CN103800284A - Dihydro aryl naphthalene compound containing gel for reducing skin hyperpigmentation and preparation method thereof - Google Patents
Dihydro aryl naphthalene compound containing gel for reducing skin hyperpigmentation and preparation method thereof Download PDFInfo
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- CN103800284A CN103800284A CN201410065451.3A CN201410065451A CN103800284A CN 103800284 A CN103800284 A CN 103800284A CN 201410065451 A CN201410065451 A CN 201410065451A CN 103800284 A CN103800284 A CN 103800284A
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Abstract
The invention belongs to the field of medicines, and relates to external gel for reducing skin hyperpigmentation and a preparation method thereof. The gel comprises the following components in percentage by weight: 0.1-5 percent of dihydro aryl naphthalene lignan, 1.5-3 percent of gel substrate, 0.1-1 percent of preservative, 5-20 percent of wetting agent, 10-30 percent of alcohol solvent and the balance of water. Compared with the prior art, the gel is simple in preparation process, low in cost, easily controllable in dosage, convenient to use and carry along. According to the gel, the water solubility of dihydro aryl naphthalene lignan can be improved, the dihydro aryl naphthalene lignan in the preparation can easily penetrate into skin; experiment basis is provided to the practicality and reasonable application mode of skin hyperpigmentation interference by dihydro aryl naphthalene lignan.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of external-use gel that reduces cutaneous pigmentation and preparation method thereof.
Background technology
Lignanoid (lignan) claim again lignan, is the compound that a class is polymerized by two molecule phenyl propanoid derivatives (C6-C3).
Be divided into (one) diaryl butanes (dibenzylbutanes) from molecular structure Shang Haikejiang lignanoid, (2) diaryl butyrolactone (dibenzyltyrolactones), (3) arylnaphthalene class (arylnaphthalenes), (4) tetrahydrofuran derivatives (tetrahydrofurans) (five) double tetrahydrofuran class (furofurans), (6) cyclohexyl biphenyl octene class (dibenzocyclooctenes), (7) benzofuran class (benzofurans), (8) double-octane class (bicyclo[3, 2, 1] octanes), (9) benzene a pair of horses going side by side dioxane class, (10) spiral shell diene ketone (spirodienones), (11) biphenyl class (biphenylenes), (12) sesquilignan (sesquilignans) and two lignanoids (dilignans).Arylnaphthalene class also comprises aryl dihydro-naphthalene class and tetrahydrochysene arylnaphthalene class, and wherein aryl dihydro-naphthalene class has following structure.
People (Chawl AS, Sharma AK, Handa SS, the et al.A lignan from Vitex negundo seeds.Phytochemistry.1992 such as Chawl AS; 31:4378-4379.) from five-leaved chaste tree seed, extract and obtain a compound with following structure, wherein R is H or Ac.But extraction and the structure of this compound are only disclosed.
People (the Masateru Ono such as Masateru Ono, Yoichiro Nishida, Chikako Masuoka, et al.Lignan derivatives and a norditerpene from the seeds of vitex negundo.Journal of Natural Product, 2004,67:2073-2075) from Fructus Viticis Negundo, separate and obtain 7 Lignanoids compounds, wherein 2 is aryl dihydronaphthalene compounds, following (IV) formula of its structure.In the document, disclose extraction and the structure of compound, and carried out the research of antioxidant activity.Toru Yamasaki equals 2008 (Toru Yamasaki, Tetsuro Kawabata, Chikako Masuoka, et al.Two new lignan glucosides from the fruit of Vitex cannabifolia.Journal of Natural Medicine.2008,62:47 – 51) from Herba Viticis Cannabifoliae, separate and obtain 2 new lignanoids containing following structure parent nucleus, wherein 3 methylols become glycosides with glucose, and this compounds have been carried out to the antioxidant activity test of scavenging ability of DPPH free radical.
Rhizoma Dysosmae Versipellis class in known lignanoid (aryl-tetralin lactone lignanoid) has anti-tumor activity.For example European patent application EP 0711767 discloses the compound of following structure.
Wherein, Ar is 3,4,5-tri-alkoxy phenyl, or 4-hydroxyl-3,5-dialkoxy phenyl; X is oxygen, sulfur or nitrogen-atoms, or thiazolinyl (as=CH-) or alkynyl (as ≡ CH-); Y is amino, virtue amino, acyl group, carboxyl, alkoxy carbonyl group, the aryloxy carbonyl of hydrogen atom or alkyl, thiazolinyl, cycloalkyl, aryl, hydroxyl, alkoxyl, amino, monoalkyl substituted-amino, two alkyl-substituted amino, cycloalkyl substituted.Dotted line indicates that a pair of key is at 7,8 or 8,8 '.
The people such as Li Yanlan (Li Yanlan, Ceng Guang Yao, Zhou Meichen etc. Fructus Viticis Negundo chemical constitution study. Central-South pharmacy .2009,7:24-26) from Fructus Viticis Negundo, separate and obtain lactams a pair of horses going side by side arylnaphthalene lignans vitedoamine A.
People (the Cheng-Jian Zheng such as Cheng-Jian Zheng, Bao-Kang Huang, Ting Han, et al.Nitric oxide scavenging lignans from Vitex negundo seeds.Journal of Natural Product.2009,72:1627 – 1630) from Fructus Viticis Negundo, separate and obtain 10 Lignanoids compounds, wherein 2 is aryl dihydronaphthalene compounds, its structure as shown in the formula.In the document, disclose extraction and the structure of compound, and carried out the research of the inhibition activity that NO is generated.
Known aryl di-hydrogen naphthalene lignans has antitumor lives, Chinese patent CN201010181364.6, and CN200680001483.0 has obtained the purposes mandate with prophylaxis of tumours medicine for the preparation for the treatment of of aryl dihydronaphthalene class.
Chinese patent 201010185760.6 discloses this compounds and has had the purposes of preparing control or treatment cyclomastopathy.
Aryl dihydro-naphthalene lignans compounds as VBE-1 etc. be the active substance extracting from Chinese medicine Fructus Viticis Negundo, VBE-1 chemistry 6-hydroxyl-4-(4-hydroxy 3-methoxybenzene base by name) 3-methylol-7-methoxyl group-3,4-dihydro (3R, 4S)-2-aldehyde radical naphthalene.Research shows, this compounds is the activity of the rate-limiting enzyme tryrosinase in check melanin biosynthesis effectively, and effect is better than conventional tyrosinase inhibitor kojic acid, therefore, this compounds is expected to make a kind of Pigmented novel tyrosinase inhibitor that reduces.
And aryl dihydro-naphthalene lignans poorly water-soluble, oral absorption is few, easily metabolism, metabolite non-activity, and the metabolism inactivation of local topical after can avoiding being administered systemically.Therefore, need to be prepared into a kind of external preparation, make it be easy to use on skin, can enter and be trapped in skin, be suppressed the tryrosinase in epiderm skin basal layer melanocyte, be reduced cutaneous pigmentation.
Conventional external preparation has ointment, gel, liniment etc.Because gel has water solublity feature, after topical, surface skin absorbs good, and meanwhile, after water-soluable gel administration, the not sticky medicated clothing of the medicine of skin surface, also makes patient take like a shot.Therefore VBE-1 being made to gel may be good selection.
Summary of the invention
The defect the object of the invention is to for overcoming prior art provides gel of a kind of minimizing cutaneous pigmentation containing aryl dihydro-naphthalene lignans compound and preparation method thereof.
The gel of minimizing cutaneous pigmentation of the present invention is a kind of semifluid gel external preparation of yellow transparent, can effectively reduce melanic generation in skin after ultraviolet radiation.
For achieving the above object, the present invention is by the following technical solutions:
Reduce a gel for cutaneous pigmentation, made by the component that comprises following weight percentage:
Described gel-type vehicle is selected from one or more in hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, hyaluronic acid, polyvinyl alcohol, sodium alginate, hyaluronic acid sodium or methylcellulose, is preferably hydroxypropyl methylcellulose.
Described antiseptic is selected from one or more in ethyl hydroxybenzoate, ethyl hydroxybenzoate, sodium benzoate, benzalkonium bromide, chlorobutanol or sorbic acid.
Described wetting agent is selected from propylene glycol or glycerol.
Described alcoholic solvent is PEG-4000 or propylene glycol.
Described aryl dihydro-naphthalene lignans, has following mother nucleus structure:
Wherein, X is H, hydroxyl (OH), alkylamino, alkoxyl, amino or alkyl;
R1, R2 are selected from H, alkyl, thiazolinyl, glucosyl group, glucal acidic group, acyl group or aryl; Alkyl substituent involved in the present invention refers to the alkyl with 1-6 carbon number of straight or branched, preferably 1-4 carbon atom, more preferably straight chained alkyl.
R3 is hydrogen atom, glucosyl group or aryl;
R4 is methoxyl group or hydrogen atom;
R5 is methoxyl group or hydrogen atom;
In parent nucleus, three and four s' hydrogen is (3R, 4S).
Described aryl dihydro-naphthalene lignans, can be for having the single compound of above-claimed cpd structure, can also be for having the compositions of more than two and two compound of said structure and the natural drug extract take above-claimed cpd as main component.
It is >10% that above-mentioned natural drug extract refers to aryl dihydro-naphthalene compounds component content.
In the present invention, propylene glycol has the effect of solubilising and moisturizing, therefore can be used as wetting agent and also can be used as alcoholic solvent.
A preparation method for the gel of above-mentioned minimizing cutaneous pigmentation, comprises the following steps:
(1) take by said ratio the gel-type vehicle that percentage by weight is 1.5-3%, add 5-20% wetting agent and be uniformly dispersed, then add water and the antiseptic of 0.1-1% swelling the spending the night that stir, obtain substrate A;
Separately take the aryl dihydro-naphthalene lignans compound of 0.1-5%, add the alcoholic solvent of 10-30%, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Aryl dihydro-naphthalene lignans compound poorly water-soluble, its suspension in vitro in transdermal penetration test skin infiltration time lag long, skin hold-up is little.Medicine is made to solution and can obviously change percutaneous penetration of drugs behavior.Inventor confirms through experiment, adds alcoholic solvent that aryl dihydro-naphthalene lignans compound is dissolved completely, can effectively shorten skin infiltration time lag, increases skin hold-up.Therefore be fixedly good selection by solution with gel-type vehicle.
In research process, also investigated the impact on the in-vitro percutaneous permeability behavior of aryl dihydro-naphthalene lignans compound in gel of gel-type vehicle concentration and drug loading, the aryl dihydro-naphthalene lignans compound gel appearance character making is good.
Compared with prior art, beneficial effect of the present invention:
(1) this gel preparation technology is simple, cost is low, is easy to control dosage, easy to use, is convenient to carry.
(2) the present invention has improved the water solublity of aryl dihydro-naphthalene lignans compound, makes the aryl dihydro-naphthalene lignans compound in preparation be easy to enter skin.
(3) the present invention intervenes cutaneous pigmentation for aryl dihydro-naphthalene lignans compound feasibility and rational pesticide supplying form provide experimental basis.
Accompanying drawing explanation
Fig. 1 is that embodiment of the present invention 1-4 prepares gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD).
Fig. 2 is that embodiment of the present invention 1-4 prepares the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD).
Fig. 3 is that embodiment of the present invention 5-7 prepares gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD).
Fig. 4 is that embodiment of the present invention 5-7 prepares the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD).
Fig. 5 is that the embodiment of the present invention 8,9 is prepared gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD).
Fig. 6 is that the embodiment of the present invention 8,9 is prepared the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD).
Fig. 7 is external unit are skin accumulative total infiltration capacity-time graph (n=5, mean ± SD) that embodiment of the present invention 10-13 prepares VBE-1 and VBE-2 total amount in gel.
Fig. 8 is the external 24h unit mass skin accumulative total hold-up (n=5, mean ± SD) that embodiment of the present invention 10-13 prepares VBE-1 and VBE-2 total amount in gel.
Fig. 9 is external unit are skin accumulative total infiltration capacity-time graph (n=5, mean ± SD) that embodiment of the present invention 14-16 prepares VBE-1 and VBE-2 total amount in gel.
Figure 10 is the external 24h unit mass skin accumulative total hold-up (n=5, mean ± SD) that embodiment of the present invention 14-16 prepares VBE-1 and VBE-2 total amount in gel.
The specific embodiment
Below in conjunction with accompanying drawing illustrated embodiment, the present invention is further illustrated.
Embodiment 1
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-10.5g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 20g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 67.5% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% VBE-1, add 20% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-10.5g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 2g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 20g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 2% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 67% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% VBE-1, add 20% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 3
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-10.5g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 2.5g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 20g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 2.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 66.5% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% VBE-1, add 20% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 4
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-10.5g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 3g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 20g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 3% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 66% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% VBE-1, add 20% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-10.5g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 62.5% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 6
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-11g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 62% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 1% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 7
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-12g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 0.5g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61% water and 0.5% swelling the spending the night that stir, obtain substrate A;
Separately take 2% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-11g by the component that comprises following weight percentage, gel-type vehicle carbomer 934 1.5g, antiseptic ethyl hydroxybenzoate 0.1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 62.4% water and 0.1% swelling the spending the night that stir, adjust pH to 7 with triethanolamine, obtain substrate A;
Separately take 1% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel (claiming again carbomer 934 gel) of cutaneous pigmentation.
Embodiment 9
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-11g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 3g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 3% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 60% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Reduce a gel for cutaneous pigmentation, make (by 100g): VBE-21g by the component that comprises following weight percentage, gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61.5% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1% VBE-1, add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 11
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: mixture 1.5g(is containing VBE-11g, VBE-20.5g), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1.5% mixture (containing VBE-11g, VBE-20.5g), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: mixture 1.5g(is containing VBE-10.75g, VBE-20.75g), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1.5% mixture (containing VBE-10.75g, VBE-20.75g), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 13
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: mixture 1.5g(is containing VBE-10.5g, VBE-21g), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1.5% mixture (containing VBE-10.5g, VBE-21g), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: the 1.5g(VBE-1+VBE-2 of Fructus Viticis Negundo lignanoid accounts for total amount 10%), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 61% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 1.5% Fructus Viticis Negundo lignanoid (VBE-1+VBE-2 accounts for total amount 10%), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: the 0.5g(VBE-1+VBE-2 of Fructus Viticis Negundo lignanoid accounts for total amount 30%), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 62% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 0.5% Fructus Viticis Negundo lignanoid (VBE-1+VBE-2 accounts for total amount 30%), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
Embodiment 16
A kind of gel that reduces cutaneous pigmentation, make (by 100g) by the component that comprises following weight percentage: the 0.3g(VBE-1+VBE-2 of Fructus Viticis Negundo lignanoid accounts for total amount 50%), gel-type vehicle hydroxypropyl methylcellulose 1.5g, preservative sodium benzoate 1g, wetting agent glycerol 10g, alcoholic solvent PEG-4000 25g, surplus is distilled water.Its preparation method is
(1) taking percentage by weight is 1.5% gel-type vehicle, add 10% wetting agent and be uniformly dispersed, then the antiseptic that adds 62.2% water and 1% swelling the spending the night that stir, obtain substrate A;
Separately take 0.3% Fructus Viticis Negundo lignanoid (VBE-1+VBE-2 accounts for total amount 50%), add 25% alcoholic solvent, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
The outer transdermal penetration test of gelinite
(1) in-vitro percutaneous permeability test scheme
The suckling pig skin of handling well is fixed on improved Franz diffusing cells method, and stratum corneum side, towards supply pool, adds about 2ml receiving liquid.The 0.2g gel that just prepared by embodiment 1-9 is evenly applied in respectively on skin, reception tank is placed in (37 scholar 1) ℃ water bath with thermostatic control, magnetic agitation rotor speed is 200rpm, respectively at 1,2,4,8,12,24h timing exhausts receiving liquid, and the receiving liquid of supplementary equivalent equality of temperature.Receiving liquid sample is in 4 ℃ of Refrigerator stores.Receiving liquid is in 0.45 μ m water system filtering with microporous membrane, and sample analysis, measures receiving liquid Chinese medicine concentration.
Skin after transdermal penetration has been tested takes off, and wipes skin surface left drug off, rinses horny layer and corium aspect (5mL/ time) respectively by the blank receiving liquid of 15mL, and filter paper blots skin surface moisture, precise weighing.Operating scissors shreds skin and is transferred in 5ml volumetric flask, adds methanol constant volume to scale, ultrasonic 30min, be cooled to room temperature after methanol constant volume to scale, obtain skin extraction liquid.Get said extracted liquid, the centrifugal 10min of 13500rpm, sample introduction analysis, the hold-up of unit of account quality skin.
(2) transdermal penetration calculation of parameter unit are skin accumulation infiltration capacity (μ g/cm
2), be calculated as follows
In formula, Q is unit are skin accumulation infiltration capacity in the t time; Cn and Ci are respectively the n time and the concentration of receiving liquid when n-1 sub-sampling; V is the cumulative volume (2mL) of receiving liquid; A is effective diffusion area (0.785cm
2)
Unit mass skin accumulation percutaneous hold-up (μ g/g), is calculated as follows
Q in formula
skinfor unit mass skin accumulation percutaneous hold-up in the t time; C is skin Chinese medicine concentration; V is the volume of skin samples solution; M is the quality of skin.
(3) result is as shown in Fig. 1-6.
External unit are skin accumulative total infiltration capacity-time graph result of the gel that wherein, embodiment 1-16 makes is as shown in Fig. 1,3,5,7,9.
Fig. 1 is that embodiment of the present invention 1-4 prepares gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD); Along with the rising of gel-type vehicle consumption, the unit are skin accumulative total infiltration capacity of VBE-1 has the trend reducing;
Fig. 3 is that embodiment of the present invention 5-7 prepares gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD); Drug loading is within the scope of 0.5%-2%, and the 24h unit are skin accumulation infiltration capacity of VBE-1 gel is drug loading dependency;
Fig. 5 is that the embodiment of the present invention 8,9 is prepared gelinite other unit area skin accumulative total infiltration capacity-time graph (n=5, mean ± SD).In the essentially identical situation of gel consistency, in carbomer 934 gel, the 24h unit are skin of VBE-1 accumulative total infiltration capacity is higher than hydroxypropyl methylcellulose gel.
Fig. 7 is external unit are skin accumulative total infiltration capacity-time graph (n=5, mean ± SD) that embodiment of the present invention 10-13 prepares VBE-1 and VBE-2 total amount in gel; The ratio of VBE-1 and VBE-2 does not have a significant effect to the unit are skin accumulative total infiltration capacity of VBE-1 and VBE-2 total amount;
Fig. 9 is external unit are skin accumulative total infiltration capacity-time graph (n=5, mean ± SD) that embodiment of the present invention 14-16 prepares VBE-1 and VBE-2 total amount in gel; Along with the rising of VBE-1+VBE-2 ratio, the unit are skin accumulative total infiltration capacity of VBE-1 and VBE-2 total amount has the trend of increase;
The result of the outer 24h unit mass skin accumulative total of the gelinite hold-up that embodiment 1-16 makes is as shown in Fig. 2,4,6,8,10.
Fig. 2 is that embodiment of the present invention 1-4 prepares the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD); Along with the rising of gel-type vehicle consumption, the unit mass skin hold-up of VBE-1 has the trend reducing;
Fig. 4 is that embodiment of the present invention 5-7 prepares the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD); Drug loading is within the scope of 0.5%-2%, and the unit mass skin hold-up of VBE-1 gel is drug loading dependency;
Fig. 6 is that the embodiment of the present invention 8,9 is prepared the outer 24h unit mass skin accumulative total hold-up of gelinite (n=5, mean ± SD); In the essentially identical situation of gel consistency, in carbomer 934 gel, the unit mass skin hold-up of VBE-1 is higher than hydroxypropyl methylcellulose gel.
Fig. 8 is the external 24h unit mass skin accumulative total hold-up (n=5, mean ± SD) that embodiment of the present invention 10-13 prepares VBE-1 and VBE-2 total amount in gel; The ratio of VBE-1 and VBE-2 does not have a significant effect to the unit mass skin hold-up of VBE-1 and VBE-2 total amount;
Figure 10 is the external 24h unit mass skin accumulative total hold-up (n=5, mean ± SD) that embodiment of the present invention 14-16 prepares VBE-1 and VBE-2 total amount in gel; Along with the rising of VBE-1+VBE-2 ratio, the unit mass skin hold-up of VBE-1 and VBE-2 total amount has the trend of increase.
It is good that embodiment of the present invention 1-4 makes VBE-1 gel appearance character, is faint yellow, and denseness increases along with the rising of HPMC concentration, and the infiltration capacity of medicine and hold-up reduce along with the rising of HPMC concentration.Drug osmotic amount and the hold-up of embodiment 5-6 present dose dependent.
The intervention of gel to cutaneous pigmentation
(1) experimental program
The depilation of brown color guinea pig back, back is divided into six isolated regions, after anesthesia, fixes with rat plate.5 districts of guinea pig back use respectively 0.5%, 1% and 2% VBE-1 gel (embodiment 5,6,7), 2% hydroquinone cream and blank gel-type vehicle, and remaining Yi Ge district does not deal with, and only carries out UVB irradiation.After administration 10min, UVB irradiation is carried out in six isolated regions, single dose is 1200mJ/cm
2.Process 7 days continuously according to above method, within the 8th day, start to stop UVB and irradiate, continue administration, in biopsy assessment in the 14th day.Experimental session records guinea pig skin reaction.
(2) evaluation methodology
Melanin dyeing
Under high power lens, contain melanin granule cell number with every square millimeter of stratum basale of the blind method every part of specimen of counting of net form eyepiece micrometer list.The random 1 place's epidermis of selecting of each light microscopy specimen, mensuration melanin granule area accounts for the percentage ratio of the cell gross area, averages and calculates melanin content index (MCI).
(3) result
Cavia porcellus external hydroquinone position starts to occur erythema in second day, uses blank substrate position and only carry out UVB irradiated site within the 3rd day, to start to occur erythema, about the 7th day, peaks, and uses VBE-1 gel position not occur obvious erythema.The 7th day to the 10th day is guinea pig skin desquamation peak period, and main desquamation position is external hydroquinone, blank substrate position and only carries out UVB irradiated site.Within 8-14 days, cutaneous pigmentation is deepened gradually, and use 1% and 2%VBE-1 gel position pigmentation degree are starkly lower than only carries out UVB irradiated site (in table 1).
The present invention lays the foundation the exploitation of intervening cutaneous pigmentation as externals such as VBE-1 for aryl dihydro-naphthalene lignans compound.
Table 1 external different pharmaceutical guinea pig skin containing melanin granule cell number (n=10, mean ± SD)
| ? | Containing melanin granule cell number/mm 2 |
| UVB | 2542±113 |
| Blank gel-type vehicle | 2326±103 |
| Hydroquinone | 1750±95** |
| 0.5%VBE-1 gel (embodiment 5) | 2231±75 |
| 1%VBE-1 gel (embodiment 6) | 1931±106* |
| 2%VBE-1 gel (embodiment 7) | 1449±128** |
Note: * P ﹤ 0.05, * * P ﹤ 0.01v.sUVB group
The melanin content index (n=10, mean ± SD) of table 2 external different pharmaceutical guinea pig skin
| ? | MCI（%） |
| UVB | 42.17±2.63 |
| Blank gel-type vehicle | 39.43±1.38 |
| Hydroquinone | 19.33±1.05** |
| 0.5%VBE-1 gel (embodiment 5) | 36.30±1.66 |
| 1%VBE-1 gel (embodiment 6) | 27.65±1.20* |
| 2%VBE-1 gel (embodiment 7) | 18.29±1.09** |
Note: * P ﹤ 0.05, * * P ﹤ 0.01v.sUVB group
Contain the calm situation that melanin granule cell number and two indexs of melanin content index can reflect skin pigment, the larger expression pigmentation of its numerical value is more.
The melanin granule cell number that contains of hydroquinone and 2%VBE-1 gel group is starkly lower than UVB matched group (P < 0.01), and the melanin recruitment of 1%VBE-1 gel group also has notable difference (P < 0.05) with UVB matched group.The melanin content index of hydroquinone and 2%VBE-1 gel group is starkly lower than UVB matched group (P < 0.01), and the melanin content index of 1%VBE-1 gel group also has notable difference (P < 0.05) with UVB matched group.Illustrate that 1% and 2% VBE-1 gel can significantly reduce pigmentation.
MCI represents melanin content index (melanin content index)
The above-mentioned description to embodiment is can understand and apply the invention for ease of those skilled in the art.Person skilled in the art obviously can easily make various modifications to these embodiment, and General Principle described herein is applied in other embodiment and needn't passes through performing creative labour.Therefore, the invention is not restricted to the embodiment here, those skilled in the art are according to announcement of the present invention, and not departing from the improvement that category of the present invention makes and revise all should be within protection scope of the present invention.
Claims (10)
1. a gel that reduces cutaneous pigmentation, is characterized in that: be made up of the component that comprises following weight percentage:
2. the gel of minimizing cutaneous pigmentation according to claim 1, is characterized in that: described gel-type vehicle is selected from one or more in hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbomer, hyaluronic acid, polyvinyl alcohol, sodium alginate, hyaluronic acid sodium or methylcellulose.
3. the gel of minimizing cutaneous pigmentation according to claim 1, is characterized in that: described antiseptic is selected from one or more in ethyl hydroxybenzoate, ethyl hydroxybenzoate, sodium benzoate, benzalkonium bromide, chlorobutanol or sorbic acid.
4. the gel of minimizing cutaneous pigmentation according to claim 1, is characterized in that: described wetting agent is selected from propylene glycol or glycerol.
5. the gel of minimizing cutaneous pigmentation according to claim 1, is characterized in that: described alcoholic solvent is PEG-4000 or propylene glycol.
6. the gel of minimizing cutaneous pigmentation according to claim 1, is characterized in that: described aryl dihydro-naphthalene lignans has mother nucleus structure as the formula (1):
Wherein, X is H, hydroxyl, alkylamino, alkoxyl, amino or alkyl; Preferably, described alkyl substituent is the alkyl with 1-6 carbon number that refers to straight or branched, and further preferred alkyl substituent group is to refer to that straight or branched has the alkyl of 1-4 carbon atom, more preferably straight chained alkyl;
R1, R2 are selected from H, alkyl, thiazolinyl, glucosyl group, glucal acidic group, acyl group or aryl;
R3 is hydrogen atom, glucosyl group or aryl;
R4 is methoxyl group or hydrogen atom;
R5 is methoxyl group or hydrogen atom;
In parent nucleus, three and four s' hydrogen is (3R, 4S).
7. according to the gel of the minimizing cutaneous pigmentation described in claim 1 or 6, it is characterized in that: described aryl dihydro-naphthalene lignans is selected from 6-hydroxyl-4-(4-hydroxy 3-methoxybenzene base) 3-methylol-7-methoxyl group-3, 4-dihydro (3R, 4S)-2-aldehyde radical naphthalene (VBE-1), 6-hydroxyl-4-(4-hydroxy 3-methoxybenzene base)-3-methylol-5-methoxyl group-3, 4-dihydro (3R, 4S)-2-aldehyde radical naphthalene (VBE-2), 6, 7-dimethoxy-4 '-(3, 4-Dimethoxyphenyl) 3-methylol-3, 4-dihydro (3R, 4S)-2-aldehyde radical naphthalene, 6-hydroxyl-4-(4-hydroxy 3-methoxybenzene base) 3-glucose yloxymethyl-7-methoxyl group-3, 4-dihydro (3R, 4S)-2-aldehyde radical naphthalene, 2, 6-dihydroxy-7-methoxyl group-4-(3, 4-dihydroxy phenyl)-3-methylol-7-3, 4-dihydro (3R, 4S) one or more in naphthalene.
8. the gel of minimizing cutaneous pigmentation according to claim 6, is characterized in that: described aryl dihydro-naphthalene lignans compound is the extract of the natural drug take aryl dihydro-naphthalene compounds as main component.
9. the gel of minimizing cutaneous pigmentation according to claim 6, is characterized in that: in described natural drug extract, the weight percentage of aryl dihydro-naphthalene lignans is >10%.
10. a preparation method for the gel of arbitrary described minimizing cutaneous pigmentation in claim 1-9, is characterized in that: comprise the following steps:
(1) take by proportioning claimed in claim 1 the gel-type vehicle that percentage by weight is 1.5-3%, add 5-20% wetting agent and be uniformly dispersed, then add water and the antiseptic of 0.1-1% swelling the spending the night that stir, obtain substrate A;
Separately take the aryl dihydro-naphthalene lignans of 0.1-5%, add the alcoholic solvent of 10-30%, Ultrasonic Heating dissolves, and obtains solution B;
(2) solution B is added in substrate A, stir, must reduce the gel of cutaneous pigmentation.
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| CN101138560A (en) * | 2007-08-17 | 2008-03-12 | 深圳海创医药科技发展有限公司 | Nitrofuran gelling agent and method of preparing the same |
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| CN101138560A (en) * | 2007-08-17 | 2008-03-12 | 深圳海创医药科技发展有限公司 | Nitrofuran gelling agent and method of preparing the same |
Non-Patent Citations (1)
| Title |
|---|
| AZHAR-UL-HAQ ET AL.: ""Tyrosinase inhibitory lignans from the methanol extract of the roots of Vitex negundo Linn. and their structure–activity relationship"", 《PHYTOMEDICINE》, vol. 13, no. 4, 13 March 2006 (2006-03-13), pages 255 - 260, XP028022123, DOI: 10.1016/j.phymed.2004.09.001 * |
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