CN103405781B - Pharmaceutical composition of compound clindamycin and tazarotene lipid complex - Google Patents
Pharmaceutical composition of compound clindamycin and tazarotene lipid complex Download PDFInfo
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- CN103405781B CN103405781B CN201310374296.9A CN201310374296A CN103405781B CN 103405781 B CN103405781 B CN 103405781B CN 201310374296 A CN201310374296 A CN 201310374296A CN 103405781 B CN103405781 B CN 103405781B
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Abstract
The invention provides a lipid complex of tazarotene and clindamycin phosphate. The lipid complex is prepared mainly by utilizing synthetic phospholipids and stearamide, is wrapped with tazarotene and is further mixed with the clindamycin to prepare cream and gel which are mainly used for treating acne vulgaris. The lipid complex is simple in preparation technique, and the stability of pharmaceuticals can be ensured in the preparation process; compared with the common cream and gel, the lipid complex has the advantages that the skin medicine retention volume is higher, the content of medicine in local skins can be increased, and the therapeutic index can be improved.
Description
Technical field
The present invention relates to a kind of containing the lipid complex of tazarotene and the pharmaceutical composition of clindamycin, be mainly used in Acne treatment, particularly acne vulgaris.
Background technology
Acne is that one involves pilosebaceous chronic inflammatory skin disease, be apt to occur in seborrhea position, the skin lesion such as acne, pimple, pustule, tuberosity, cyst and cicatrix can be shown as, its definite cause of disease is still not known, it is believed that causing its main associated factors to comprise sebum secretion increases, by the inflammatory development stimulating the androgen of sebaceous gland and breeding thus degraded sebum cause with the propionibacterium acnes forming free fatty in hair sebum gland, follicular keratosis entirely (follicular parakeratosis) and heredodiathesis.Acne vulgaris is the one of acne, is especially common in hebetic men and women.Acne vulgaris betides pilosebaceous chronic inflammatory skin disease, its mechanism is completely not clear, and the pathogenesis of generally acknowledging at present comprises following 4 morbidity links: the immunoreation of the effect of microorganism in infundibulum of hair follicle portion hyperkeratosis, androgen and sebaceous gland hyperfunctioning, pilosebaceous unit, inflammation and host.
After acne is formed, be roughly divided into 3 grades according to skin lesion situation: slight, moderate and severe acne.Drug therapys all be at present in theory all by more than: the intervention of 4 links is carried out.Tretinoin medicines and topical antibiotic are the active drugs that current acne treatment is conventional.Tazarotene be the 3rd generation how fragrant tretinoin; within 1997, be used for the treatment of facial acne vulgaris and patch shape psoriasis by U.S. FDA approval; in treatment acne vulgaris; this medicine can adjust dyskeratosis; make it normalization; reduce hair follicle KC adhesion and work acne effect of loosening, and can prevent new micropowder thorn from being formed.Suppress micropowder thorn to form and dredge hair follicle and block generation and the differentiation that indirectly can reduce inflammatory damage.In addition, this medicine can suppress the expression of migration inhibitory factor associated protein-8 (MRP-8), ICAM-1 (ICAM-1) and HLA-DR, shows direct anti-inflammatory effect.Except tretinoin medicines, some topical antibiotic can suppress Propiobacterium, reduce acne to be formed, leukocyte chemotaxis can be made and play antiphlogistic effects, can be used for light moderate inflammatory acne, general and tretinoin medicines share, and should not be used alone, wherein clindamycin phosphate and erythromycin are this kind of medicine Typical Representatives.
Therapeutic alliance is standard treatment that is light, moderate acne at present, and the clinical efficacy of such as antibiotic and the coupling of topical Retinoids class preparation is significantly better than antibiotic and is used alone, and can reduce the generation of drug resistance.GCS recommends use topical antibiotic morning, uses A acids medicine evening, at least administration 2 times every day.The externally used compound preparation of tretinoin medicines and antibiotic combinations, can reach two kinds of pharmaceutical compositions and use simultaneously, plays pharmacology synergism, reach raising curative effect of medication, reduce the object of poisonous side effect of medicine, and improve patient dependence, become the important directions of such medicament research and development.
The medicine of Acne treatment is mostly folk prescription treatment, act on more single, such as, medicine mainly for acne mostly is antibiotic, comprises erythromycin, clindamycin, chloromycetin etc., main play antibacterial action, but longly easily cause drug resistance problems antibiotic service time; And have tretinoin, benzoyl peroxide, salicylic acid, lactic acid etc. mainly for the medicine of non-inflammatory acne, but these medicines show some effects, but mostly cause side effect, and as skin erythema, skin hypersensitivity or photosensitivity reaction.Find according to research, the treatment of acne more may need combined therapy and long-term treatment strategy.(for example, see Thiboutot D.New treatments and therapeutic strategies for acne.ArchFamily Med2000; 9:179-187; Gollnick H, Cunliffe W, the people such as Berson D, Management of acne, a report from a Global Alliance to ImproveOutcomes in Acne.J Am Acad Dermatol.2003; 49 (lsuppl): S1-S37).
At present, Tazarotene gel and emulsifiable paste are developed both at home and abroad, be used for the treatment of acne vulgaris, but clinical research proves to be used alone the effect of 0.05% concentration Tazarotene gel Acne treatment and not obvious, therefore the Tazarotene gel concentration being used for the treatment of acne vulgaris of listing is both at home and abroad 0.1%, trade name
be mainly used in facial light, the moderate acne for the treatment of.But single preparations of ephedrine therapeutic effect relative mistake, and due to the concentration of tazarotene high, the zests such as the skin caused are also larger, patient be difficult to withstand prolonged use.Therefore LG-DOW pharmaceutical science company limited develops compound clindamycin Avita Gel, trade name
concentration: clindamycin phosphate 1.2%, all-trans retinoic acid 0.025%.This compound preparation is for acne different onset link, and play synergism, clinical effectiveness is obviously better than the single preparations of ephedrine of clindamycin phosphate and all-trans retinoic acid.All-trans retinoic acid belongs to the retinoic acid of the first generation, has multiple double bond in molecular structure, and the change of double bond and single key structure makes it very easily have an effect with multiple retinoid receptor, thus causes multiple physiology to be expressed, and causes many side effect irrelevant with treatment.And tazarotene belongs to third generation receptor-selective retinoic acid, due to the specificity of acceptor selection, avoid the series of side effects of other retinoid medicines widely caused by pharmacological action.
Chinese patent CN1210041C discloses the externally used compound preparation of a kind of tazarotene and antibacterials, containing following effective active composition (percentage by weight) in the medium carrier of wherein complex external medicine: tazarotene 0.01-2%, antimicrobial drug is clindamycin, erythromycin, chloromycetin, tetracycline, tinidazole etc. such as.It is after being mixed with medium carrier by two kinds of effective ingredient, forms emulsifiable paste or gel or liniment or liniment.But this belongs to general ointment formulation, often need high speed homogenisation process just can obtain even particle size distribution, fine and smooth emulsifiable paste, tazarotene dissolubility in water is low in addition, and in long-term put procedure, easy crystallize out, affects the treatment.
Chinese patent CN102600196A discloses a kind of externally-applied medicinal composition being used for the treatment of acne vulgaris.Described pharmaceutical composition contains tazarotene, clindamycin and O/W emulsion-type substrate, and it is prepared into the dosage forms such as emulsifiable paste.It adopts polyoxyethylene stearate (40) ester or polyoxyethylene stearate (15) ester can improve the stability of ointment in put procedure as emulsifying agent.Results of stability and animal experiment result of study show, after with the addition of this solvent components, the stability of medicine is better, storage process can not be separated out tazarotene crystal, and be there will not be the phenomenon of oil-water separation.Particularly, surprisingly, in the test of animal Acne Model therapeutic effect, the ointment therapeutic effect containing solvent composition is obviously better than not containing the ointment of solvent composition.But the dermal drug hold-up of this proprietary preparation is still poor, and agent permeates therethrough rate is also not ideal enough, and these effects are not fully up to expectations.
Summary of the invention
In order to overcome the defect of prior art, the invention provides a kind of pharmaceutical composition, this pharmaceutical composition comprises lipid complex containing tazarotene and clindamycin, first it by being prepared into lipid complex by tazarotene, and then mix with clindamycin further, add other substrate again, be prepared into lipid complex emulsifiable paste or gel.Compared with common compound preparation, in skin, lipid composite preparation has higher medicine retention amount and lower agent permeates therethrough rate, better skin Targeting Effect can be reached, the Transdermal absorption reducing medicine enters sanguimotor amount, reach increase curative effect of medication, reduce poisonous side effect of medicine object.
One object of the present invention is to provide a kind of pharmaceutical composition, it comprises lipid complex containing tazarotene and clindamycin, the described lipid complex containing tazarotene is made up of tazarotene, synthetic phospholipid and stearmide, wherein the usage ratio of tazarotene, synthetic phospholipid and stearmide is 0.1-10: 20-100: 10-50 by weight, preferably, the usage ratio of tazarotene, synthetic phospholipid and stearmide is 1-2: 30-50: 20-30 by weight; Such as its consumption is 0.1-0.5: 20-100: 10-50; The usage ratio of tazarotene and clindamycin is by weight: 1-5: 50-200, and preferably, the usage ratio of tazarotene and clindamycin is 2.5: 100 by weight.
In the present invention, described synthetic phospholipid is selected from phosphatidic acid, phosphatidyl glycerol, phosphatidylinositols, Phosphatidylserine; Preferably, described synthetic phospholipid is selected from Phosphatidylserine.
In one embodiment, pharmaceutical composition of the present invention is the form of cream preparation, and it comprises lipid complex, clindamycin, oil phase substrate, emulsifying agent, wetting agent, stabilizing agent, antibacterial, pH value regulator and water containing tazarotene.
In a preferred version, contain in every 1000mg cream preparation:
(1) tazarotene 0.1mg-0.5mg;
(2) clindamycin 5mg-20mg; Clindamycin can be clindamycin phosphate or Clindamycin Hydrochloride;
(3) Phosphatidylserine 20mg-100mg;
(4) stearmide 10mg-50mg;
(5) oil phase substrate 150-300mg;
(6) emulsifying agent 30mg-60mg;
(7) wetting agent 50-90mg;
(8) stabilizing agent 0.1-5mg;
(9) antibacterial 1-50mg;
(10) pH value regulator, regulates aqueous pH values to 5-6;
Surplus is purified water.
Preferably, wherein, oil phase substrate can be selected from the mixture of one or more in liquid paraffin, white vaseline; Emulsifying agent is selected from one or both mixture of Arlacel-60 or Tween 80; Wetting agent is glycerol; Stabilizing agent is selected from disodium edetate or calcium disodium edetate; Antibacterial can be selected from benzyl alcohol; PH value regulator is selected from triethylamine.
In another embodiment, pharmaceutical composition of the present invention is the form of gel preparation, and it comprises lipid complex, clindamycin, Acritamer 940, stabilizing agent, antibacterial, pH value regulator and water containing tazarotene.
In a preferred version, it is characterized in that containing in every 1000mg gel preparation:
(1) tazarotene 0.1-10mg, preferred 0.1mg-0.5mg;
(2) clindamycin 5mg-20mg; Clindamycin can be clindamycin phosphate or Clindamycin Hydrochloride;
(3) Phosphatidylserine 20mg-100mg
(4) stearmide 10mg-50mg
(5) Acritamer 940 100-200mg;
(6) stabilizing agent 0.1-5mg;
(7) antibacterial 1-50mg;
(8) pH value regulator, regulates aqueous pH values to 7-8;
Surplus is purified water.
Wherein stabilizing agent is selected from disodium edetate or calcium disodium edetate; Antibacterial is selected from benzyl alcohol; PH value regulator is selected from triethylamine.Wherein Acritamer 940 is gel-type vehicle.
Another object of the present invention is the preparation method providing described pharmaceutical composition, the preparation process of the lipid complex wherein containing tazarotene is: by tazarotene and synthetic phospholipid, stearmide is dissolved in 9-10 times of weight (with tazarotene and synthetic phospholipid, the total weight of stearmide) dichloromethane and ethanol mixture in, the ratio of the mixture of dichloromethane and ethanol is 1: 1, be placed in Rotary Evaporators, under 50-60 DEG C of condition, evaporating organic solvent, form medicine immobilized artificial membrane, add the phosphate buffer of the pH value 4.5-5.5 of appropriate volume, vibration aquation, form thick lipid complex suspension, lipid complex suspension is passed through the even secondary of high pressure breast again, finally by 100nm polycarbonate membrane, obtain the lipid complex suspension of bag medicine carrying thing.Wherein the appropriate volume of phosphate buffer reasonably can be determined by those skilled in the art, and such as adjust ph scope is at 4.5-6.5, preferred 4.8-5.2, the suitable volumes of such as 5.0; Its mesohigh breast is even adopts high pressure dispersing emulsification machine known in the art, reaches state lower than 100nm to make particle diameter; Model such as can be used for NS1001L, by the high pressure dispersing emulsification machine of Italian GEA Niro Soavi company import.
The preparation method of cream preparation of the present invention is: get oil phase substrate and sorbester p18 (when select sorbester p18 as emulsifying agent or together with Tween 80 as emulsifying agent time) be heated to 80 DEG C of meltings, obtain oil phase; Separately get the lipid complex suspension of bag medicine carrying thing, add purified water dilution, add Tween 80 (when selecting Tween 80 as emulsifying agent), wetting agent, stabilizing agent, antibacterial, clindamycin stirring and dissolving are even, triethylamine adjust ph, to 5-6, obtains lipid complex aqueous phase; 80 DEG C of conditions, lipid complex aqueous phase is added to oil phase with thread, limit edged stirs, and is cooled to room temperature afterwards, obtains O/W ointment.When wherein " adding purified water dilution ", the water yield used is the water of surplus in cream preparation composition, and those skilled in the art can determine according to concrete pharmaceutical formulation.
The preparation method of gel preparation of the present invention is: the lipid complex suspension getting medicine carrying thing, add purified water dilution, add gel-type vehicle dispersion, fully swelling 7-9 hour (under generic condition, such as 8 hours), triethylamine adjust ph, to 7-8, adds clindamycin in prescription, stabilizing agent, antibacterial successively, stirs, the purified water dilution adding amount of calculation evenly, to obtain final product.
An also object of the present invention is to provide the purposes of described pharmaceutical composition in the medicine preparing Acne treatment, particularly acne vulgaris.
In the present invention, medicine clindamycin can also be Clindamycin Hydrochloride, clindamycin phosphate.In the present invention, when relating to the usage ratio of tazarotene, the consumption of clindamycin or itself and other material, consumption still in the content of the tazarotene wherein comprised, clindamycin for benchmark.
In the present invention, if do not mentioned especially, the material used, device etc., and the condition such as temperature, time is all that art technology is known, or those skilled in the art are according to the instruction of present specification, and conveniently knowledge is obtainable.
Technical scheme of the present invention compared with prior art, the following technological merit of main existence: the lipid composite preparation of invention is compared with common common ointment or gel preparation, active component hold-up in skin has and significantly improves, medicine is improved significantly at the content of dispersion of local skin, there has been obvious prolongation active component onset time, thus significantly improves therapeutic index.Be used for the treatment of acne especially, especially during acne vulgaris, curative effect is good especially, and compare with the medicine of tazarotene with the commercially available clindamycin that comprises simultaneously, curative effect exists significant difference.
Dermal drug hold-up is tested: adopt lipid complex ointment of the present invention, lipid complex gel of the present invention, usual cream agent, ordinary gel agent, carry out isolated skin permeability test.
Usual cream agent: get oil phase substrate and sorbester p18, is heated to 80 DEG C of meltings, adds tazarotene and dissolves, obtain oil phase; Separately get clindamycin, Tween 80, glycerol, stabilizing agent, antibacterial, add purified water stirring and dissolving even, triethylamine adjust ph, to 5-6, obtains aqueous phase; 80 DEG C of conditions, aqueous phase is added to oil phase with thread, limit edged stirs, and is cooled to room temperature, obtains O/W ointment.
Ordinary gel agent: get tazarotene, clindamycin, adds purified water and dissolves, and adds gel-type vehicle dispersion, abundant swelling 8 hours, triethylamine adjust ph, to 7-8, adds stabilizing agent in prescription, antibacterial successively, stirs, the purified water dilution adding amount of calculation evenly, to obtain final product.
Isolated skin permeability test, after healthy rat anesthesia is put to death, belly wool is eliminated with shears, take off undamaged skin, removing subcutaneous tissue, be fixed on the supply chamber of Franz diffusion cell after cleaning, add the normal saline of 20%PEG400 in receiving chamber as release medium, keep endodermis and solution close contact.Getting quantitative sample puts in supply chamber, and regulate water-bath to make outer jacket layer temperature constant in (37 ± 1) DEG C, mixing speed is 100r/min, when 24h, take off skin, measures medicament contg in skin.The results are shown in following table.
* 1identical with the content of same composition in embodiment 1 ointment in this usual cream agent, the content of other component is determined according to this area routine techniques
* 2identical with the content of same composition in embodiment 4 gel in this ordinary gel agent, the content of other component is determined according to this area routine techniques
Result shows: in the skin of lipid composite preparation of the present invention, medicine retention amount is apparently higher than ordinary preparation, P < 0.05; Embodiment ointment and the gel of wood application are significant difference (P < 0.05) with the result that the common ointment contrasted and ordinary gel agent obtain.
embodiment
There is provided following detailed description of the invention to carry out further illustrating technical solution of the present invention, it should be regarded as merely the explanation to technical solution of the present invention, and can not be interpreted as the restriction to the technology of the present invention offshoot program.
Embodiment 1-embodiment 3: compound recipe tazarotene clindamycin lipid complex emulsifiable paste
Preparation process is: by tazarotene and Phosphatidylserine, stearmide is dissolved in the dichloromethane of 9-10 times of weight and the mixture of ethanol, the ratio of the mixture of dichloromethane and ethanol is 1: 1, then Rotary Evaporators is placed in, under 50-60 DEG C of condition, evaporating organic solvent, form medicine immobilized artificial membrane, add the phosphate buffer of the pH value 4.5-5.5 of appropriate volume, vibration aquation, form thick lipid complex suspension, lipid complex suspension is passed through the even secondary of high pressure breast again, finally by 100nm polycarbonate membrane, obtain the lipid complex suspension of bag medicine carrying thing.
Get oil phase substrate liquid paraffin and white vaseline is heated to 80 DEG C of meltings; Separately get the lipid complex suspension of the bag medicine carrying thing of above-mentioned preparation, add purified water dilution, add Tween 80, glycerol, disodium edetate, benzyl alcohol, clindamycin stirring and dissolving evenly, triethylamine adjust ph 5-6; At 80 DEG C, lipid complex aqueous phase is added to oil phase with thread, limit edged stirs, to being condensed to room temperature.Obtain O/W ointment.
Embodiment 4-embodiment 6: compound recipe tazarotene clindamycin lipid complex gel
Preparation process is: tazarotene and Phosphatidylserine, stearmide are dissolved in the dichloromethane of 9-10 times of weight and the mixture of ethanol, the ratio of the mixture of dichloromethane and ethanol is 1: 1, then, be placed in Rotary Evaporators, under 50-60 DEG C of condition, evaporating organic solvent, form medicine immobilized artificial membrane, add the phosphate buffer of the pH value 4.5-5.5 of appropriate volume, vibration aquation, form lipid complex suspension, then by lipid complex suspension by the even secondary of high pressure breast, finally by 100nm polycarbonate membrane.
Get the lipid complex suspension of the bag medicine carrying thing of above-mentioned preparation, add purified water dilution, add the dispersion of Acritamer 940 gel-type vehicle, fully swelling,, triethylamine adjust ph, to 7-8, adds disodium edetate, benzyl alcohol successively, stir, the purified water dilution adding amount of calculation evenly, to obtain final product.
Claims (1)
1. a pharmaceutical composition, it comprises lipid complex containing tazarotene and clindamycin acid esters, and the described lipid complex containing tazarotene is made up of tazarotene, Phosphatidylserine and stearmide, and the prescription of said composition is:
Or
。
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| CN113181191A (en) * | 2021-01-27 | 2021-07-30 | 云南柏脉生物科技有限公司昆明分公司 | Ointment containing halometasone and tazarotene and preparation method thereof |
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| CN1210041C (en) * | 2003-09-29 | 2005-07-13 | 中国医学科学院皮肤病研究所 | Complex external medicine for treating acne |
| MXPA06008988A (en) * | 2006-08-08 | 2008-02-07 | Fernando Ahumada Ayala | Topical antiacne preparations containing retinoid (tazarotene or adapalene), antibiotic (clindamycin phosphate) and/or keratolytic (miscrosponged benzoyl peroxide). |
| CN101732241A (en) * | 2009-12-26 | 2010-06-16 | 鲁南制药集团股份有限公司 | Cream of butenafine hydrochloride and preparation method thereof |
| CN102600196B (en) * | 2012-02-21 | 2013-03-27 | 江苏圣宝罗药业有限公司 | Externally applied medicine composition for treating common acne |
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