CN1850101A - Compound vitamin A acid gel preparation for treating acne and its preparing method - Google Patents
Compound vitamin A acid gel preparation for treating acne and its preparing method Download PDFInfo
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- CN1850101A CN1850101A CN 200610038624 CN200610038624A CN1850101A CN 1850101 A CN1850101 A CN 1850101A CN 200610038624 CN200610038624 CN 200610038624 CN 200610038624 A CN200610038624 A CN 200610038624A CN 1850101 A CN1850101 A CN 1850101A
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Abstract
The present invention discloses a compound gel preparation-compound tretinoin gel preparation for curing acnes. It is made up by using carbomer, glycerine, propylene alcohol, Tween, triethanolamine, clindamycin phosphate, tretinoin, EDTA and distilled water as raw material through a certain preparation process. Said invention also provides the concrete steps of its preparation method.
Description
One, technical field
The present invention relates to field of traditional Chinese, specifically relating to Chinese crude drug is a kind of compound vitamin A acid gel preparation for the treatment of acne of feedstock production and preparation method thereof.
Two, background technology
According to interrelated data, there is nearly 80% people to suffer from acne among 12～25 years old the crowd, this potential great market has attracted many drugmakers exploitation Retinoids, Retin-A, Renova, Accutane.Someone predicts that the Retinoids, Retin-A, Renova, Accutane field might produce cookle formula medicine, and therefore, the market competition of acne medicine is with more and more fierce.At present abroad begin to develop the compound drug of this treatment acne, and domesticly also do not had this quasi drugs listing.
Adopt the compound compatibility technology of retinoic acid and clindamycin phosphate, and make the gel dosage form.These and other Retinoids, Retin-A, Renova, Accutane has significant difference, has obvious superiority.
Clindamycin phosphate pharmacological action characteristics, widely distributed in vivo.Can enter in some main organs and body fluid and the osseous tissue, seldom the blood brain barrier by human body enters maincenter.It is obvious that clindamycin phosphate is used for the treatment of the acne produce effects, and adverse reaction rate is low.Liu Yiwen etc. test demonstration: compound recipe clindamycin phosphate liniment treated acne, back all around total obvious effective rate 83%, adverse reaction rate 1.9%.The clindamycin phosphate antibacterial action is strong, and toxicity is little, and propionibacterium acnes is had stronger inhibitory action, so can be used for anti-inflammation treatment acne.Clindamycin phosphate has suppressed corynebacterium acnes by to the early stage synthetic inhibitory action of bacterioprotein, has eliminated inflammation, thereby reaches the purpose of treatment acne.
Retinoic acid effect characteristics are used for the treatment of acne vulgaris safety, effective, and better tolerance.Shalita etc. are to 446 examples, and the moderate acne vulgaris is studied, and the result shows that non-inflammatory skin lesion and the total number average of skin lesion significantly reduce.
Compound recipe uses clindamycin phosphate, retinoic acid, and two components have summation action to remedy of acne, can shorten the course of treatment.
Therefore, research and develop the new drug of this compound gel, will produce the huge social economic benefit as the treatment acne.
The medicine that is used for the treatment of acne at present is a lot, and Tri-Biocin is exactly one of to use always.The dominant mechanism of such medicine is
Kill the inflammatory mediator that propionibacterium acnes produces, the antibiosis that is usually used in topical therapeutic have erythromycin, clindamycin phosphate, metronidazole, chloromycetin, clindamycin.The p chloromethylbenzoic acid lincomycin of " U-21251 " skin sore water system 1% of producing as the general strong pharmaceutical factory of the U.S., Guilin collection fine jade " skin is scorching peaceful " liniment is 2% chloromycetin liniment, " the acne king " of Yunnan, Kunming rainbow Pharmaceutical is " clindamycin phosphate+metronidazole " compound liniment." Benzamycin " gel system " 3% erythromycin+5% benzoyl peroxide " of Shandong dolantin gram.The compound recipe isotretinoin gel system " 2% erythromycin+0.015% isotretinoin " of this Alexandre Tuffere company of Britain, antibiotic tetracycline, erythromycin, Roxithromycin, minocycline, doxycycline, clindamycin phosphate, Sulfamonomethoxine---the sulfamethoxazole of oral medication acne commonly used.The common consumption of tetracycline and erythromycin 500～1000mg/ time, every day 2 times.
And this product to be compound recipe by clindamycin phosphate and retinoic acid develop, preparation technology and prescription all have the characteristic of oneself.The effect of this product treatment acne is mainly from the pharmacodynamics aspect of clindamycin phosphate and retinoic acid, and their compatibility effect is considered.Relevant documents and materials show at present: have therapeutical effect during external retinoid medicine low concentration, the infiltration deficiency does not affect the treatment, the pharmacokinetics of external retinoid medicine obviously is better than system's retinoic acid, and their energy orientations are in target position, and system toxicity greatly reduces.But external preparation also can produce untoward reaction such as in various degree pruritus, xerosis cutis, burning sensation, erythema, edema, desquamation, twinge under recommended dose.
1. to the propagation of endotheliocyte and the influence and the mechanism thereof of apoptosis
The precursor substance of the internal metabolism all-trans-retinoic acid of all-trans-retinoic acid is a retinal, be that vitamin A is transported to target cell with the protein bound form of retinol in blood plasma, combine by cell with the retinal protein receptor and to take in, the retinol that enters endochylema combines with cellular retinol binding protein (CRBP), generates retinoic acid by the dehydrogenase of NADP mediation and the effect of cell retinal dehydrogenase.CRBP I and retinol very high affinity is arranged and in mature tissue wide expression, their combination has prevented by the P450 oxidation in the microsome.ATRA and cell retinoic acid conjugated protein (CR Δ BP) are easily by the P450 oxidation inactivation in the endochylema.Other isomer 9-cis-retinoic acid of retinoic acid, 13-cis retinoic acid can be transformed into all-trans-retinoic acid under the effect of isomerase.Have only free all-trans-retinoic acid to combine with its nuclear receptor, bring into play its biologic activity by nuclear membrane.
(retinoic acid RA) is the important activity form of vitamin A to retinoic acid, and RA is by bringing into play its biological effect with the RA receptors bind in vivo.The receptor of the structure of retinoid receptor and binding mode mediation retinoic acid biological effect is the member's retinoid receptor and the retinoic acid receptor X of non-steroid hormone nuclear receptor superfamily, retinoid receptor RARs comprises that RAR α, RAR β, RAR γ three class hypotypes are respectively by 17q21,13q24, the 12q13 chromosome coding, RARs has A, B, C, D, six structure function zones of E, F, the C district is the DNA land, there are two zinc fingerses in this zone, make receptor protein can discern special DNA sequence, activation target gene; The E district is a ligand binding domain, and ligand binding domain also makes the nuclear receptor dimerization except that with part combines, and induces to intersect to activate or suppress and transcribes.Retinoic acid receptor X (RXRs) comprises RXR α, RXR β, RXR γ three class hypotypes, lacks a F district, all the other and retinoid receptor structural similarity.RARs, RXRs have transcriptional activation domain (AFs), wherein are present in aminoterminal A district, the B district be the AF-1 district, what be present in hydroxyl E district is the AF-2 district.The AF-1 district is an autonomous active region of non-ligand dependent, the aminoacid sequence mutability.Conduction receptor in AF-2 district is transcribed with the bonded signal activation target gene of part, is the ligand dependent transcriptional activation domain, and aminoacid sequence is more constant, disappearance afterwards ATRA still with the RAR1 combination.As the nuclear factor of part, after RA and the RA receptors bind,, also participate in the adjusting of other transcription factor in the pair cell except directly combining the transcriptional activity of target gene with RA response element (RARE) according to patience.
Retinoic acid is fat-soluble micromolecule chemical substance, and has a hormonal activity, general its action pathway plays a role by nuclear receptor with the steroidal steroid hormone is similar, retinoic acid combines with retinoid receptor and retinoic acid receptor X as part, the activated receptor of part is as retinoid receptor reaction component (RARE or the RXRE) combination with it in the transcription factor identification, the promoter or the enhancer of RARE or RXRE Chang Zuowei genes of interest, by inhibition or the enhancing that trans-acting regulation and control target gene is transcribed, produce corresponding active substance and start the proliferation and differentiation apoptosis of a series of signal transduction impelling cell.
2. inducing cancer cell strain apoptosis
MK be in cell surface and epimatrix, exist glucosamine polysaccharide heparin and heparin sulfate are had the polypeptide of high affinity, be found at first in the mice embryonic tumor cell and induce the early stage of differentiation through tretinoin.In recent years [5] are discovered, MK is not only fetus and the neonate important regulatory factor in the growth course again, and growth of tumor is shifted and angiogenesis has close contact.MK highly is expressed in various malignant cells, and the expression by gene or pharmaceutical methods blocking-up MK suppresses its action pathway, can reach the purpose of impelling apoptosis of tumor cells.ATRA is a kind of differentiation agent of inducing, and can induce polytype apoptosis of tumor cells, and remarkable antitumor effect is arranged, and its mechanism still under study for action.Discover, the mechanism that RA regulates the transcriptional expression of corresponding gene is what finish by a kind of tretinoin response element in Gene regulation district, RA receptor dimer (RAR/RXR) can combine with this key area, the RAR/RXR DNA complex that forms makes self structure look like to change in conjunction with the R Δ, carries out thereby promote corresponding DNA to transcribe.Pedraza etc. have discovered retinoic acid increased response in the people MK gene, are positioned at upstream 2.3kb sequence.
The result of researchs such as yellow Wen Guang shows that ATRA is at low concentration 10
-6But both cell death inducing during mol/L effect 6d can make the MK expression increase again; Though concentration increases the apoptosis-induced rate that can improve ATRA, do not significantly improve the expression of MK.Discovering in the past, when ATRA uses separately the effect of its induced tumor not remarkable, and when it and other drug (as with cisplatin) can improve the intensity of killing tumor cells during combined effect.Have the scholar to detect discovery, cisplatin acts on tumor cell reduces its MK expression.Because the positivity effect that MK plays in the growth of tumor development, so infer the inductive apoptotic effect of simple ATRA and not really strong, and with cisplatin, interferon] wait the associating of other derivants or cytokine can strengthen its effect, analyzing its reason, may to produce MK in the apoptosis-induced process of ATRA relevant, but still wait to confirm.How MK is concrete in the apoptosis-induced process of ATRA acts on the research of also still needing.These will help to understand the apoptosis-induced mechanism of ATRA, and for its tumor prevention and the treatment in applied research reference is provided.
3. clindamycin phosphate is the derivant of semisynthetic clindamycin, enter and be hydrolyzed to clindamycin in the body rapidly, and show antibacterial activity, its mechanism of action is the 50S subunit that acts on bacterial ribosome, stop the prolongation of peptide chain, thereby suppress the synthetic of bacterioprotein.Because clindamycin phosphate is the clindamycin of Phosphation, fat-soluble and permeability is all good than clindamycin, blood drug level is greatly increased.Be mainly used in treatment gram-positive cocci, part gram negative bacilli and the microbial infection of anaerobism clinically.
Three, summary of the invention
1. goal of the invention
The object of the present invention is to provide a kind of compound vitamin A acid gel preparation, it is good that this gel preparation has the skin surface stretchability, no greasy feeling, and pollution clothes not, Transdermal absorption speed is than characteristics such as ointment is fast.
Another object of the present invention provides the preparation method of this gel preparation.
2, technical scheme
(1) raw material of compound vitamin A acid gel preparation is formed and weight proportion.
A kind of compound vitamin A acid gel preparation, it is characterized in that it is to be made by following materials of weight proportions medicine: contain carbomer 5～25g in each kilogram gel consumption, glycerol 50～150g, propylene glycol 100～300g, tween 5～50g, triethanolamine 5～50g, clindamycin phosphate 5～50g (by clindamycin), retinoic acid 0.1～1g, EDTA 0.5～5g and adding distil water are to 1000g.
According to the needs of the acne state of an illness, can also in above-mentioned prescription, add clindamycin phosphoric acid 5-50g, retinoic acid 0.1-1g.
(2) preparation method of compound vitamin A acid gel preparation, its preparation process is:
1. 5～25g carbomer is added in about 10～50g distilled water, add glycerol 50～100g, propylene glycol 35～100g, fully swelling adds the stirring of 5～50g triethanol ammonium and makes into clear gel substrate;
2. get clindamycin phosphate 5～50g water dissolution, get retinoic acid 0.1～1g and dissolve with propylene glycol 35～100g, tween 5～50g;
3. above-mentioned medicinal liquid is joined in the clear gel substrate successively, add EDTA 0.5～5g and propylene glycol 35～100g.
4. supply distilled water to 1000g, stir, get the faint yellow transparent compound vitamin A acid gel agent that gets.
(3) application of compound vitamin A acid gel preparation in the preparation Retinoids, Retin-A, Renova, Accutane.
3, beneficial effect
Compound vitamin A acid gel preparation of the present invention adopts the compound compatibility technology of retinoic acid and clindamycin phosphate, and makes the gel dosage form.These and other Retinoids, Retin-A, Renova, Accutane has significant difference, has obvious superiority.
Gel is a kind of novel exterior-applied formulation.It is good to be used for the skin surface stretchability, no greasy feeling, not pollution clothes, Transdermal absorption speed is faster than ointment, compares with the externally used solution agent, and gel is long in the time that skin surface stops, to the skin nonirritant, so gel is a kind of dosage form that is suitable for acne treatment easy to use.
And the compound recipe of employing clindamycin phosphate and retinoic acid.Clindamycin phosphate is to anaerobe, and corynebacterium acnes etc. have antibacterial action.Retinoic acid can suppress the secretory function of sebaceous gland, and the effect of slightly stripping off is arranged.Clindamycin phosphate belongs to lincomycin series antibiotics, and it has good antibacterial action to staphylococcus aureus and most of anaerobe.Have the advantage that antibacterial action is strong, toxicity is little, propionibacterium acnes is had stronger inhibitory action.The content of AR in the patients with acne skin histology (androgen receptor) increases, and with the morbidity of acne tangible relation is arranged.Androgen combines with corresponding autoreceptor, causes the synthetic of some regulatory factor and discharges, and promotes the hypertrophy of gland.Interrelated data shows in sebum and the sebaceous gland to have retinoid receptor, and retinoic acid and receptors bind influence the AR level by regulating target gene expression.Two kinds of compatibility of drugss are used for acne treatment and have complementary action, can shorten the course of treatment, and this point is the breakthrough that realizes on the medicine of in the past treating acne.
Four, the specific embodiment:
The raw material of embodiment 1 compound vitamin A acid gel preparation is formed and weight proportion
A kind of compound vitamin A acid gel preparation, it is characterized in that it is to be made by following materials of weight proportions medicine: each kilogram gel consumption carbomer 20g, glycerol 80g, propylene glycol 260g, tween 25g, triethanolamine 40g, clindamycin phosphate 20g (by clindamycin), retinoic acid 0.3g, EDTA 2g, adding distil water is to 1000g.
The preparation method of 2 one kinds of compound vitamin A acid gel preparations of embodiment, its preparation process is:
1. the 20g carbomer is added in about 50g distilled water, add glycerol 80g, propylene glycol 80g, fully swelling adds the stirring of 40g triethanol ammonium and makes into clear gel substrate;
2. get clindamycin phosphate 20g water dissolution, get retinoic acid 0.3g and dissolve with propylene glycol 100g, tween 25g;
3. above-mentioned medicinal liquid is joined in the clear gel substrate successively, add EDTA 2g and propylene glycol 80g;
4. supply distilled water to 1000g, stir, get faint yellow transparent compound vitamin A acid gel agent.
Claims (4)
1, a kind of compound vitamin A acid gel preparation, it is characterized in that it is to be made by following materials of weight proportions medicine: contain carbomer 5～25g in each kilogram gel consumption, glycerol 50～150g, propylene glycol 100～300g, tween 5～50g, triethanolamine 5～50g, clindamycin phosphate 5～50g (by clindamycin), retinoic acid 0.1～1g, EDTA0.5～5g and adding distil water are to 1000g.
2, compound vitamin A acid gel preparation according to claim 1 is characterized in that also can adding clindamycin phosphate 5～50g (by clindamycin), retinoic acid 0.1～1g.
3, a kind of method for preparing claim 1 compound vitamin A acid gel preparation, its preparation process is:
(1) 5～25g carbomer is added in 10～50g distilled water, add glycerol 50～100g, propylene glycol 35～100g, fully swelling adds the stirring of 5～50g triethanol ammonium and makes into clear gel substrate;
(2) get clindamycin phosphate 5～50g water dissolution, get retinoic acid 0.1～1g, get medicinal liquid with propylene glycol 35～100g, tween 5～50g dissolving;
(3) above-mentioned medicinal liquid is joined in the clear gel substrate successively, add EDTA0.5～5g and propylene glycol 35～100g;
(4) supply distilled water to 1000g, stir, get faint yellow transparent compound vitamin A acid gel agent.
4, the application of the compound vitamin A acid gel preparation of claim 1 in the preparation Retinoids, Retin-A, Renova, Accutane.
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| CN 200610038624 CN1850101A (en) | 2006-03-06 | 2006-03-06 | Compound vitamin A acid gel preparation for treating acne and its preparing method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101292991B (en) * | 2008-06-20 | 2011-09-14 | 重庆医药工业研究院有限责任公司 | Compound gelling agent containing clindamycinum |
| CN102335113A (en) * | 2010-07-20 | 2012-02-01 | 杭州赛利药物研究所有限公司 | Clindamycin phosphate vaginal sustained-release gel and its preparation method |
| CN101485675B (en) * | 2008-01-18 | 2012-05-02 | 兆科药业（合肥）有限公司 | Adapalene and hydrochloric clindamycin compound gel preparation and preparation method thereof |
| CN103610688A (en) * | 2013-11-25 | 2014-03-05 | 浙江万马药业有限公司 | Gel reagent pharmaceutical composition and preparation method thereof |
| CN114209687A (en) * | 2021-12-20 | 2022-03-22 | 重庆华邦制药有限公司 | Composition of tretinoin external medicine |
| CN115518031A (en) * | 2022-10-28 | 2022-12-27 | 云飞生物药业(吉林)有限公司 | Carbomer hemorrhoid gel |
-
2006
- 2006-03-06 CN CN 200610038624 patent/CN1850101A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101485675B (en) * | 2008-01-18 | 2012-05-02 | 兆科药业（合肥）有限公司 | Adapalene and hydrochloric clindamycin compound gel preparation and preparation method thereof |
| CN101292991B (en) * | 2008-06-20 | 2011-09-14 | 重庆医药工业研究院有限责任公司 | Compound gelling agent containing clindamycinum |
| CN102335113A (en) * | 2010-07-20 | 2012-02-01 | 杭州赛利药物研究所有限公司 | Clindamycin phosphate vaginal sustained-release gel and its preparation method |
| CN103610688A (en) * | 2013-11-25 | 2014-03-05 | 浙江万马药业有限公司 | Gel reagent pharmaceutical composition and preparation method thereof |
| CN103610688B (en) * | 2013-11-25 | 2016-05-11 | 浙江万晟药业有限公司 | A kind of gel reagents pharmaceutical composition and preparation method |
| CN114209687A (en) * | 2021-12-20 | 2022-03-22 | 重庆华邦制药有限公司 | Composition of tretinoin external medicine |
| CN115518031A (en) * | 2022-10-28 | 2022-12-27 | 云飞生物药业(吉林)有限公司 | Carbomer hemorrhoid gel |
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