CN102525877A - Preparation of butoconazole nitrate in-situ gel - Google Patents
Preparation of butoconazole nitrate in-situ gel Download PDFInfo
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- CN102525877A CN102525877A CN2010106131319A CN201010613131A CN102525877A CN 102525877 A CN102525877 A CN 102525877A CN 2010106131319 A CN2010106131319 A CN 2010106131319A CN 201010613131 A CN201010613131 A CN 201010613131A CN 102525877 A CN102525877 A CN 102525877A
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- nitric acid
- acid butoconazole
- butoconazole
- lutrol
- solid dispersion
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- 238000002360 preparation method Methods 0.000 title abstract description 13
- ZHPWRQIPPNZNML-UHFFFAOYSA-N butoconazole nitrate Chemical compound O[N+]([O-])=O.C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 ZHPWRQIPPNZNML-UHFFFAOYSA-N 0.000 title abstract description 8
- 229960002120 butoconazole nitrate Drugs 0.000 title abstract description 8
- 238000011065 in-situ storage Methods 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 114
- 229910017604 nitric acid Inorganic materials 0.000 claims description 114
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 claims description 110
- 229960005074 butoconazole Drugs 0.000 claims description 109
- 229920001983 poloxamer Polymers 0.000 claims description 41
- 239000007962 solid dispersion Substances 0.000 claims description 25
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- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 14
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- 238000000034 method Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
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- 238000001035 drying Methods 0.000 claims description 8
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- 239000008118 PEG 6000 Substances 0.000 claims description 6
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- 239000000463 material Substances 0.000 claims description 6
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
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- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 1
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 1
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- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a formulation for external use, namely a gel of an antifungal medicine butoconazole nitrate and a preparation process for the gel. The butoconazole nitrate is a commonly used clinical medicine; and the conventional formulation is mainly cream. The gel is prepared by taking the butoconazole nitrate as a main medicine and adding different excipients, and the medicine concentration at the local affected part is improved through dermal or mucosal administration, so that the effective inhibitory concentration is quickly achieved, and the therapeutic effect is quickly exerted. Compared with the conventional product, the invention has the advantages that: the obtained butoconazole nitrate in-situ gel has stable properties and is convenient to use; and moreover, the antibacterial effect of the butoconazole nitrate is also improved.
Description
Technical field:
The present invention relates to medical technical field, is preparation and the application of a kind of Nitric acid butoconazole (Butoconazole Nitrate) at the body gel.
Background technology:
Nitric acid butoconazole (Butoconazole Nitrate), its chemical name: (±)-1-[4-(right-chlorphenyl)-2 [2, the 6-Dichlorobenzene base) sulfenyl]] butyl] imidazoles] nitrate.For having the imdazole derivatives of antifungal activity, be mainly used in the treatment vaginitis.The Nitric acid butoconazole relative molecular mass is 474.79, for white to off-white color crystalline powder, is slightly soluble in methanol, is slightly soluble in chloroform, dichloromethane, acetone, ethanol, and the atomic ethyl acetate that is dissolved in is water-soluble hardly.
Colpitis mycotica medically calls monilial infection to fungal infection again, so colpitis mycotica also claims monilial vaginitis, is more common in youngest daughter, anemia of pregnant woman, diabetics, and once uses the patient of more heavy dose of estrin treatment after the menopause.Colpitis mycotica patient shows as leucorrhoea grow in quantity, and Chang Fahong, edema, epidermis change varied around pudendum, pruritus of vagina, burning sensation, painful urination, the pudendum; Very shallow vesicle pimple can take place; It is rotten to the corn also can to form the eczema shape; Can cause small white pustule individually, ulcer takes place when serious.
Nitric acid butoconazole mainly is applicable to the treatment vulvovaginal candidiasis, and its mechanism of action is the same with other imidazole derivatives, is to work through suppressing the synthetic of steroid.Imidazoles through suppressing the conversion of lanosterol to ergosterol, causes the change that the fungal cell membrane lipid is formed usually.The change of membrane structure causes the variation of cell permeability, finally causes the not normal or growth inhibited of fungal cell's permeability, promptly suppresses the synthetic of steroid class material.The antimicrobial spectrum of Nitric acid butoconazole and other glyoxaline compounds are similar.Gram-positive bacterium is had antibacterial activity, to the gram negative bacteria non-activity, good to aspergillus fungi and candidiasis antibacterial activity.External have inhibitory action to Candida, trichophyton, Microsporon, Epidermophyton, and some gram-positive bacterias are also had certain inhibitory action.The vaginal infection height that clinically Candida albicans, Oidium tropicale etc. is caused is effective.External a large amount of clinical trial and clinical practice data show that Nitric acid butoconazole has safety preferably and effectiveness.
Nitric acid butoconazole is the imdazole derivatives with antifungal activity, and by U.S. Sytnex company exploitation, 1985 at first in U.S.'s list marketing, the back respectively at 1987 and 1988 in Switzerland and French list marketing.And in a plurality of national applications registrations such as Britain, Italy, Japan, Canada, Mexico, Brazil, Spain, Portugal; Wherein the U.S. at first the dosage form of list marketing be vaginal cream (5g:100mg) and vaginal suppository (100mg/ piece), its commodity are called Femstat.1997, U.S. FDA was ratified the vaginal cream novel form (5g:100mg) of the employing local sustained release technology of KV Pharm company again, and its commodity are called Gynazole-1, only need medication 1 time the whole course of treatment.
The main dosage form of Nitric acid butoconazole is this ointment on the market, because it contains mineral oil, can exert an influence to latex or rubber product such as condom or vaginal contraception barrier film, therefore, with in 72 hours of this ointment treatment, should not use above-mentioned contraception product.Nitric acid butoconazole is formed in the body gel, can avoids the influence of mineral oil using.But find through test of many times, because the water-insoluble of Nitric acid butoconazole is difficult to be made into uniformly at the body gel.Test is found; Process solid dispersion with PEG or polyvinylpyrrolidone (PVP) etc. and Nitric acid butoconazole, can improve the dissolution of Nitric acid butoconazole, therefore develop a kind of Nitric acid butoconazole solid dispersion; Be used to prepare it at the body gel, have very big actual application prospect.The Nitric acid butoconazole gel, has and does not pollute clothes compared with ointment because it adopts water-soluble medium, is prone to characteristics such as cleanings, and gel is a single-phase dispersion system, does not have problems such as layering, stability better, and process conditions are low with respect to the ointment requirement.
Summary of the invention:
The invention provides a kind of drug-delivery preparation of Nitric acid butoconazole---gel and preparation method thereof.
Gel can reduce systemic blood concentration through skin or mucosa delivery, reduces central inhibitory action, improves the drug level in local affected part, and has the administration number of times, easy to use of minimizing, improves the characteristics such as compliance of patient's medication.Because it adopts water-soluble medium, compared with ointment, have and do not pollute clothes, be prone to the characteristics of cleaning, gel is a single-phase dispersion system, does not have problems such as layering, stability better, and process conditions require low with respect to ointment.Because gel has many good characteristics, development in recent years is very fast, domestic existing procucts listing.Nitric acid butoconazole is formed in the body gel, for the clinical use of Nitric acid butoconazole provides a kind of new dosage form.
Nitric acid butoconazole at the body gel by medicine, macromolecular material, solvent composition.Medicine is a Nitric acid butoconazole; Macromolecular material available polyethylene ketopyrrolidine (PVP), PEG4000, PEG6000, Lutrol F68, Lutrol F127 etc.; Solvent is water or phosphate buffer.
Method for preparing of the present invention: at first Nitric acid butoconazole is processed solid dispersion, then Lutrol F68, LutrolF127 are added water or phosphate-buffered salt swelling, add prepared solid dispersion in proportion, stir, promptly get gel.
The preparation of solid dispersion:
Nitric acid butoconazole mixes with PVP, and the weight ratio of the two is 1: 1～50.
Nitric acid butoconazole mixes with PEG4000, and the weight ratio of the two is 1: 1～100.
Nitric acid butoconazole mixes with PEG6000, and the weight ratio of the two is 1: 1～100.
The method for preparing of solid dispersion is following:
Nitric acid butoconazole and PVP or PEG are dissolved in the certain amount of organic solvent, and heated and stirred gets clear solution.After with gained solution at 60 ℃ of following vacuum distillation dryings, the pulverulent solids that obtains is the solid dispersion of Nitric acid butoconazole.The liquid that said method obtains can also obtain the solid dispersion of Nitric acid butoconazole with its lyophilization.
Another method for preparing of Nitric acid butoconazole solid dispersion of the present invention is following:
PVP or PEG are at high temperature fused, add Nitric acid butoconazole then, stir, get transparency liquid.Lyophilization obtains the solid dispersion of Nitric acid butoconazole.
The above-mentioned organic solvent of selecting for use can be methanol, ethanol, acetone, propylene glycol etc., also can be any two kinds, and is perhaps two or more.Preferred alcohol wherein.
The solid dispersion that the present invention processes through PVP, PEG and Nitric acid butoconazole, thus the dissolution of Nitric acid butoconazole in water improved, be applied in the preparation of body gel, the active component Nitric acid butoconazole is directly discharged.
Nitric acid butoconazole is in the preparation of body gel:
Nitric acid butoconazole solid dispersion and a certain proportion of Lutrol F68 and Lutrol F127 are mixed at a certain amount of water or phosphate buffer, under the low temperature, stir, obtain Nitric acid butoconazole at the body gel after leaving standstill 24h.
The present invention at first is the solubilising to Nitric acid butoconazole, overcomes the use limitation of insoluble drug, and the back prepares it at the body gel.Nitric acid butoconazole is directly coated the affected part at the body gel, and it is high to have local curative effect concentration, acts on characteristics such as rapid, that systemic side effects is little; This preparation nature is stable simultaneously; Preparation technology is simple, and is easy to use, for the clinical practice of Nitric acid butoconazole provides a kind of new dosage form.
The specific embodiment:
The comparative example:
Prescription:
Nitric acid butoconazole 0.1g
Lutrol?F68 2.5g
Lutrol?F127 0.5g
A certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml distilled water, and the back adds the crude drug Nitric acid butoconazole, stirs, and leaves standstill 24h.
Because Nitric acid butoconazole is insoluble in water, test of many times can't obtain being evenly distributed at the body gel.
Embodiment 1.
Prescription 1:
Nitric acid butoconazole 0.1g
PVP 0.2g
Lutrol?F68 2.5g
Lutrol?F127 0.5g
Nitric acid butoconazole and PVP are dissolved in a certain amount of ethanol; Obtain settled solution, back drying under reduced pressure, the solid dispersion of Nitric acid butoconazole; After itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml distilled water, obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Embodiment 2.
Prescription 2:
Nitric acid butoconazole 0.1g
PVP 0.6g
Lutrol?F68 2.8g
Lutrol?F127 0.2g
Nitric acid butoconazole and PVP are dissolved in a certain amount of ethanol; Obtain settled solution; Back drying under reduced pressure; The solid dispersion of Nitric acid butoconazole, after itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml phosphate buffer (pH 4.0), obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Embodiment 3.
Prescription 3:
Nitric acid butoconazole 0.1g
PEG4000 0.6g
Lutrol?F68 2.6g
Lutrol?F127 0.4g
Nitric acid butoconazole and PEG4000 are dissolved in a certain amount of ethanol; Obtain settled solution; Back drying under reduced pressure; The solid dispersion of Nitric acid butoconazole, after itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml phosphate-buffered salt (pH 4.5), obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Embodiment 4.
Prescription 4:
Nitric acid butoconazole 0.1g
PEG6000 0.3g
Lutrol?F68 2.4g
Lutrol?F127 0.6g
Nitric acid butoconazole and PEG4000 are dissolved in a certain amount of ethanol; Obtain settled solution, back drying under reduced pressure, the solid dispersion of Nitric acid butoconazole; After itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml distilled water, obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Embodiment 5.
Prescription 5:
Nitric acid butoconazole 0.1g
PVP 0.5g
Lutrol?F68 2.4g
Lutrol?F127 0.6g
Nitric acid butoconazole and PVP are dissolved in a certain amount of ethanol; Obtain settled solution, back drying under reduced pressure, the solid dispersion of Nitric acid butoconazole; After itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml distilled water, obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Embodiment 6.
Prescription 6:
Nitric acid butoconazole 0.1g
PVP 1.0g
Lutrol?F68 2.4g
Lutrol?F127 0.6g
Nitric acid butoconazole and PVP are dissolved in a certain amount of ethanol; Obtain settled solution, back drying under reduced pressure, the solid dispersion of Nitric acid butoconazole; After itself and a certain proportion of Lutrol F68 and Lutrol F127 are dissolved in the 20ml distilled water, obtain Nitric acid butoconazole at the body gel.
Through measuring, in the time of 25 ℃, the dissolubility of Nitric acid butoconazole reaches 5mg/ml, meets the requirement of a consumption per day 100mg of Nitric acid butoconazole.
Experimental example 1: Nitric acid butoconazole is at the bacteriostatic experiment of body gel:
Contrast bacterium group: the used strain passage number of times of this experiment was for 3 generations.Candida albicans (Candida albicans) [CMCC (F) 98 001].
Laboratory sample: crude drug Nitric acid butoconazole (reference substance), prescription three, prescription four, prescription six prepared Nitric acid butoconazoles are at the body gel.
Test sample is prepared:
(1) gets crude drug Nitric acid butoconazole 10g; Place sterilized conical flask, add pH 7.0 aseptic sodium chloride-peptone buffer agent 80ml, add an amount of aseptic polyoxyethylene sorbitan monoleate; Jolting makes it emulsifying; Add pH 7.0 aseptic sodium chloride-peptone buffer agents again to 100ml, shake up, as 1: 10 test liquid.
(2) get prescription three obtained Nitric acid butoconazoles at body gel 10g; Place sterilized conical flask, add pH 7.0 aseptic sodium chloride-peptone buffer agent 80ml, add an amount of aseptic polyoxyethylene sorbitan monoleate; Jolting makes it emulsifying; Add pH 7.0 aseptic sodium chloride-peptone buffer agents again to 100ml, shake up, as 1: 10 test liquid.
(3) get prescription four obtained Nitric acid butoconazoles at body gel 10g; Place sterilized conical flask, add pH 7.0 aseptic sodium chloride-peptone buffer agent 80ml, add an amount of aseptic polyoxyethylene sorbitan monoleate; Jolting makes it emulsifying; Add pH 7.0 aseptic sodium chloride-peptone buffer agents again to 100ml, shake up, as 1: 10 test liquid.
(4) get prescription six obtained Nitric acid butoconazoles at body gel 10g; Place sterilized conical flask, add pH 7.0 aseptic sodium chloride-peptone buffer agent 80ml, add an amount of aseptic polyoxyethylene sorbitan monoleate; Jolting makes it emulsifying; Add pH 7.0 aseptic sodium chloride-peptone buffer agents again to 100ml, shake up, as 1: 10 test liquid.
Bacterium liquid preparation: the fresh cultured thing of inoculation Candida albicans was cultivated 24～48 hours for 25 ℃ to improveing in Martin's culture medium, and above-mentioned culture uses 0.9% aseptic sodium chloride solution to process every 1ml to contain the bacteria suspension that the bacterium number is 50～100cfu.
Experimental technique:
Adopt membrane-filter procedure,, add 100ml 0.1% aseptic sodium chloride-peptone buffer agent respectively with four groups of test liquid 10ml; Behind membrane filtration, with the peptone water solution flushing filter membrane of 500ml 0.1%, each 100ml; Totally 5 times, add experimental bacteria in the last flushing liquor.Filter membrane is removed in the flushing back, and bacterium faces up to be affixed on the nutrient agar and cultivates.Aseptic sodium chloride-peptone solution 1ml is got in the negative control test, according to the method operation of front, as negative control.Cultivate counting.
Experimental result: the bacterial strain response rate=(experimental group bacterium number-test sample matched group bacterium number)/bacterium liquid group bacterium is counted * 100%
Table 1. biocidal property relatively
Experiment conclusion: Nitric acid butoconazole is compared with the crude drug Nitric acid butoconazole at the body gel, and it is lower than the crude drug Nitric acid butoconazole to the oidiomycetic response rate of white.Explain and preparedly be superior to the crude drug Nitric acid butoconazole at body gel fungistatic effect.
Experimental example 2: Nitric acid butoconazole gel influence factor experiment:
Main investigation illumination, high temperature, high humidity is to the influence of Nitric acid butoconazole gel.
Laboratory sample: Nitric acid butoconazole (reference substance), prescription three, prescription four, prescription six prepared Nitric acid butoconazoles are at the body gel.
Experimental technique:
(1) illumination experiment: with Nitric acid butoconazole in the body gel is placed on the lighting box that daylight lamp is housed, with illumination 4500lux held 10 days, in the 5th day with sampling in the 10th day, detection, sample size does not have significant change.
(2) high temperature experiment: 60 ℃ of held 10 days, in the 4th day with sampling in the 10th day, detection, content does not have significant change.
(3) high humidity experiment: 25 ℃, 90%RH held 10 days, in the 5th day with sampling in the 10th day, detect, its moisture absorption is increased weight 4.3%, meets the requirements.
Experiment conclusion: the crude drug Nitric acid butoconazole is behind preparation, and its stability does not have significant change.Explain that Nitric acid butoconazole is stable in body gel character.
Claims (7)
1. a Nitric acid butoconazole is at the body gel, by medicine, macromolecular material, solvent composition.Medicine is a Nitric acid butoconazole, macromolecular material available polyethylene ketopyrrolidine (PVP), PEG4000, PEG6000, Lutrol F68, Lutrol F127 etc., and solvent is water or phosphate buffer.
2. said by claim 1, a kind of Nitric acid butoconazole contains Nitric acid butoconazole solid dispersion, Lutrol F68 and Lutrol F127 at the body gel.The weight ratio of Lutrol F68 and Lutrol F127 is 1: 1～30.Wherein the consumption per day of Nitric acid butoconazole is 100mg.
3. said by claim 2, Nitric acid butoconazole is characterized in that earlier Nitric acid butoconazole being processed solid dispersion at the body gel.The macromolecular material that adopts can be PVP, PEG4000, PEG6000 etc.
4. said by claim 3, a kind of solid dispersion of Nitric acid butoconazole is characterized in that, contains Nitric acid butoconazole and PVP or PEG, and the weight ratio of Nitric acid butoconazole and PVP is 1: 1～50, weight ratio is preferably 1: 1～and 20; The weight ratio of Nitric acid butoconazole and PEG4000 or PEG6000 is 1: 1～100, weight ratio is preferably 1: 1～and 20.
5. said by claim 3, the method for preparing of Nitric acid butoconazole solid dispersion is characterized in that; Nitric acid butoconazole and PVP or PEG are dissolved in the organic solution 50 ℃ of heated and stirred, reduction vaporization under the 60-70 ℃ of temperature according to certain ratio; Drying obtains solid dispersion.Perhaps PVP or PEG are at high temperature fused, add Nitric acid butoconazole then, stir, get transparency liquid.Lyophilization obtains the solid dispersion of Nitric acid butoconazole.
6. said by patent requirement 1-5.A certain amount of Lutrol F68 and Lutrol F127 and Nitric acid butoconazole solid dispersion are dissolved in gauge water or the phosphate buffer, stir, spend the night, Nitric acid butoconazole at the body gel.
7. a Nitric acid butoconazole is mainly used in the treatment colpitis mycotica at the body gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010106131319A CN102525877A (en) | 2010-12-30 | 2010-12-30 | Preparation of butoconazole nitrate in-situ gel |
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| CN2010106131319A CN102525877A (en) | 2010-12-30 | 2010-12-30 | Preparation of butoconazole nitrate in-situ gel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721353A (en) * | 2009-07-08 | 2010-06-09 | 济南宏瑞创博医药科技开发有限公司 | Stable thermosensitive gelatin composite |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721353A (en) * | 2009-07-08 | 2010-06-09 | 济南宏瑞创博医药科技开发有限公司 | Stable thermosensitive gelatin composite |
| 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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Application publication date: 20120704 |