CN102120032B - Water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof - Google Patents
Water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof Download PDFInfo
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- CN102120032B CN102120032B CN2010106112623A CN201010611262A CN102120032B CN 102120032 B CN102120032 B CN 102120032B CN 2010106112623 A CN2010106112623 A CN 2010106112623A CN 201010611262 A CN201010611262 A CN 201010611262A CN 102120032 B CN102120032 B CN 102120032B
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- boningmycin
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Abstract
The invention discloses a water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof. The water-soluble substrate is prepared by co-melting and uniformly mixing the following components in part by weight: 30 to 40 parts of polyoxyethylene (40) stearate and 60 to 70 parts of fatty alcohol-polyoxyethylene ether (peregal O). The invention also discloses the application of the water-soluble substrate in the preparation of a water-soluble preparation of the bleomycin, a water-soluble preparation of pingyangmycin, a water-soluble preparation of boanmycin or a water-soluble preparation of boningmycin. The water-soluble substrate does not contain water, but can be dissolved in water, so that the medicinal preparations prepared by the water-soluble substrate are convenient to wash and remove; and when the medicinal preparations are used, the user does not need to directly touch the medicinal preparations by hands, so that the waste of the medicinal preparations is reduced and the irritation to the hands is reduced.
Description
Technical field
The present invention relates to a kind of water-soluble substrate, relate in particular to a kind of not moisture but substrate and the application in preparation bleomycin or its homologue Bleomycin A5, B1eomycin or Z-893 Boningmycin water soluble preparation thereof that can be water-soluble.
Technical background
Bleomycin is claimed bleomycin A5 again, is made up of a plurality of components, and bleomycin is with A
2Be main the composition, Bleomycin A5 is A
5, B1eomycin is A
6, Z-893 Boningmycin is the acetylation B1eomycin.
The complex intercalation of DNA of bleomycin and ferrum causes dna single chain and double-strand break.It does not cause the RNA chain interruption.The first step of effect is that the two thiophene cuo of these article encircle between the G-C base pair of the intercalation of DNA, and the zheng electric charge and the effect of DNA phosphate of terminal san peptide ammino acid are unwind it simultaneously.Second step of effect is the generation that these article and the complex of ferrum cause ultra oxygen or hydroxy radical, causes the DNA chain interruption.
Bleomycin A5 system separates a kind of antibiotic that obtains from the soil of China's Zhejiang Pingyang County, close with the bleomycin structure.The Bleomycin A5 mechanism of action is also similar with bleomycin, mainly suppresses thymidine and mixes DNA, combines with DNA, makes it to destroy, and destroys dna profiling, stops dna replication dna, impels cancerous cell degeneration, necrosis.Experimentation shows, the antitumor action of mouse hypodermic inoculation colon cancer C26, esophageal carcinoma SGA-73 and Lewis lung cancer all is better than MMC and bleomycin.Bleomycin is a cell cycle nonspecific agent (CCNSA), have that anti-tumor activity is strong, antitumor spectra is wide, instant effect, short treating period, side effect are light, to characteristics such as hemopoietic and immunologic function are harmless basically.
B1eomycin is AGPM one kind new medicine of China's initiative exploitation.Be that wheel branch streptomycin bacterium Pingyang new variant produces, belong to the renewal product of Bleomycin A5 and bleomycin.B1eomycin also has very high inhibition ability to hepatocarcinoma, gastric cancer, pulmonary carcinoma, colon cancer except having the anticancer spectrum identical with bleomycin, and lung toxicity significantly is lower than other like products, is low toxicity of new generation chemotherapy of tumors product efficiently.
Z-893 Boningmycin pharmacodynamic experiment: 1. the research of human papillomavirus (HPV) therapeutical effect is not still had animal model; Therefore the cream of processing with the pure article of Z-893 Boningmycin is tested Lac Bovis seu Bubali finger-like tumor and verruca plana that bovine papilloma virus causes, and the result shows has very good curative effect.2. the injection of processing with the pure article of Z-893 Boningmycin is significantly sure to the effect of dairyman's itch model, and is evident in efficacy to parapsoriasis and the seborrheic dermatitis of house pet.3. antitumor action: to the ehrlich carcinoma of mice, S-180, the esophageal carcinoma, hepatocarcinoma suppression ratio all more than 90%.Biology characteristics: the 1. acute toxicity LD50 of Z-893 Boningmycin: the LD50 of intravenously administrable is mice 239.7mg/kg, rat 213.89mg/kg.The toxicity of Z-893 Boningmycin is starkly lower than similar compound.2. lung toxicity is low: with Japan go on the market in recent years low with lung toxicity be that the peplomycin (Pepleomycin) of characteristics is contrast; The result shows; Z-893 Boningmycin is similar with the lung toxic degree that peplomycin causes during 5mg/kg dosage, and Z-893 Boningmycin is significantly slighter than the lung disposition that peplomycin causes during 10mg/kg dosage.3. skin irritation test: the ointment of 4 ‰ and 8 ‰ Z-893 Boningmycins all has no stimulation to two kinds of animal injury skins.4. transdermal experiment shows that Z-893 Boningmycin can not Transdermal absorption.5. it can be injected, also can external, do not damage immune system and hemopoietic system.
Because bleomycin or its homologue Bleomycin A5, B1eomycin, Z-893 Boningmycin etc. have similar pharmacological action; Relatively local irritation is less with other antitumor drug; At present increasingly treated various dermatosiss, like psoriasis, vitiligo, condyloma acuminatum, hemangioma etc. by topical application.But because its facile hydrolysis does not still have suitable external preparation to come out.
Given this, the exploitation bleomycin that is suitable for preparing or its homologue Bleomycin A5, B1eomycin, Z-893 Boningmycin etc. are not moisture but can water-soluble preparation significant.
Summary of the invention
Deficiency to prior art; The object of the present invention is to provide a kind of water-soluble substrate that is suitable for preparing bleomycin and the water-soluble preparation of homologue thereof, and the application in preparation bleomycin water soluble preparation, Bleomycin A5 water soluble preparation, B1eomycin water soluble preparation or Z-893 Boningmycin water soluble preparation.
The water-soluble substrate that is suitable for preparing bleomycin and the water-soluble preparation of homologue thereof according to the invention is characterized in that, melts mixing altogether by the component of following weight portion and processes:
30～40 parts of polyoxyethylene (40) stearates
70～60 parts of fatty alcohol-polyoxyethylene ether (paregal O).
Above-mentioned water-soluble matrix optimization melts mixing altogether by the component of following weight portion to be processed:
30 parts of polyoxyethylene (40) stearates
70 parts of fatty alcohol-polyoxyethylene ether (paregal O).
The application of above-mentioned water-soluble substrate in preparation bleomycin water soluble preparation, Bleomycin A5 water soluble preparation, B1eomycin water soluble preparation or Z-893 Boningmycin water soluble preparation.
Wherein, the specific embodiment is to be that substrate adds bleomycin with said water-soluble substrate, is mixed with the water-soluble cream or the water-soluble rod that contain bleomycin 0.1%～0.2% by percentage to the quality; Perhaps, be that solvent adds Bleomycin A5 with said water-soluble substrate, be mixed with the water-soluble cream or the water-soluble rod that contain Bleomycin A5 0.1%～0.2% by percentage to the quality; Perhaps, be that solvent adds B1eomycin with said water-soluble substrate, be mixed with the water-soluble cream or the water-soluble rod that contain B1eomycin 0.1%～0.2% by percentage to the quality; Perhaps, be that solvent adds Z-893 Boningmycin with said water-soluble substrate, be mixed with the water-soluble cream or the water-soluble rod that contain Z-893 Boningmycin 0.1%～0.2% by percentage to the quality.
The content of bleomycin or its homologue Bleomycin A5, B1eomycin or Z-893 Boningmycin is preferably respectively by percentage to the quality in above-mentioned water-soluble cream or the water-soluble rod: 0.1% or 0.2%.
Utilize water-soluble substrate according to the invention can process the water-soluble pharmaceutical preparation of convenient application bleomycin, Bleomycin A5, B1eomycin or Z-893 Boningmycin.
Above-mentioned water-soluble pharmaceutical preparation contains the of the present invention water-soluble substrate of bleomycin, Bleomycin A5, B1eomycin or Z-893 Boningmycin and the corresponding preparations consumption of Chinese Pharmacopoeia ormal weight respectively.
The water-soluble pharmaceutical preparation method of quality control of bleomycin according to the invention, Bleomycin A5, B1eomycin or Z-893 Boningmycin, the Bleomycin A5 that records with Chinese Pharmacopoeia is that example describes:
1. these article of shape are faint yellow, paste or lipstick shape.
2. differentiate
(1) get these article and Bleomycin A5 hydrochloride. reference substance, add water respectively and process the solution that contains 0.1mg among every 1ml, according to the method test under the assay item, the retention time of test sample main peak should be consistent with the retention time of reference substance main peak.
(2) get these article 0.4g, add water 10ml and make dissolving, add 3% copper-bath 0.05ml, measure, absorption maximum is arranged in the wavelength of 242nm ± 2nm and 291nm ± 2nm according to spectrophotography (appendix IV A).
3. inspection
The microbial limit sterile working takes by weighing these article 5g, and adding has immediately been melted and has been incubated in 45 ℃, shakes up immediately, and the gradation adding has been incubated 45 ℃ of sterile salines 85ml altogether, shakes up immediately, makes into even emulsion, is 1: 20 test liquid.According to microbial limit test (two appendix XI of Chinese Pharmacopoeia version in 2010 J) inspection, per 1 gram contains the bacterium number and must not cross 1000, and fungi count must not be crossed 100, and must not detect bacillus pyocyaneus and staphylococcus aureus.
Other should meet each item regulation (two appendix I of Chinese Pharmacopoeia version in 2010 F) relevant under the ointment item.
4. assay is measured according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test use octadecylsilane chemically bonded silica to be filler; [get sodium pentanesulfonate 0.96g and Calcium Disodium Versenate 1.86g, add the 0.08mol/L acetum and make dissolving and be diluted to 1000ml, regulate pH value to 4.3 with ammonia]-methanol-acetonitrile (76: 16: 8) is a mobile phase with sodium pentanesulfonate solution; Detecting wavelength is that the 254nm number of theoretical plate should be not less than 700 by the calculating of Bleomycin A5 peak.
Algoscopy is got 10 of these article, mixing, and precision takes by weighing about 10mg, puts in the 10ml measuring bottle, is dissolved in water and is diluted to scale, shakes up, and gets 10 μ l and injects chromatograph of liquid; Other gets the Bleomycin A5 hydrochloride. reference substance, measures with method.By the content of external standard method with Bleomycin A5 hydrochloride. in the calculated by peak area test sample.
Applying solid of the present invention or semi-solid surfactants have been developed and a kind ofly have been applicable to not moisture but substrate that can be water-soluble such as bleomycin or its homologue Bleomycin A5, B1eomycin, Z-893 Boningmycin, and utilize it to prepare bleomycin, Bleomycin A5, B1eomycin or Z-893 Boningmycin water soluble preparation.In the whole process of formulation preparation, do not contact, do not influence the stability of bleomycin, Bleomycin A5, B1eomycin or Z-893 Boningmycin, fully guaranteed drug effect with water.
The surfactant polyoxyethylene that the present invention selects for use (40) stearate (being called for short S-40), fatty alcohol-polyoxyethylene ether are prone to dissolving in water, it is convenient to have guaranteed with the pharmaceutical preparation eccysis of its preparation; And realized that the pharmaceutical preparation application does not need directly to contact medicine with hands, has reduced the waste of medicine and adversary's stimulation.
The specific embodiment
Embodiment 1
Water-soluble substrate preparation:
In every weight portion is 1 kilogram, takes by weighing following component:
70 parts of polyoxyethylene (40) stearates
30 parts of fatty alcohol-polyoxyethylene ether (paregal O);
Said components after claiming is melted mixing altogether, process water-soluble substrate.
Embodiment 2
Water-soluble substrate preparation:
In every weight portion is 1 kilogram, takes by weighing following component:
60 parts of polyoxyethylene (40) stearates
40 parts of fatty alcohol-polyoxyethylene ether (paregal O);
Said components after claiming is melted mixing altogether, process water-soluble substrate.
Embodiment 3
The water-soluble substrate of selecting embodiment 1 preparation for use is that solvent adds bleomycin, is mixed with the water-soluble cream that contains bleomycin 0.1% or 0.2% by percentage to the quality.
Embodiment 4
The water-soluble substrate of selecting embodiment 1 preparation for use is that solvent adds Bleomycin A5, is mixed with the water-soluble cream that contains Bleomycin A5 0.1% or 0.2% by percentage to the quality.
Embodiment 5
The water-soluble substrate of selecting embodiment 1 preparation for use is that solvent adds B1eomycin, is mixed with the water-soluble cream that contains B1eomycin 0.1% or 0.2% by percentage to the quality.
Embodiment 6
The water-soluble substrate of selecting embodiment 1 preparation for use is that solvent adds Z-893 Boningmycin, is mixed with the water-soluble cream that contains Z-893 Boningmycin 0.1% or 0.2% by percentage to the quality.
Embodiment 7
The water-soluble substrate of selecting embodiment 2 preparations for use is that solvent adds bleomycin, is mixed with the water-soluble cream that contains bleomycin 0.2% by percentage to the quality.
Embodiment 8
The water-soluble substrate of selecting embodiment 2 preparations for use is that solvent adds Bleomycin A5, is mixed with the water-soluble cream that contains Bleomycin A5 0.2% by percentage to the quality.
Embodiment 9
With the clinical research of the water-soluble cream treatment of embodiment 4 said Bleomycin A5s condyloma acuminatum
60 routine condyloma acuminatum patients, male 43 examples, women 17 examples; Genital area 52 examples, crissum 8 examples.With the treatment of the water-soluble cream of Bleomycin A5, the result shows: skin lesion fully or the patient who almost completely removes account for 97% (58/60).
Claims (7)
1. a water-soluble substrate that is suitable for preparing bleomycin or B1eomycin or the water-soluble preparation of Z-893 Boningmycin is characterized in that, melts mixing altogether by the component of following weight portion and processes:
30～40 parts of polyoxyethylene (40) stearates
0 70～60 parts of peregals.
2. water-soluble substrate as claimed in claim 1 is characterized in that, it is characterized in that, melts mixing altogether by the component of following weight portion and processes:
30 parts of polyoxyethylene (40) stearates
0 70 parts of peregals.
3. claim 1 or the 2 said water-soluble substrate application in preparation bleomycin water soluble preparation, B1eomycin water soluble preparation or Z-893 Boningmycin water soluble preparation.
4. application as claimed in claim 3 is characterized in that, is that solvent adds bleomycin with said water-soluble substrate, is mixed with the water-soluble cream or the water-soluble rod that contain bleomycin 0.1%～0.2% by percentage to the quality.
5. application as claimed in claim 3 is characterized in that, is that solvent adds B1eomycin with said water-soluble substrate, is mixed with the water-soluble cream or the water-soluble rod that contain B1eomycin 0.1%～0.2% by percentage to the quality.
6. application as claimed in claim 3 is characterized in that, is that solvent adds Z-893 Boningmycin with said water-soluble substrate, is mixed with the water-soluble cream or the water-soluble rod that contain Z-893 Boningmycin 0.1%～0.2% by percentage to the quality.
7. like claim 4,5 or 6 described application, it is characterized in that the content of bleomycin, B1eomycin or Z-893 Boningmycin is respectively by percentage to the quality in said water-soluble cream or the water-soluble rod: 0.1% or 0.2%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010106112623A CN102120032B (en) | 2010-12-29 | 2010-12-29 | Water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010106112623A CN102120032B (en) | 2010-12-29 | 2010-12-29 | Water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof |
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| Publication Number | Publication Date |
|---|---|
| CN102120032A CN102120032A (en) | 2011-07-13 |
| CN102120032B true CN102120032B (en) | 2012-02-29 |
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| CN2010106112623A Expired - Fee Related CN102120032B (en) | 2010-12-29 | 2010-12-29 | Water-soluble substrate suitable for preparing water-soluble preparations of bleomycin and homologues thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370453A (en) * | 2005-12-14 | 2009-02-18 | 扎尔斯制药公司 | Compositions and methods for dermal delivery of drugs |
| CN101810563A (en) * | 2009-09-25 | 2010-08-25 | 宋洪涛 | Tacrolimus ophthalmic in-situ gel preparation and preparation method thereof |
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2010
- 2010-12-29 CN CN2010106112623A patent/CN102120032B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370453A (en) * | 2005-12-14 | 2009-02-18 | 扎尔斯制药公司 | Compositions and methods for dermal delivery of drugs |
| CN101810563A (en) * | 2009-09-25 | 2010-08-25 | 宋洪涛 | Tacrolimus ophthalmic in-situ gel preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 闫军 等.平阳霉素凝胶剂的制备及临床观察.《中国药房》.2001,第12卷(第1期),27-28. * |
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| CN102120032A (en) | 2011-07-13 |
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Granted publication date: 20120229 Termination date: 20161229 |