CN103893766A - External preparation containing clindamycin phosphate - Google Patents
External preparation containing clindamycin phosphate Download PDFInfo
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- CN103893766A CN103893766A CN201410161068.8A CN201410161068A CN103893766A CN 103893766 A CN103893766 A CN 103893766A CN 201410161068 A CN201410161068 A CN 201410161068A CN 103893766 A CN103893766 A CN 103893766A
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- clindamycin phosphate
- component
- external preparation
- solution
- clindamycin
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- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 title claims abstract description 65
- 229960002291 clindamycin phosphate Drugs 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 13
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical group CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims description 9
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- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 2
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- 239000008363 phosphate buffer Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
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- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
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- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an external preparation containing clindamycin phosphate. The external preparation comprises a component A and a component B, wherein the component A is isopropyl myristate liquor of clindamycin phosphate; the component B is aqueous liquor of a water-based gel matrix, an emulsifier and a preservative. The external preparation disclosed by the invention is simple in preparation process, free of a special storage condition, good in product stability and easy for large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of external preparation that contains clindamycin phosphate, relate in particular to a kind of Clindamycin Phosphate Gel agent.
Background technology
The factors such as the generation of acne is main stops up with hypersteatosis, pilosebaceous duct, antibacterial infection and inflammatory reaction are closely related.After adolescing in human body androgen particularly the level of testosterone raise rapidly, promote sebaceous gland to grow and produce a large amount of sebums.The dyskeratosis of pilosebaceous duct causes conduit to stop up simultaneously, dyssebacia, and forming horn plug is micropowder thorn.Especially propionibacterium acnes amount reproduction of multiple-microorganism in hair follicle, the lipase that propionibacterium acnes produces decomposes sebum and generates free fatty, chemotactic inflammatory cell and medium simultaneously, final induction exacerbate inflammation reaction.
Skin lesion is apt to occur in face and upper chest and back.The non-inflammation skin lesion of acne shows as opening and closed comedones.The typical skin lesion of closed comedones (claiming again hoary hair) is the colour of skin pimple of approximately 1 mm in size, without obvious hair follicle opening.Open comedones (claiming again blackhead) shows as the significantly hair follicle opening of expansion of dome-shaped pimple companion.Acne further develop and can develop into various struvite skin lesion, show as inflammatory pimple, pustule, tuberosity and cyst.Inflammatory pimple takes on a red color, and 1～5 millimeter of diameter is not etc.; Pustule is in the same size, has wherein been full of white pus; Tuberosity diameter is greater than 5 millimeters, and having of touching hardened and pain; The position of cyst is darker, has been full of the mixture of pus and blood.These skin lesion also can merge and form large inflammatory speckle and sinus tract etc.After disappearing, struvite skin lesion usually leaves over pigmentation, erythema perstans, pitting or hypertrophic cicatrix.According to acne lesions character and the order of severity, acne is divided into 3 degree, 4 grades clinically: 1 grade (slightly): only have acne; 2 grades (moderate): except acne, also have some inflammatory pimples; 3 grades (moderate): except acne, also have more inflammatory pimple or pustule; 4 grades (severe): outside acne, inflammatory pimple and pustule, go back nodosity, cyst or cicatrix.
Incidence of acne is higher, according to interrelated data, in the crowd in 12-25 year, has nearly 80% people to suffer from acne.The external used medicine of Acne treatment comprises tretinoin medicines and antibiotics, such as lincomycin, clindamycin, benzoyl peroxide etc.Compared with lincomycin, the antibacterial activity of clindamycin strengthens 4～8 times, and untoward reaction is low.
It is synthetic first that clindamycin replaced in lincomycin molecule the hydroxyl of 7th by Magerlerin etc. with chlorine in 1966.Clindamycin phosphate is the derivant of semisynthetic clindamycin, there is no in vitro antibacterial activity, but have fat-soluble, be easy to Transdermal absorption compared with clindamycin, enter and in body, be hydrolyzed to clindamycin rapidly and show antibacterial activity, its mechanism of action is synthetic in early days by anti-bacteria protein, thereby has suppressed corynebacterium acnes, and has eliminated inflammation.
WO2006089070 discloses a kind of preparation method of the compound gel that contains clindamycin phosphate and retinoic acid, using the mixture that contains carbomer, propylene glycol and water as first-phase, using the mixture that contains tretinoin, laureth 9, methyl hydroxybenzoate etc. as second-phase, using the aqueous solution that contains clindamycin phosphate and citric acid, tromethane as third phase, second-phase is joined and in first-phase, obtains mixture, again third phase is added in mixture, as for stirring in vacuum, cooling.
EP0479518 discloses a kind of compound vitamin A acid gel agent and preparation method of Acne treatment, and the method is that then carbomer is sprinkled into by water-soluble clindamycin phosphate, propylene glycol and a certain amount of methanol, make it swelling completely, make aqueous colloidal.Retinoic acid and propyl gallate are dissolved in remaining methanol, add ethylenediamine, after dissolving, make alcoholic solution.Alcoholic solution is slowly joined in aqueous colloidal, make gel.
CN102335121A discloses a kind of clindamycin phosphate responsive to temperature type and pH sensitive in situ gels research, and said preparation is solution at non-physiological state, and physiological status changes gel mutually into.Wherein clindamycin phosphate responsive to temperature type gel is finally to make by the suitable proportioning of employing poloxamer (Poloxamer) 407 (being called for short F127) and PLURONICS F87 (being called for short F68).Said preparation has extended the holdup time of clindamycin phosphate at vagina, has improved bioavailability and curative effect.
CN102335113A discloses a kind of clindamycin phosphate vagina slowly-releasing gel and preparation method thereof, said preparation comprises the component of following percentage by weight: clindamycin phosphate 1%-5%, poloxamer (188) 5%-15%, poloxamer (407) 8%-20%, carmethose 0.5%-2%, carbomer (980) 0.05%-2%, additive 0.02%-5%, remains as water.Clindamycin phosphate vagina slowly-releasing gel described in this invention is long in the intravaginal holdup time, and drug effect sustained release can long-time onset.
CN101292991A discloses a kind of compound gel that contains clindamycin, the clindamycin that comprises effective dose or its officinal salt or ester, tretinoin and cellulose derivative gel-type vehicle, this invention has overcome the interference that carbomer gel substrate is measured clindamycin, is conducive to detection and the quality control of product.
Owing to containing phosphate ester, amido link in clindamycin phosphate structure, therefore to poor heat stability, facile hydrolysis, the Drug Percutaneous Absorption performance after hydrolysis reduces, and has affected curative effect of medication.Based on this, the clindamycin phosphate external preparation that a kind of stability is high is provided, this seems particularly important.
Summary of the invention
In order to solve the problem of the poor stability that clindamycin phosphate structure facile hydrolysis causes, the inventor is through lot of experiments and persistent exploration, prescription and technique to clindamycin phosphate preparation are improved, be surprised to find that medicine dissolution in a certain amount of isopropyl myristate, the stability of medicine significantly improves, thereby the clindamycin phosphate external preparation that a kind of stability is higher is provided.
The object of the present invention is achieved like this:
An external preparation that contains clindamycin phosphate, described external preparation comprises component A and B component, the isopropyl myristate solution that described component A is clindamycin phosphate; Described B component is the aqueous solution of aqueous gel substrate, emulsifying agent and antiseptic.
Preferably, the external preparation that contains clindamycin phosphate as above, wherein the quality percentage composition of clindamycin phosphate in described component A is 3%-10%.
Further preferably, the external preparation that contains clindamycin phosphate as above, wherein the quality percentage composition of clindamycin phosphate in described component A is 4.5%-5.5%.
Preferably, the external preparation that contains clindamycin phosphate as above, wherein said aqueous gel substrate is carbomer 934, the quality percentage composition in described B component is 6%-15%.
Further preferably, the external preparation that contains clindamycin phosphate as above, what wherein said emulsifying agent adopted is Tween 80.
Again further preferably, the external preparation that contains clindamycin phosphate as above, wherein said component A with B component by 1: after the mass ratio of 2-9 mixes, be Clindamycin Phosphate Gel agent.
The present invention also provides a kind of preparation method of clindamycin phosphate external preparation, comprises the steps:
(1) clindamycin phosphate is dissolved in isopropyl myristate, obtains component A, fill is in container;
(2) carbomer 934, Tween 80, methyl hydroxybenzoate are dissolved in water, obtain B component, fill is in container.
The using method of clindamycin phosphate external preparation provided by the present invention is: before use, by component A with B component by 1: after the mass ratio of 2-9 mixes, stir, obtain Clindamycin Phosphate Gel agent, be applied in affected part.
Compared with prior art, the clindamycin phosphate external preparation the present invention relates to, its preparation technology is simple, and without particular storage condition, product stability is good, is easy to industrialized great production.
The specific embodiment
Now further describe preparation process of the present invention and implementation result by following examples, embodiment is only for the object of illustration, do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.
Embodiment 1
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the isopropyl myristate of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Embodiment 2
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the isopropyl myristate of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Embodiment 3
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the isopropyl myristate of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Comparative example 1 adopts soybean oil to replace the solvent of isopropyl myristate as clindamycin phosphate
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the soybean oil of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Comparative example 2 adopts medium chain triglyceride to replace the solvent of isopropyl myristate as clindamycin phosphate
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the medium chain triglyceride of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Comparative example 3 adopts oleic acid polyethyleneglycol glyceride to replace the solvent of isopropyl myristate as clindamycin phosphate
Preparation technology:
(1) clindamycin phosphate of recipe quantity is dissolved in the oleic acid polyethyleneglycol glyceride of recipe quantity, using filled with solution in container as component A;
(2) recipe quantity carbomer 934, Tween 80 and methyl hydroxybenzoate be dissolved in prescription water gaging in, using filled with solution in container as B component.
Before use, component A is joined in B component, stir, obtain Clindamycin Phosphate Gel.
Accelerate experiment front and back Clindamycin Phosphate Gel assay
1. content.Chromatographic column: the stainless steel column of Lichrosorb RP18200 × 4mm.Mobile phase: mixture of acetonitrile-phosphate buffer (78.5: 21.5), compound method is as follows: take in the water-soluble 1000ml of anhydrous potassium dihydrogenphosphate 13.6g, with 80% phosphorus acid for adjusting pH be 2.5; Get this buffer 785ml, add acetonitrile 215ml, mix and get final product.
The preparation of inner mark solution: precision takes parahydroxyacet-ophenone 37.5mg, is placed in 500ml measuring bottle, dissolves and standardize solution by mobile phase, obtains the inner mark solution of 0.0075% (w/v).Detect wavelength: 210nm; Flow velocity: 1.0ml/min.
2. determination of related substances.
(1) need testing solution: get component A prepared by each embodiment, be diluted to the solution of 0.3mg/ml by mobile phase.Separately get above-mentioned need testing solution is diluted to 3.0mg/ml solution with method, make related substance and analyze test liquid.
(2) reference substance solution: get respectively clindamycin phosphate, clindamycin and lincomycin reference substance appropriate, accurately weighed; Add mobile phase and dissolve the quantitative mixed solution of making containing above-mentioned three kinds of each about 0.3mg/ml of reference substance that dilutes.
(50mm × 4.6mm, m), conventional H PLC analyzes and adopts Apollo C18 (250mm × 4.6mm, m) chromatographic column of 5 μ 2.5 μ to adopt Waters XTerraTM MS C18 hydridization post.Mobile phase is 0.1mol/L potassium dihydrogen phosphate buffer salt (85% phosphoric acid is adjusted pH3.5): acetonitrile: methanol (700: 150: 150) (needing with 0.22 μ m membrane filtration); Detect wavelength 210nm; Flow velocity is respectively 1.5ml/min (UFLC) and 1.0ml/min (conventional H PLC); 25 ℃ of column temperatures; Test sample concentration 0.3mg/ml (containing surveying), 3.0mg/ml (related substance); Sampling volume is respectively 2 μ l (UFLC) and 10 μ l (conventional H PLC).
Table 1 accelerates experiment front and back Clindamycin Phosphate Gel related substances and assay result
Can find out from the result of the test of table 1, the product of embodiment of the present invention 1-3 is after accelerating investigation, and related substance, content are substantially constant; And after comparative example 1-3 adopts respectively soybean oil, medium chain triglyceride, oleic acid polyethyleneglycol glyceride to replace isopropyl myristate as solvent, solution related substance after accelerating obviously increases, content significantly declines, this may be that concrete reason also needs further research because of clindamycin phosphate poor stability in these solvents.
Claims (6)
1. an external preparation that contains clindamycin phosphate, is characterized in that: described external preparation comprises component A and B component, the isopropyl myristate solution that described component A is clindamycin phosphate; Described B component is the aqueous solution of aqueous gel substrate, emulsifying agent and antiseptic.
2. the external preparation that contains clindamycin phosphate according to claim 1, is characterized in that: the quality percentage composition of clindamycin phosphate in described component A is 3%-10%.
3. the external preparation that contains clindamycin phosphate according to claim 2, is characterized in that: the quality percentage composition of clindamycin phosphate in described component A is 4.5%-5.5%.
4. the external preparation that contains clindamycin phosphate according to claim 1, is characterized in that: described aqueous gel substrate is carbomer 934, and the quality percentage composition in described B component is 6%-15%.
5. the external preparation that contains clindamycin phosphate according to claim 4, is characterized in that: described emulsifying agent is Tween 80.
6. the external preparation that contains clindamycin phosphate according to claim 5, is characterized in that: described component A after mixing by the mass ratio of 1:2-9 with B component, be Clindamycin Phosphate Gel agent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014834A1 (en) * | 2004-05-11 | 2006-01-19 | Mohan Vishnupad | Retinoid solutions and formulations made therefrom |
| CN1839872A (en) * | 2005-03-28 | 2006-10-04 | 深圳市天和医药科技开发有限公司 | Preparation method of clindamycin phosphate solution formulation and its applying sheet |
| US20060280715A1 (en) * | 2004-05-11 | 2006-12-14 | Mohan Vishnupad | Retinoid solutions and formulations made therefrom |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014834A1 (en) * | 2004-05-11 | 2006-01-19 | Mohan Vishnupad | Retinoid solutions and formulations made therefrom |
| US20060280715A1 (en) * | 2004-05-11 | 2006-12-14 | Mohan Vishnupad | Retinoid solutions and formulations made therefrom |
| CN1839872A (en) * | 2005-03-28 | 2006-10-04 | 深圳市天和医药科技开发有限公司 | Preparation method of clindamycin phosphate solution formulation and its applying sheet |
Non-Patent Citations (2)
| Title |
|---|
| WILLIAM J.CUNLIFFE,ET AL: "A randomized,double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris", 《CLINICAL THERAPEUTICS》, vol. 24, no. 7, 31 December 2002 (2002-12-31), pages 1117 - 1133 * |
| 李海涛等: "复方克林霉素磷酸酯凝胶的制备及质量控制", 《药学进展》, vol. 30, no. 6, 31 December 2006 (2006-12-31), pages 270 - 273 * |
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