CN100496471C - Dithranol stick - Google Patents
Dithranol stick Download PDFInfo
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- CN100496471C CN100496471C CNB2007100981407A CN200710098140A CN100496471C CN 100496471 C CN100496471 C CN 100496471C CN B2007100981407 A CNB2007100981407 A CN B2007100981407A CN 200710098140 A CN200710098140 A CN 200710098140A CN 100496471 C CN100496471 C CN 100496471C
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Abstract
The present invention relates to one new medicine form of dithranol, and is especially wax rod preparation with dithranol as the active component and comprising dithranol, wax, salicylic acid and castor oil.
Description
Technical field
The present invention relates to a kind of new pharmaceutical dosage form of dithranol, particularly is the rod wax preparation of active component with the dithranol.
Background technology
Dithranol treatment psoriasis is continued to use for a long time determined curative effect.Since the seventies, though constantly there is new antipsoriatic thing to come out, one of psoriatic choice drug of treatment but dithranol still be can yet be regarded as so far, to think that all dithranol is still the external curing psoriasis so far the most effective for majority in the external relevant psoriatic research document, the most frequently used medicine, using widely in countries such as America and Europes, particularly psoriatic intractable skin lesion is had curative effect faster, is the standard treatment of plaque psoriasis.From present home and abroad to the present situation and the level of psoriatic external therapy, comparatively popular corticosteroid, vitamin D 3 analogs (as its salts), dithranol and the tar class preparation of being still.
Dithranol, its chemical name is: 1,8-2 hydroxyl-9-anthrone.
Structural formula:
Chemical characteristic: dithranol (anthralin) also claims dihydroxy anthrone (dithranol), is the derivant of anthrol, is Reducing agent the strongest in the medicine for external use, is yellow powder.Being soluble in chloroform, benzene, dimethylbenzene, is ether, acetone and ethanol secondly.
Because dithranol is strong reductant-oxidant, can from tissue, capture oxygen during methylene oxidation on its 10, taking place stimulates and inflammation.Become anthraquinone after the dithranol oxidation, form the brown insoluble polymer, dye.The antipsoriatic action principle of dithranol:
Dithranol is captured oxygen epidermis cell can not be utilized in the reduction-oxidation process, thereby reduces cell proliferation, and the spinous layer that thickens is recovered, and proof can suppress mitosis recently, reduces the synthetic of DNA, the performance antiproliferative effect.There are some researches show that also dithranol has reduced the expression of TGF-amRNA, also reduced the epithelial cells of being handled by dithranol and combined, but the activity of report Profilin kinase c is also arranged with the epidermal hyperplasia factor acceptor.
The transition and the improvement of dithranol prescription and dosage form:
Nineteen fifty-three has at first reported systematically that by Ingram he uses dithranol to treat psoriatic experience, and document sees reference: Heikki B:Ditrastick Combined with UVB.alternativ regimen forplague psoriasis.Acta Derm Venereol Suppl (stockh) 1989; 146:102-103., dithranol is made into paste.Its prescription is: dithranol 0.13g, salicylic acid 0.65g, zinc oxide 8.0g, starch 8.0g, vaseline are added to 31.0g.Be characterized in being difficult for scattering, can remain on and embrocate the position, zinc oxide in the prescription and salicylic acid can form zinc salicylate and protect dithranol.
Seville was made into hardened ointment with dithranol in 1975, document sees reference: F.M.Larussa, et al:Topical Treat ment of Psoriasis:Clinical Trial of Dithranol in a stickFormulation Acta Derm Venereol (stockh) 1984; Suppl, 113:139-141., its clinical efficacy are equally good, and have more increased the stability of dithranol, fill a prescription to be dithranol 0.5%, salicylic acid 0.5%, chloroform 2.5%, paraffin and white vaseline half and half are added to 100%.The wherein salicylic acid cutin effect of loosening also can prevent the dithranol oxidation, and this kind preparation can be preserved more than 1 year still effective.
Although hardened ointment has improved hardness, be dissolved in the dithranol of vaseline, still easily exceed the skin lesion border during coating, normal skin is had stimulation, and vaseline is at skin surface also easy cleaning not.Nineteen eighty-two, Shao's ancient Chinese name for Venus was mixed with oil in water emulsion with dithranol, and document sees reference: the clinical department of dermatologry magazine 1983 of Shao Changkang; 12 (6): 316., be characterized in easy to clean, but curative effect lowers than ointment, 4 all cure rates only 62.5%, and with the contrast of hardening ointment, cure rate is 85%.
In order to keep the antipsoriatic curative effect of dithranol, reduce stimulation and dyeing simultaneously to greatest extent to normal skin.External Chalmers etc. is mixed with Dithranol stick greatly reduces stimulation and painted side effect, and document sees reference: Chalmers RJG, et al:A novel wax stick preparation of anthralin.Acta Derm Venereol 1982; 62:181..And produce by the Orion Orion drugmaker of Finland, commodity be called Ditrastick, and domestic Zhang Furen in 1991 has reported with Dithranol stick and has treated psoriasis 40 examples that document sees reference: Zhang Furen etc., clinical department of dermatologry magazine 1991; 20 (5): 247. treatments, 4 all cure rates 80%, and stimulate and dyeing obviously alleviates.Zhang Furen, Wang Zenggui in 1993 have reported that document sees reference: Zhang Furen etc., clinical department of dermatologry magazine 1993 with the rod wax that is made into high concentration 1-3%; 22 (3): 130..But there is no the prescription and the preparation technology of Dithranol stick in the above-mentioned document.Dithranol is made the rod wax dosage form, and is not only easy to use, improves curative effect, reduces side effect, and pollution clothes does not then have excellent development and is worth and vast market prospect.But use dithranol preparation for treating psoriasis, should adopt the cumulative method of dithranol concentration in principle, begin promptly to tolerate, but low concentration preparation curative effect is not as the curative effect of high concentrate formulation with high concentrate formulation patient Chang Buneng.
Dithranol is because reproducibility is strong, and preparation is usually unstable, and it is very difficult to make preparation stable and that stripping is fast, and the present invention has found dithranol is made the prescription that is fit to of rod wax dosage form in a large amount of prescriptions is screened for this reason, has solved the difficult problem on the preparation.
Summary of the invention
Purpose of the present invention just is to provide a kind of technology maturation, easy to use, bland Dithranol stick, and wax, fat and their the suitable ratios that comprises Dithranol stick employing different cultivars of the present invention made the suitable and good stability of medicine hardness.Wherein also add an amount of salicylic acid and be used for protecting dithranol, prevent the dithranol oxidation, salicylic acid also has concurrently and strengthens the psoriatic effect of treatment simultaneously.
The invention provides a kind of new Dithranol stick preparation, said preparation is made by the prescription of following weight proportion
Dithranol 30-70g
Brazil wax 300-400g
Cera Flava 1500-2000g
Glyceryl monostearate 800-1000g
Oleum Ricini 2000-3000g
Paraffin 700-900g
Salicylic acid 30-40g
Above proportioning can be made into Dithranol stick preparation 6000-7000g
The present invention preferably fills a prescription composed as follows:
(1) Dithranol stick (6.5g:32.5mg) 1000 components
(2) Dithranol stick (6.5g:65mg) 1000 components
The preparation method of Dithranol stick preparation of the present invention is as follows
(1) the wax class is mixed fusing;
(2) dithranol and salicylic acid are added an amount of Oleum Ricini porphyrize mixing;
(3) (1), (2) are mixed, moulding, cooling are promptly.
The present invention also comprises the method for quality control of Dithranol stick preparation, and this method may further comprise the steps:
[character] this product is the yellow solid rod wax.
Fusing point 55-68 ℃ (two appendix VIC second methods of Chinese Pharmacopoeia version in 2005)
1 of rod wax under the weight differential item is got in [discriminating] (1), takes by weighing weight (being equivalent to dithranol 5mg approximately), and hydro-oxidation sodium test solution 5ml puts in the water-bath after the heating, and it is red that solution should show.
(2) get this product an amount of (being equivalent to dithranol 1.5mg approximately), put in the beaker, heating makes the substrate fusing in water-bath, add and be preheated to about 70 ℃ 0.05mol/L sodium hydroxide solution 25ml, stir and extracted 5 minutes, put that cooling is solidified substrate in the psychrolusia, filter, get filtrate, in the wave-length coverage of 400 ~ 650nm, measure absorbance, absorption maximum is arranged at the wavelength place of 502nm ± 3nm according to ultraviolet-visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A).
[inspection] hardness is got this product, is cut into the thick sheet of about 1cm, puts in the tablet hardness tester and measures, and when gauge hand stops deflection, reads indicated value, should be greater than 0.5kg.
Uniformity of dosage units is got 10 rod waxs, measures content respectively according to content assaying method, checks according to uniformity of dosage units inspection technique (two appendix XE of Chinese Pharmacopoeia version in 2005), should be up to specification.
Microbial limit should be up to specification according to microbial limit test (two appendix XI of Chinese Pharmacopoeia version in 2000 J) inspection.
Loading amount is pressed minimum fill inspection technique (two appendix X of Chinese Pharmacopoeia version in 2005 F) inspection,
Should be up to specification.
[assay] gets 5 of this product, and accurate the title decides, and heating in water bath makes thawing, mix homogeneously, put coldly, precision takes by weighing this product an amount of (being equivalent to dithranol 5mg approximately), adds chloroform and makes dissolving in right amount, move in the 100ml measuring bottle, and be diluted to scale, shake up, filter, discard filtrate just, accurate filtrate 5ml, put in the 25ml measuring bottle, be diluted to scale, shake up with chloroform, according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2005 A), measure trap at the wavelength place of 356 ± 2nm, press C
14H
10O
3Absorptance (E) be 463 to calculate, promptly.
Prescription of the present invention obtains through screening, and the prescription of screening is as follows
Prescription 1 (1.0%)
Prescription 2 (1.0%)
Prescription 3 (1.0%)
Prescription 4 (1.0%)
Prescription 5 (1.0%)
Prescription 6
More than fill a prescription through stability experiment, irritant experiment, visual examination waits multinomial data relatively, proves that prescription 4 is best.
Following data declaration beneficial effect of the present invention by experiment:
Dithranol stick preparation of the present invention has been carried out pharmacodynamic study, used Dithranol stick and Anthra-Derm and compare, its curative effect and side effect have been compared.The result shows, have 5 routine patients to drop by the wayside this research in the 45 routine patients with psoriasis vulgaris of observing, wherein 2 examples promptly can not tolerate at the dithranol of first all foot couples 0.25%, and edematous erythema all appears in both sides skin lesions circumferece normal skin, conscious twinge unbearably, the ointment side is even more serious; 1 example is lost the 2nd weekend and is visited; 2 examples can be pressed the doctor's advice medication the 3rd weekend.Finish among the 40 routine patients of research, 32 routine bilateral skin lesion all obtain recovery from illness, cure rate 80%.Paired t-test show 1,2,3,4 weekend the rod wax side side effect significantly less than ointment side (P＜0.01).In the therapeutic process, do not find to cause isomorphic response after dithranol stimulates.
Done comparative study with of short duration coating of Dithranol stick of the present invention (SCT) and conventional coating (CCT) treatment psoriasis.Result of study shows that 30 routine patients all finish treatment according to plan, to the 4th weekends 25 routine patient's bilateral skin lesion all reach the recovery from illness standard.More among the person, 2 examples (coin shape, persisting type, moderate) are in the phase of carrying out to 5 examples all the time, and in the therapeutic process, though original skin lesion disappears gradually, other position constantly has new skin lesion to occur, and to the 4th weekend, extremity and trunk still have the drop shape infringement that is dispersed in; 2 examples original skin lesion in therapeutic process increases the weight of suddenly, questions closely medical history, may be relevant with diet; The two lower limb skin lesion of 1 example (persisting type, resting stage, speckle shape, moderate) do not disappear all the time.
At the 1st, 2 weekends of treatment, 30 routine patient SCT sides are soaked into index and are significantly higher than the CCT side, but to this difference disappearance at the 3rd weekend.Bilateral erythema index did not all have significant difference treatment in the 1st, 2,3,4 weeks, and this shows that SCT and CCT bilateral curative effect do not have significant difference.The stimulation of SCT side and Di the treatment the 1st, 2,3,4 weekends all significantly be lower than the CCT side (the 4th weekend the bilateral stimulation index do not have significant difference).
Toxicologic study
The animal skin irritation test
The intact skin group: remove medicine after 1 hour, visible coating skin has obvious erythema and edema, and 24 alleviate after little, after 48 hours, significantly recover.Be coated with excipient skin end show speckle and edema.
Table 1 intact skin treated animal skin irritation reaction grade form
The damaged skin group:
Removed medicine 1 hour, serious erythema and obvious edema appear in coating district skin, and 24 hours begin to recover, obviously recover after 48 hours.Excipient district skin is show speckle and edema not.
Table 2 damaged skin group skin irritation reaction grade form
Conclusion
The irritant test that carries out at damaged skin and intact skin shows that this medicine has certain zest to skin, and is particularly strong to the damaged skin zest.After removing medicine, recover slower.
The animal skin acute toxicity test
Result of the test
The damaged skin group
Phenomenons such as perpendicular hair, movable increase appear in animal after the administration, in 24 hours animal dead take place.Behind the flush away medicine, do not occur dead.After dead rat was dissected, important organs such as the heart, liver, kidney, brain did not have macroscopic pathological changes.
10 of blank groups, none death the results are shown in Table.
According to Sun Shi improvement Kou Shi composite accounting, obtain LD50
50And LD
5095% fiducial limit.Dithranol is used to have the LD of damaged skin outward
50Be 2691.44mg/kg, its 95% credible 2691.44 ± 338.42mg/kg that is limited to.
The intact skin group
Dosage is 4000mg/kg, surpasses clinical valid density more than 20 times, and the behavior of animal, activity, the no abnormal variation of diet were observed 14 days, did not see death.Matched group does not also have death.
Conclusion
Result of the test shows, the anxious poison test of the skin of dithranol, damaged skin, its LD
50Be 2691.44 ± 338.42mg/kg.The intact skin dosage reaches 4000mg/kg, does not see death.
Research conclusion
Dithranol stick treatment plaque psoriasis using method is easy, determined curative effect, and toleration is better, and untoward reaction shows as partial irritation, is worth clinical expansion to use.The suggestion using method is: adopt the cumulative therapy of concentration, and external every day 1 time, coating is flush away after 30 minutes, 8 to 10 weeks of the course of treatment.
It is little that composition of the present invention has side effect, easy to use, good stability, and curative effect is superior, and preparation is fast simple, is suitable for suitability for industrialized production, and detection method is highly sensitive, and the degree of accuracy height has solved the problem of quality control difficulty in the production process.
The present invention also provides a kind of novel medicament preparation combination, and adopting has each 1 of 0.5% and 1% Dithranol stick in the packing, and in use, with the preparation of low concentration, the preparation of reuse high concentration not only makes the patient tolerate easily, and can improve curative effect earlier.
The specific embodiment
Further specify the present invention by the following examples.
Embodiment 1
(1) Dithranol stick (6.5g:32.5mg) 1000 components
Preparation:
(1) the wax class is mixed fusing;
(2) dithranol and salicylic acid are added an amount of Oleum Ricini porphyrize mixing;
(3) (1), (2) are mixed, moulding, cooling are promptly.
Embodiment 2
(2) Dithranol stick (6.5g:65mg) 1000 components
Preparation:
(1) the wax class is mixed fusing;
(2) dithranol and salicylic acid are added an amount of Oleum Ricini porphyrize mixing;
(3) (1), (2) are mixed, moulding, cooling are promptly.
Embodiment 3
Method is with embodiment 1
Embodiment 4
Method is with embodiment 1
Claims (6)
1, a kind of Dithranol stick compositions is characterized in that, it is composed as follows to fill a prescription:
Dithranol 30-70g
Brazil wax 300-400g
Cera Flava 1500-2000g
Glyceryl monostearate 800-1000g
Oleum Ricini 2000-3000g
Paraffin 700-900g
Salicylic acid 30-40g
More than prescription is made Dithranol stick preparation 6000-7000g.
2, the Dithranol stick compositions of claim 1 is characterized in that, it is composed as follows to fill a prescription:
Dithranol 32.5g
Brazil wax 325g
Cera Flava 1950g
Glyceryl monostearate 975g
Oleum Ricini 2340g
Paraffin 845g
Salicylic acid 32.5g
More than prescription is made Dithranol stick preparation 6500g.
3, the Dithranol stick compositions of claim 1 is characterized in that, it is composed as follows to fill a prescription:
Dithranol 65g
Brazil wax 325g
Cera Flava 1950g
Glyceryl monostearate 975g
Oleum Ricini 2340g
Paraffin 812.5g
Salicylic acid 32.5g
More than prescription is made Dithranol stick preparation 6500g.
4, the preparation of compositions method of claim 1 is characterized in that step is as follows:
(1) the wax class is mixed fusing;
(2) dithranol and salicylic acid are added an amount of Oleum Ricini porphyrize mixing;
(3) (1), (2) are mixed, moulding, cooling are promptly.
5, the detection method of the compositions of claim 1 is characterized in that, step is as follows:
[character] this product is the yellow solid rod wax, fusing point 55-68 ℃,
1 of rod wax under the weight differential item is got in [discriminating] (1), takes by weighing weight and is equivalent to dithranol 5mg, and hydro-oxidation sodium test solution 5ml puts in the water-bath after the heating, and it is red that solution should show,
(2) get this product and be equivalent to dithranol 1.5mg, put in the beaker, heating makes the substrate fusing in water-bath, adds to be preheated to about 70 ℃ 0.05mol/L sodium hydroxide solution 25ml, stirs and extracts 5 minutes, putting to cool off in the psychrolusia solidifies substrate, filter, get filtrate, in the wave-length coverage of 400-650nm, measure absorbance according to two appendix IV of Chinese Pharmacopoeia version in 2005 A ultraviolet, one visible spectrophotometry, there is absorption maximum at wavelength place at 502nm ± 3nm
[inspection] hardness is got this product, is cut into the thick sheet of about 1cm, puts in the tablet hardness tester and measures, and when gauge hand stops deflection, reads indicated value, should be greater than 0.5kg,
Uniformity of dosage units is got 10 rod waxs, measures content respectively according to content assaying method, checks according to the uniformity of dosage units inspection technique, should be up to specification,
Microbial limit should be up to specification according to the microbial limit test inspection,
Loading amount should be up to specification by the inspection of minimum fill inspection technique,
[assay] gets 5 of this product, and accurate the title decides, and heating in water bath makes thawing, mix homogeneously, put coldly, precision takes by weighing this product and is equivalent to dithranol 5mg, adds chloroform and makes dissolving in right amount, moves in the 100ml measuring bottle, and be diluted to scale, and shake up, filter, discard filtrate just, accurate filtrate 5ml puts in the 25ml measuring bottle, be diluted to scale with chloroform, shake up, according to spectrophotography, measuring trap at the wavelength place of 356 ± 2nm, is 463 to calculate by the absorptance E of C14H1003, promptly.
6, a kind of pharmaceutical preparation assembly packaging is characterized in that, has 0.5% and each 1 of the described Dithranol stick compositions of claim 1 of 1% dithranol in packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100981407A CN100496471C (en) | 2007-04-17 | 2007-04-17 | Dithranol stick |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100981407A CN100496471C (en) | 2007-04-17 | 2007-04-17 | Dithranol stick |
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| CN101032465A CN101032465A (en) | 2007-09-12 |
| CN100496471C true CN100496471C (en) | 2009-06-10 |
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| CNB2007100981407A Expired - Fee Related CN100496471C (en) | 2007-04-17 | 2007-04-17 | Dithranol stick |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102139111B (en) * | 2010-12-29 | 2012-08-08 | 济南市皮肤病防治院 | Water-soluble matrix and application thereof in preparation of dithranol water-soluble preparations |
| CN103932978B (en) * | 2014-04-16 | 2016-11-02 | 西安碑林科大医院 | A kind of Anthra-Derm agent and preparation technology thereof |
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2007
- 2007-04-17 CN CNB2007100981407A patent/CN100496471C/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| 地蒽酚蜡棒治疗寻常型银屑病. 田洪青等.中国新药与临床杂志，第25卷第1期. 2006 |
| 地蒽酚蜡棒治疗寻常型银屑病. 田洪青等.中国新药与临床杂志，第25卷第1期. 2006 * |
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Owner name: WANG SHULING WANG CHUNBAO JIANG XIN |
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Effective date of registration: 20110627 Address after: 519080 Tsinghua Science and Technology Park Pioneer Building, 101 University Road, Tang Wan Town, Guangdong, Zhuhai, A-908 Co-patentee after: Wang Shuling Patentee after: Sun Meng Co-patentee after: Wang Chunbao Co-patentee after: Jiang Xin Address before: 519080 Tsinghua Science and Technology Park Pioneer Building, 101 University Road, Tang Wan Town, Guangdong, Zhuhai, A-908 Patentee before: Sun Meng |
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