CN100548287C - Transdermal absorption formulation - Google Patents
Transdermal absorption formulation Download PDFInfo
- Publication number
- CN100548287C CN100548287C CNB2004100106939A CN200410010693A CN100548287C CN 100548287 C CN100548287 C CN 100548287C CN B2004100106939 A CNB2004100106939 A CN B2004100106939A CN 200410010693 A CN200410010693 A CN 200410010693A CN 100548287 C CN100548287 C CN 100548287C
- Authority
- CN
- China
- Prior art keywords
- acrylic copolymer
- acid
- preparation
- fatty acid
- adhesive phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title description 8
- 238000010521 absorption reaction Methods 0.000 title description 7
- 238000009472 formulation Methods 0.000 title description 3
- -1 fatty acid ester Chemical class 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 239000000853 adhesive Substances 0.000 claims abstract description 42
- 230000001070 adhesive effect Effects 0.000 claims abstract description 42
- 229920006243 acrylic copolymer Polymers 0.000 claims abstract description 37
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 28
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- 229930195729 fatty acid Natural products 0.000 claims abstract description 28
- YWPABLWXCWUIIT-UHFFFAOYSA-N 2-(2-phenylphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1C1=CC=CC=C1 YWPABLWXCWUIIT-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960000192 felbinac Drugs 0.000 claims abstract description 23
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- SEZLYIWMVRUIKT-UHFFFAOYSA-N isopiperitenone Natural products CC(=C)C1CCC(C)=CC1=O SEZLYIWMVRUIKT-UHFFFAOYSA-N 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000009740 moulding (composite fabrication) Methods 0.000 description 1
- YRVUCYWJQFRCOB-UHFFFAOYSA-N n-butylprop-2-enamide Chemical compound CCCCNC(=O)C=C YRVUCYWJQFRCOB-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 150000004831 organic oxygen compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical class [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920001568 phenolic resin Polymers 0.000 description 1
- 239000005011 phenolic resin Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229950000845 politef Drugs 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001228 polyisocyanate Polymers 0.000 description 1
- 239000005056 polyisocyanate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a kind of Percutaneously administrable preparation, wherein contain acrylic copolymer in the adhesive phase and/or contain the fatty acid ester that mixes with this acrylic copolymer, and contain biphenylacetic acid or its salt, also can contain thin He alcohol as required, and the preparation that at least one face of supporting material, forms.Said preparation makes the percutaneous absorbability of biphenylacetic acid good, and makes lasting medicine.Low to skin irritation, and adhering skin is good.
Description
Technical field
The present invention relates to contain biphenylacetic acid or its salt, serially the preparation of transdermal administration in human body.
Technical background
Biphenylacetic acid is very strong anti-inflammatory analgesic, but because it is not suitable for oral administration, so a lot of researchs about Percutaneously administrable preparation are arranged.Hydrogel adhesive, liquid varnish and cataplasma etc. that this medicine is just arranged abroad.But hydrogel adhesive, liquid varnish have a lot of shortcomings, as being difficult to its dosed administration of control, bioavailability low and use in to pollute clothes, one day administration number of times many etc.Therefore for to address these problems the cataplasma that the someone has developed this medicine, can not keep long-time stickup but its bonding force is weak and cause to bring into play fully the persistence of its drug effect.
Recent years, patent is also arranged about being substrate, and contain the Percutaneously administrable preparation of biphenylacetic acid with polystyrene-isobutyl diene-polystyrene block copolymer.Open flat 4-321624 communique and international publication number sign indicating number WO98/24423 communique as the spy.But because that polystyrene-isobutyl diene-polystyrene block copolymer presents is very strong nonpolar, this medicine is crossed and is lowly made its transdermal limited speed owing to dissolubility in this substrate, and can not reach long-time persistent purpose.
Summary of the invention
The technical problem to be solved in the present invention is to disclose a kind of biphenylacetic acid Percutaneously administrable preparation with high Transdermal absorption energy.By being the substrate of Percutaneously administrable preparation, can successfully dissolve this medicine, and keep long-time persistence drug effect with acrylic copolymer.Particularly, make the adhering skin that adhesive phase is soft and maintenance is fit to, can reduce the zest of skin by containing fatty acid ester.In addition, contain fatty acid ester, thereby reach lucky cohesive and flexibility by the crosslinked high concentration that realizes.
The scheme of technical solution problem of the present invention is as follows
1, a kind of by acrylic copolymer and biphenylacetic acid or its salt, and can contain the adhesive phase that approaches He alcohol as required, and the Percutaneously administrable preparation that at least one face of supporting material, forms.
2, the Percutaneously administrable preparation of record in (1), the fatty acid ester and biphenylacetic acid or its salt that wherein contain acrylic copolymer in the adhesive phase, mix with this acrylic copolymer, and also can contain the adhesive phase that approaches He alcohol as required, and the Percutaneously administrable preparation that at least one face of supporting material, forms.
3, the Percutaneously administrable preparation of record in (2), the weight ratio that wherein contains acrylic copolymer and fatty acid ester in the adhesive phase is 1: 0.1～1: 0.5.
4, the Percutaneously administrable preparation of record in (2), the weight ratio that wherein contains acrylic copolymer and fatty acid ester in the adhesive phase is 1: 0.2～1: 2, and this acrylic copolymer takes place crosslinked.
5, Percutaneously administrable preparation of record in (4), wherein crosslinked is alkoxide from titaniferous or aluminum, and selects at least a cross-linking agent to carry out in the isocyanates of trifunctional.
The supporting material that Percutaneously administrable preparation of the present invention is used is not particularly limited.But biphenylacetic acid that contains in the adhesive phase and fatty acid ester can not cause content and reduce that the material that does not promptly see through these compositions is preferred thoroughly to the supporting material back side.
Specifically can select polyester such as poly terephthalic acid diol ester; Polyamine such as nylon; Polyolefin such as polyethylene and polypropylene; The monofilm of metal formings such as polrvinyl chloride, plasticity polrvinyl chloride, plasticity vinyl acetate-chloride copolymer, Vingon, ethylene-vinyl acetate copolymer, cellulose acetate, ethyl cellulose, ethylene-ethyl acrylate copolymer, politef, polyurethane, ionic cross-linked polymer resin and aluminium foil etc. or their laminated film etc.For example can enumerate paper, weave cotton cloth, the film of non-woven fabrics, machine drilling etc., particularly paper, weave cotton cloth, non-woven fabrics is preferred.
Percutaneously administrable preparation of the present invention is to form following adhesive phase at least on a face of above-mentioned supporting material.This adhesive phase contains acrylic copolymer and biphenylacetic acid.
Though the content of biphenylacetic acid can be according to suitably design such as administration purpose in the bonding agent layer, contain 0.3～15 weight % in the common adhesive phase, preferably contain 0.5～10 weight %.If content is lower than 0.3 weight %,, when content is higher than 15 weight %, can cause unnecessary waste and uneconomical because of the effective dose that can not discharge treatment is not suitable for.
The used acrylic copolymer of the present invention copolymer that to be the alkyl carbon atoms number obtain for the main constituent copolymerization greater than 4 alkyl acrylate and/or alkyl methacrylate (following also alkyl acrylate and/or alkyl methacrylate are called (methyl) alkyl acrylate).
As (methyl) alkyl acrylate, wherein alkyl can concrete example enumerate have butyl, carbon number such as amyl group, hexyl, heptyl, octyl group, nonyl, certain herbaceous plants with big flowers base, undecyl or dodecyl is 4～12 straight chained alkyl or (methyl) alkyl acrylate of branched alkyl, can use a kind of in them also can be more than two kinds.
As with the monomer of above-mentioned (methyl) alkyl acrylate copolymer, can use the monomer that functional group is arranged on the side chain of (methyl) acrylate of containing following groups etc., for example, (methyl) acrylic acid, clothing enanthic acid, maleic acid etc. contain carboxylic monomer; Styrene sulfonic acid, acrylic sulfonic acid, sulfopropyl (methyl) acrylate, (methyl) acryloyl oxidation LOMAR PWA EINECS 246-676-2, acrylamide methyl propane sulfonic acid etc. contain the sulfonyloxy monomer; The monomer of hydroxyls such as (methyl) 2-(Acryloyloxy)ethanol, (methyl) Hydroxypropyl acrylate; Amide-containing monomers such as (methyl) acrylamide, dimethyl (methyl) acrylamide, N-butyl acrylamide, N hydroxymethyl acrylamide, N-hydroxymethyl-propane (methyl) acrylamide; (methyl) acrylic-amino ethyl ester, (methyl) acrylic acid dimethylamino ethyl ester, (methyl) acrylic acid tert-butylamine base ethyl ester etc. contain the monomer of aminoalkyl; (methyl) alkoxyalkyl acrylates such as (methyl) acrylic acid methoxyl group ethyl ester, (methyl) acrylic acid ethoxy ethyl ester; Alkoxyls (or side chain has ehter bond) such as (methyl) acrylic acid tetrahydro furfuryl ester, (methyl) acrylic acid methoxyl group glycol ester, the fluorine-based binaryglycol ester of (methyl) acrylic acid first, (methyl) acrylic acid methoxy poly (ethylene glycol) ester, (methyl) acrylic acid MPEG 2-methoxy-propane-1,3-diol. ester etc.And, except that above-mentioned monomer, as other comonomer, for example, vinyl monomers such as (methyl) acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-Pyrrolidone, vinylpyridine, vinyl piperitenone, vinyl pyrimidine, vinyl piperazine, vinylpyrazine, vinyl pyrrole, vinyl imidazole, caprolactam, vinyl oxazole, vinyl morpholine.These monomers can be with a kind of, also can be with combined polymerization more than two kinds.Cross-linking reaction consideration from bonding force and the cohesiveness and the binding agent of binding agent, preferably containing the monomer of carboxyl and contain in the monomer of carboxyl at least a conduct must composition, and it is preferred carrying out copolymerization with above-named other comonomers as required.
For the cohesiveness of regulating adhesive phase and the dissolubility of biphenylacetic acid, also can select other comonomers beyond (methyl) alkyl acrylate.The copolymerization amount of these other comonomers can be set arbitrarily according to purpose, but usually in order to prepare the acrylic compounds copolymer, it is all accounting for 2～50 weight % in the monomer, preferably 3～40 weight %.
With above-mentioned (methyl) alkyl acrylate and with the used acrylic copolymer of its comonomer copolymerization the present invention the time, can synthesize with usual way.For example, solution polymerization process, emulsion polymerization, mass polymerization and suspendible polymerization etc.
The adhesive phase that the present invention is used, acrylic copolymer preferably, and natural rubber, synthetic rubber and polysiloxanes base polymer are not preferred.Because these are unfavorable for the dissolving of biphenylacetic acid in adhesive phase.
In addition, the adhesive phase that the present invention is used further preferably contains the adhesive phase that the fatty acid ester that mixes with the aforesaid propylene acid copolymer constitutes, and can make its softness, slows down the zest to skin.The gel type binder layer that more preferably contains the fatty acid ester formation that mixes with the aforesaid propylene acid copolymer, thus, the fatty acid ester that can contain high concentration is brought into play cohesive to skin surface, softness better and is had enough cohesivenesss, thereby reduces the zest to skin.
In addition, in this gel type binder layer, it is preferred that acrylic copolymer takes place crosslinked.
The fatty acid ester that the present invention is used has the character that mixes with the aforesaid propylene acid copolymer, makes adhesive phase plasticizing, gives flexibility, can reduce adhesive phase when skin surface is peeled off and the pain and the skin irritation that cause.As long as therefore this class fatty acid ester has plastication.But in order to improve the percutaneous absorbability of biphenylacetic acid, what employing had the Transdermal absorption facilitation is preferred.As this fatty acid ester, can enumerate adipic acid esters such as diisopropyl adipate, diisobutyl adipate, Adipol 10A; Certain herbaceous plants with big flowers two esters of gallic acid such as certain herbaceous plants with big flowers two diethyl phthalates, certain herbaceous plants with big flowers diacid diisopropyl ester; Myristic acid esters such as fatty acid glyceride, isopropyl myristate, different 13 esters of myristic acid, myristic acid tetradecylic acid alkane ester; Lauric acid such as ethyl laurate, lauric acid hexyl ester esters; Oleic acid esters such as ethyl oleate, oleic acid oleic alcohol ester, oleic acid certain herbaceous plants with big flowers ester; Palmic acid esters such as isopropyl palmitate, octyl palmitate, cetyl palmitate, Palmic acid isostearate, acetates such as triethyl citrate, benzyl acetate, n-butyl acetate; Stearic acid polyoxy sorbitan fatty acid ester, methyl glycol fatty acid ester etc.These can be a kind of, also can be to be used more than two kinds.Wherein, from with aforesaid propylene acid copolymer intermiscibility and formulation preparation process be not heated and evaporable requirement is considered, carbon number is 8～18, and preferably carbon number is that 10～16 higher fatty acids and carbon number are that the fatty acid ester that 1～4 lower alcohol forms is preferred.
In containing the gel type binder layer of fatty acid ester, the weight ratio of acrylic copolymer and fatty acid ester is 1: 0.1～1: 0.5 not carrying out when crosslinked, preferably 1: 0.1～1: 0.3.Its weight ratio is 1: 0.2～1: 2 when crosslinked carrying out, preferably 1: 0.3～1: 1.
Carrying out crosslinked method as the aforesaid propylene acid copolymer can enumerate, and carries out chemical crosslinking with general polyisocyanate compounds, organic oxygen compound, organic metal salt, alkoxide, metallo-chelate and polyfunctional compound etc. as cross-linking agent and handles.
In the present invention, consider that from the reactivity and the manipulation aspect of these cross-linking agent the isocyanates of trifunctional, the alkoxide or the metallo-chelate that are made of titanium or aluminum are fit to.These cross-linking agent do not cause the tackified phenomenon of solution before coating and drying, so good operation performance.The cross-linking agent use level is to cooperating 0.01～2 weight portion in the 100 parts by weight of acrylic analog copolymers in this case, preferably 0.05～1.5 weight portion.
In the present invention, be preferred in the scope of its bonding force at 300～2000g/25mm when the speed that 180 degree directions are divided with 300mm/ on Berlet phenolic resins plate of the bonding force in the adhesive phase is peeled off, the bonding force that contains the gel type binder layer of fatty acid ester is preferred in the scope of 50～1000g/25mm.
The thickness of this adhesive phase is generally 10～200 microns, preferably 15～150 microns.
This adhesive phase also can contain thin He alcohol as required, since effects such as that thin He alcohol itself has is refrigerant, antiinflammatory, the anti-inflammatory analgesic effect that can improve this Percutaneously administrable preparation.In addition, because thin He alcohol has the Transdermal absorption facilitation, also help the Transdermal absorption of biphenylacetic acid.
This adhesive phase can also cooperate known additives such as viscosifier, other absorption enhancers, surfactant, plasticizer, filler and deterioration preventing agent as required.
To Percutaneously administrable preparation of the present invention, its preparation method is not particularly limited.For example can or be dispersed in the solvent acrylic copolymer, fatty acid ester, biphenylacetic acid dissolving, at least one face of supporting material, drying forms adhesive phase on the supporting material surface the solution coat that obtains.In addition, on stripping film, drying forms adhesive phase on stripping film above-mentioned solution coat, adhesive phase is laminated on the supporting material to form then.
Percutaneously administrable preparation of the present invention, make, transportation or preserve, bonding in order to prevent, and prevent from the deterioration of preparation from can press stripping film at adhesive phase with adhesive phase with useless utensil and container etc.In use stripping film is peeled off, adhesive surface is attached to administration on the skin.
As stripping film,, and be not particularly limited as long as can peel off from adhesive phase easily in use.For example, with the contact surface of adhesive phase on handle or with films such as polyester, polrvinyl chloride, Vingon, poly terephthalic acid dioctyl phthalate glycol esters with polysiloxanes, or with good quality paper or cellophane and polyolefinic laminated film etc.The thickness of this stripping film is generally less than 1000 microns, preferably 30～200 microns.
The dosage of Percutaneously administrable preparation of the present invention, because of patient's age, body weight and symptom different.Usually, the adult is each with the preparation that contains 10～1000 milligrams of biphenylacetic acids, at 20～200cm
2On the skin, paste every day 1～2 time.
The specific embodiment
With embodiment the present invention is described below, but the present invention is not limited.In the record below, " part " reaches " % " and refers to parts by weight and weight % respectively.
The preparation of acrylic copolymer A
In noble gas, with 77 parts of 2-EHAs and N-ethylene and-3 parts in 20 parts of 2-Pyrrolidones and acrylic acid, copolymerization in ethyl acetate and obtain the solution of acrylic copolymer A.
The preparation of acrylic copolymer B
In noble gas, with 5 parts in 95 parts of 2-EHAs and acrylic acid, copolymerization in ethyl acetate and obtain the solution of acrylic copolymer B.
The preparation of acrylic copolymer C
In noble gas, with 45 parts of 1-Octyl acrylates, 40 parts of 2-EHAs, N-ethylene and-2 parts in 13 parts of 2-Pyrrolidones and acrylic acid, copolymerization in ethyl acetate and obtain the solution of acrylic copolymer C.
The preparation of acrylic copolymer D
In noble gas, with 5 parts in 95 parts of 1-Octyl acrylates and acrylic acid, copolymerization in ethyl acetate and obtain the solution of acrylic copolymer D.
The preparation of rubber adhesive
50 parts of polyisobutylene (VIST ANEX MML-80, viscosity-average molecular weight is 990000), 20 parts of Liquid Paraffins and alicyclic petroleum resin (ア Le コ Application P-100) be dissolved in for 30 parts obtain polyisobutylene class binder solution in the hexane.
The preparation of hydrogel adhesive
Get 2 parts of polyacrylic acid sodium salts, 5 parts of sanloses, 10 parts in gelatin, 5 parts of titanium oxides, 25 parts of glycerol, 50 parts of distilled water, 1.5 parts of methyl pyrrolidones, 1 part of biphenylacetic acid and two pyrolle alkane-2,0.5 part of 4-diketone has prepared the hydrogel adhesive patch that contains biphenylacetic acid according to note method down.Promptly earlier biphenylacetic acid is dissolved in the methyl pyrrolidone and mixes with every other composition again, and regulate pH value in the scope of 4.5-5.0, mixing.With the mixture that obtains at polyester non-woven fabric (the order amount of paying 80g/m
2) go up coating, making the thickness of adhesive phase is 1 millimeter, covers the polyester stripping film, severing becomes required size promptly to obtain the hydrogel patch of biphenylacetic acid.
As shown in table 1, embodiment 1-7 and comparative example 1-4 are according to proportioning in the table, the binder solution that obtains is coated on (75 micron thickness) on the polyester stripping film, making dried adhesive phase thickness is 60 microns (adhesive phase thickness is 1 millimeter in the comparative example 4), drying is laminated to polyester non-woven fabric (the order amount of paying 80g/m with the adhesive phase that obtains
2) side, and the Percutaneously administrable preparation that obtains.But when in embodiment 4-7 and comparative example 3, adding cross-linking agent, place 40 ℃ baking oven to heat 72 hours the Percutaneously administrable preparation that obtains, implement crosslinked.
Table 1
| Polymer (%) | Biphenylacetic acid (%) | Menthol (%) | Fatty acid ester (%) | Cross-linking agent (%) | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 | Acrylic copolymer A (79.0) acrylic copolymer B (97.0) acrylic copolymer C (79.0) acrylic copolymer D (56.7) acrylic copolymer A (43.7) acrylic copolymer B (50.5) acrylic copolymer C (58.7) | 6.0 3.0 3.0 3.0 6.0 3.0 3.0 | - - 8 - - 6 8 | IPM (15) IPM (0) IPP (10) IPM (40) IPP (50) IPM (40) IPM (30) | ---aluminum-chelate (0.3) isocyanates (0.3) isocyanates (0.5) aluminum-chelate (0.3) |
| Comparative example 1 comparative example 2 comparative examples 3 comparative examples 4 | Acrylic copolymer B (47.0) ＊Acrylic copolymer C (26.7) xRubber adhesive (98.5) hydrogel adhesive (99) | 3.0 3.0 1.5 1.0 | - - - - | IPM (50) IPP (70) - - | -aluminum-chelate (0.3)-- |
IPM: isopropyl myristate
IPP: isopropyl palmitate
*: so the adhesive layer of comparative example 2 can not paste it and uses three tests below doing because cohesiveness destroys.
x: owing to separating out, IPM loses cohesive in the comparative example 3 from adhesive layer, so three tests below also not doing.
With the Percutaneously administrable preparation of the various embodiments described above 1-7 and comparative example 3,4, carry out following transdermal test, skin irritation test and adhering skin test.
The transdermal test
With rat anesthesia, shave off belly wool, extraction skin is removed fat and is used for the transdermal test.Above-mentioned preparation is attached on the skin, and (effective area is 0.785cm to be loaded on the Franz disperser
2) in carry out the test of 24 hours transdermals.Collect the mixed liquor of liquid with PEG400 and distilled water (1: 3), be 1,3,5,7,24 hour sample time, and the drug level that sees through is quantitative with high performance liquid chromatography.
Chromatographic condition
Post: Cosmosil (4.6x150mm, Nakarai tesque system)
Mobile phase: phosphate buffer (pH 2): acetonitrile (50: 50)
Column temperature: 40 ℃
Flow velocity: 1.0ml/min
Detector: UV 240nm
As shown in table 2, the transdermal amount of sample time transdermal cumulant (meansigma methods of one group of three example, microgram/cm after administration
2) represent.
Table 2
| 1 hour | 3 hours | 5 hours | 7 hours | 24 hours | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 | 9.2 9.6 8.6 17.4 14.3 15.2 23.3 | 26.8 19.1 20.6 39.1 36.4 72.1 48.0 | 47.5 38.8 48.9 67.8 93.2 108.6 91.1 | 96.3 42.6 64.7 92.4 204.3 135.4 117.4 | 178.0 125.5 165.7 202.9 332.1 285.3 265.1 |
| Comparative example 4 comparative examples 5 | 0.3 3.3 | 2.7 7.8 | 5.4 24.6 | 12.8 38.9 | 30.8 65.3 |
The result as seen, the Percutaneously administrable preparation of embodiment 1-7 demonstrates good transdermal performance, and can be lasting.
The skin irritation test
10 of adult males have been carried out skin tests as object.Be about to the size that above-mentioned Percutaneously administrable preparation is cut into 2.5x2.5cm, every kind of preparation pastes a slice in the back, peels off paster after 24 hours, carries out perusal to pasting the position, according to following note method record skin irritation index, obtain the meansigma methods of proprietary skin irritation index summation and list in the table 3.
Skin irritation index
Non-stimulated 0
Very slight erythema 1
Very clearly erythema 2
Moderate erythema 3
The erythema and the edema 4 of height
Table 3
| Skin irritation index | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 | 0.3 0.7 0.3 0.1 0 0.2 0.2 |
| Comparative example 4 comparative examples 5 | 1.1 0 |
The result as seen, embodiment 1-7 demonstrates lower skin irritation, especially embodiment 4-7 is very low to skin irritation.
The adhering skin test
10 of adult males have been carried out the adhering skin test as object.Be about to the size that above-mentioned Percutaneously administrable preparation is cut into 2.5x2.5cm, every kind of preparation pastes a slice in the back, observes the stickup situation of paster after 24 hours, and the result is charged in the table 4.
Table 4
The result as seen, the Percutaneously administrable preparation of embodiment 1-7 has good cohesive.
The present invention makes the transdermal amount height of biphenylacetic acid, and can grow lastingly, and the cohesive of said preparation is good, and skin irritation is low.
Claims (2)
1, a kind of active component is biphenylacetic acid or its salt, the fatty acid ester that contains acrylic copolymer in the adhesive phase, mixes with this acrylic copolymer, contain thin He alcohol as required, and the Percutaneously administrable preparation that at least one face of supporting material, forms, wherein the weight ratio of acrylic copolymer and fatty acid ester is 1: 0.2～1: 2, and this acrylic copolymer takes place crosslinked, and fatty acid ester is the fatty acid ester of the higher fatty acids of 8～18 carbon numbers and the lower alcohol formation that carbon number is 1～4.
2, according to the Percutaneously administrable preparation of record in the claim 1, wherein crosslinked is alkoxide from titaniferous or aluminum, and selects at least a cross-linking agent to carry out in the isocyanates of trifunctional.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100106939A CN100548287C (en) | 2004-02-20 | 2004-02-20 | Transdermal absorption formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100106939A CN100548287C (en) | 2004-02-20 | 2004-02-20 | Transdermal absorption formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1657041A CN1657041A (en) | 2005-08-24 |
| CN100548287C true CN100548287C (en) | 2009-10-14 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100106939A Expired - Lifetime CN100548287C (en) | 2004-02-20 | 2004-02-20 | Transdermal absorption formulation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100548287C (en) |
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2004
- 2004-02-20 CN CNB2004100106939A patent/CN100548287C/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| CN1657041A (en) | 2005-08-24 |
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Effective date of registration: 20090206 Address after: 18, Baishan Hutong, Chaoyang District, Jilin, Changchun, China: 130061 Applicant after: Quan Yingshu Co-applicant after: Beijing Lingrui High-Tech. Co.,Ltd. Address before: 18, Baishan Hutong, Chaoyang District, Jilin, Changchun, China: 130061 Applicant before: Quan Yingshu |
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