good stability.
The preparation method of bexarotene gel of the present invention comprises:
(1) the carbonyl ethylene polymer is added water and expands after, add glycerol, organic amine is made solution.Make preparation gel PH scope 6.0-9.0 with the organic amine adjusting, 7.5-9.0 is better.
(2) bexarotene adds in the lower alcohol, mixes with stock solution, adds remaining water, stir, gel.
Gel of the present invention is compared with existing dosage form has following advantage:
Bexarotene gel of the present invention can reduce the blood drug level of whole body administration by the local skin administration, avoids the toxic reaction of whole body administration.The clinical report determined curative effect, patient is coating voluntarily, and must be not frequent go seen the doctor, and be easy to use, improves the compliance of patient's medication.
It is early stage or to the invalid skin T-cell lymphoma patient's that maybe can not tolerate of other treatment method skin symptom, clinical effective rate is 63% that bexarotene gel of the present invention is mainly used in treatment.Side effect mainly occurs in uses the position, and slight.Comprise erythra, scratch where it itches that application site is painful, do not have serious adverse to produce.
Gel ointment smooth in appearance provided by the invention in addition, transparent exquisiteness, be easy to the coating.Less to skin irritation, good stability, pollution clothes is not well suited for practical application.
Further specify good effect of the present invention below in conjunction with stability experiment and safety experiment:
1, stability experiment:
Investigated the influence of factors such as light, heat (40 ℃, 60 ℃) low temperature to bexarotene gel stability, the result shows: the every index of bexarotene gel there is no significant change.
With the accelerated tests (40 ℃, RH75%) of routine 6 months, every index there is no significant change.
Room temperature was placed 12 months, and every index there is no significant change.
2, safety experiment:
Carry out the local skin irritant experiment with this gel sample.The bexarotene gel is given the guinea pig skin external application, and Cavia porcellus intact skin, damaged skin are all had slight irritant reaction.Main irritant reaction erythema occurs for the coating position, and erythematous response appearred in 7 days in the intact skin administration, and damaged skin is 5 days.Remove medicine after 48 hours erythematous response all disappear.Remove medicine after 72 hours local skin draw materials, do pathological examination, no abnormality seen.Result of the test shows: this bexarotene gel has slight stimulation to guinea pig skin.Experiment showed, that bexarotene gel makes medicine directly act on the affected part, rapid-action, reduced whole body blood drug level, reduced systemic side effects.The pharmacokinetic parameters of gel of the present invention and peroral dosage form blood drug level relatively sees Table 1
The comparison of table 1 bexarotene gel and oral blood drug level
| Administering mode | Maximum plasma concentration C max | Peak time T max | Half-life T 1/2 |
| 150mg/m 2The QD oral soft capsule | 7.56ug/ml | 1.3h | 7.63h |
| 1% gel dermatologic | 0.1598ug/ml | 8.67h |
Conclusion: bexarotene gel of the present invention is a kind of safe and effective, easy to use, stable dosage form.
The specific embodiment:
The present invention is described further below in conjunction with embodiment.Embodiment only is to explanation of the present invention, can not be used for limiting the present invention with this.
Embodiment 1
Bexarotene 0.3 gram
Carbomer 1,342 1.0 grams
Triethanolamine 3.6 grams
Glycerol 5.0 grams
Dehydrated alcohol 10 grams
Distilled water adds to 100 grams
Preparation method: after 1.0 gram carbomers 1342 add 40 gram water expansions, add 5.0 gram glycerol, 3.6 gram triethanolamine.0.3 the gram bexarotene adds 10 gram dehydrated alcohol.Two kinds of solution are mixed, add remaining water, stir.(PH8.0)
Embodiment 2
Bexarotene 1.0 grams
Acritamer 940 1.0 grams
Ethamine 0.8 gram
Diisopropanolamine (DIPA) 2.6 grams
Glycerol 8.0 grams
Isopropyl alcohol 30 grams
Distilled water adds to 100 grams
Preparation method: after 1.0 gram Acritamer 940s add 40 gram water expansions, add 8.0 gram glycerol, 0.8 gram ethamine, diisopropanolamine (DIPA) 2.6.1.0 the gram bexarotene adds in the 30 gram isopropyl alcohols.Two kinds of solution are mixed, add remaining water, stir.(PH7.6)
Embodiment 3
Bexarotene 0.5 gram
Carbomer 910 1.0 grams
Triethanolamine 3.0 grams
Glycerol 8.0 grams
Dehydrated alcohol 30 grams
Distilled water adds to 100 grams
Preparation method: after 1.0 gram carbomers 910 add 40 gram water expansions, add 8.0 gram glycerol, 3.0 gram triethanolamine, 0.5 gram bexarotene adds 30 and restrains dehydrated alcohol, and two kinds of solution are mixed, and adds remaining water, stirs.(PH7.4)
Embodiment 4
Bexarotene 1.0 grams
Carbomer 934 1.0 grams
Diisopropanolamine (DIPA) 3.6 grams
Glycerol 5.0 grams
Dehydrated alcohol 20 grams
Distilled water adds to 100 grams
Preparation method: after 1.0 gram carbomer 934s add 40 gram water expansions, add 5.0 gram glycerol, 3.6 gram diisopropanolamine (DIPA)s, 1.0 gram bexarotenes addings, 20 gram dehydrated alcohol mix two kinds of solution, add remaining water, stir.(PH8.4)
Embodiment 5
Bexarotene 0.5 gram
Carbomer 910 1.0 grams
Triethanolamine 2.2 grams
Ethamine 0.8 gram
Glycerol 8.0 grams
Dehydrated alcohol 30 grams
Distilled water adds to 100 grams
Preparation method: after 1.0 gram carbomers 910 add 40 gram water expansions, add 8.0 gram glycerol, 2.2 gram triethanolamine, ethamine 0.8 gram, 1.0 restrain bexarotenes adds 30 gram dehydrated alcohol, and two kinds of solution are mixed, and adds remaining water, stirs.(PH7.5)
Claims (3)
1, a kind of bexarotene gel is characterized in that, is made up of bexarotene, carbonyl ethylene polymer, organic amine, glycerol, rudimentary alcohol and water, and the percentage by weight of each constituent content is:
Bexarotene 0.1-1.0%
Carbonyl ethylene polymer 0.5-5.0%
Organic amine 0.5-5.0%
Glycerol 1-20%
Lower alcohol 5-50%
Distilled water surplus;
Wherein said carbonyl ethylene polymer is carbomer 910, carbomer 934, Acritamer 940 or carbomer 1342;
Described organic amine is: triethanolamine, diisopropanolamine (DIPA), ethamine, two butanolamines or triethanolamine-ethamine mixed liquor;
Described lower alcohol is methanol, ethanol or propanol; The consumption of lower alcohol is gel weight 5%-50%; Amounts of glycerol is gel weight 1%-20%.
2, bexarotene gel as claimed in claim 1, wherein said organic amine consumption are the 0.5-5.0% of gel weight.
3, a kind of preparation method of bexarotene gel according to claim 1 is characterized in that: earlier the carbonyl ethylene polymer is added water and expand, adding glycerol, organic amine are made solution for standby; Bexarotene adds in the lower alcohol, mixes with stock solution, adds remaining water, stir, adjusting pH 6.0-9.0, gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410094094XA CN100434068C (en) | 2004-12-30 | 2004-12-30 | Bexarotene gel and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410094094XA CN100434068C (en) | 2004-12-30 | 2004-12-30 | Bexarotene gel and its preparation method |
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| Publication Number | Publication Date |
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| CN1799536A CN1799536A (en) | 2006-07-12 |
| CN100434068C true CN100434068C (en) | 2008-11-19 |
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| CNB200410094094XA Expired - Fee Related CN100434068C (en) | 2004-12-30 | 2004-12-30 | Bexarotene gel and its preparation method |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998654A (en) * | 1997-07-25 | 1999-12-07 | Ligand Pharmaceuticals Incorporated | Retinoic acid receptor antagonist compounds and methods |
| WO1999063980A1 (en) * | 1998-06-12 | 1999-12-16 | Ligand Pharmaceuticals Inc. | Treatment of anti-estrogen resistant breast cancer using rxr modulators |
| US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| CN1429807A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Synthesis of antitumour medicine bexarotene |
-
2004
- 2004-12-30 CN CNB200410094094XA patent/CN100434068C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998654A (en) * | 1997-07-25 | 1999-12-07 | Ligand Pharmaceuticals Incorporated | Retinoic acid receptor antagonist compounds and methods |
| WO1999063980A1 (en) * | 1998-06-12 | 1999-12-16 | Ligand Pharmaceuticals Inc. | Treatment of anti-estrogen resistant breast cancer using rxr modulators |
| US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| CN1429807A (en) * | 2001-12-29 | 2003-07-16 | 中国科学院上海药物研究所 | Synthesis of antitumour medicine bexarotene |
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| CN1799536A (en) | 2006-07-12 |
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