CN100361652C - Gel type dexketoprofen plaster and method for preparing the same - Google Patents
Gel type dexketoprofen plaster and method for preparing the same Download PDFInfo
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- CN100361652C CN100361652C CNB2006100187225A CN200610018722A CN100361652C CN 100361652 C CN100361652 C CN 100361652C CN B2006100187225 A CNB2006100187225 A CN B2006100187225A CN 200610018722 A CN200610018722 A CN 200610018722A CN 100361652 C CN100361652 C CN 100361652C
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Abstract
The present invention discloses a gel type dextro ketoprofen patch which is made from back lining materials, gel type medicine library materials and antisticking materials. The medical gel type medicine library materials contain 0.5 to 30.0 wt% of active drug ingredients, 5.0 to 80.0 wt% of gel type medicine library materials, 0.5 to 40.0 wt% of medicant solvent, 0.5 to 30.0 wt% of humectants, and 0.5 to 8.0 wt% of accelerating agents with transdermal absorption. The gel type medicine library material comprises polyvinyl pyrrolidone with large molecular weight and low molecular weight or copolymer containing vinyl pyrrolidine units, polyvinyl alcohol, or polyvinyl alcohol and polyethylene glycol, cross linking agents and water. The present invention also provides a preparation method. The present invention has the characteristics of good biocompatibility with skins, large medicine loading quantity, good transdermal penetration effect of medicant, good ventilation and permeability, good pasting performance, suitable stripping, etc., and can satisfy clinic therapy requirements of dextro ketoprofen.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of gel type dexketoprofen plaster and preparation method thereof.
Background technology
Ketoprofen (Ketoprofen) is 2-aryl propionic non-steroid antipyretic-antalgic and anti-inflammatory drug, clinical treatment rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis etc. and acute sprain or the soft tissue contusion etc. of being mainly used in.The ketoprofen molecule has a chiral carbon atom, for a long time, this medicine general all with the form of racemic modification for clinical use.Separate discovery through optical isomer, the levo form of ketoprofen is non-activity almost, mainly be d-isomer performance antiinflammatory rheumatism and analgesia therapy effect, the antiinflammatory action of ketoprofen d-isomer is about 2 times of (Evans AM.Pharmacodynamics and pharmacokinetics of the profens:enantioselectivity of ketoprofen, clinical implications, and special reference toS (+)-ibuprofen.J.Clin.Pharmacol., 1996,36 (Suppl): S7-S15.).Dexketoprofen (Dexketoprofen) is gone on the market in Spain in 1996 first by the exploitation of Italian Menarini company.The preparation of dexketoprofen listing at present be mainly tablet or enteric coated capsule (the dexketoprofen enteric coatel tablets of producing as Hubei Allianz pharmaceutcal corporation, Ltd (and trade name: Finley), approval number: H20030967).But dexketoprofen has detrimental effect to gastrointestinal tract mucosa and causes untoward reaction such as protein minimizing, bile malabsorption, severe patient even cause gastrointestinal hemorrhage.And the dexketoprofen biological half-life is short, the medicine administration was 3-4 time in common one day, thereby gastrointestinal dysfunction (Barbanoj MJ appears in a lot of patients, Antonijoan RM, Gich I.Clinicalpharmacokinetics of dexketoprofen.Clin.Pharmacokinet., 2001,40 (4): 245-262.).Especially all kinds of arthritis patients need accept long-term treatment, thereby adverse reaction rate is higher.Therefore, be necessary to develop other route of administration except that oral.
Because the principal indication of dexketoprofen is a joint disease, even for general immunity diseases such as rheumatoid arthritiss, its symptom also mainly shows on the local joint, therefore is necessary to develop the transdermal delivery system of dexketoprofen.Transdermal delivery system (Transdermal Drug DeliverySystems) is by the skin surface administration, and medicine sees through each layer of skin with relative constant speed, enters the administering mode that the body circulation produces whole body or local therapeutic effects.Comprise: 1. by skin barrier, medicine reaches in the skin or target tissue such as skin lower floor and the process that plays a role.2. the medicine transdermal flux enters subcutaneous tissue, absorbs through blood capillary to enter the systemic blood system, is delivered to the process of site of action.Percutaneous dosing is as a kind of new route of administration, have avoid medicine in liver first pass effect and gastrointestinal stimulated, make short medicine of half-life realize the Sustainable Control administration, keep constant blood drug level or pharmacodynamics effect, strengthen therapeutic effect, the blood drug level peak valley undulatory property that oral administration produces can not occur, reduce the effects such as generation of untoward reaction.Simultaneously transdermal delivery system also has prolong drug action time, reduces the medication number of times; Characteristics such as independently medication of patient also can be ended medication at any time, and patient's medication is convenient, and compliance is good, therefore extremely people pay close attention to.
For dexketoprofen, by percutaneous dosing, at first treat the inflammation in local joint, medicine directly infiltration reaches lesions position, increases the drug level of lesions position, effectively strengthens medicine to local arthritis and treatment of pain effect; After drug transdermal enters the body circulation, the effect of performance whole body therapeutic, the gastrointestinal tract toxicity of avoiding medicine to produce, the dexketoprofen percutaneous drug administration preparation can improve the effect of diseases such as its treatment rheumatoid arthritis by transdermal administration, reduce the toxicity and the untoward reaction of medicine simultaneously, increase the compliance of patient's long-term prescription, select for all kinds of arthritics provide more excellent medication.
" containing the transdermal delivery system compositions of nonsteroidal anti-inflammatory " (publication number: CN1181931A as effective ingredient, day is disclosed: the compositions that on May 20th, 1998) discloses the transdermal delivery system that is loaded with nonsteroidal anti-inflammatory, it is characterized by one or more nonsteroidal anti-inflammatory (ketoprofens, flurbiprofen, the loxoprofen, pranoprofens etc.) be dispersed in the nonpolar sticky polymers matrix, nonpolar sticky polymers is selected from natural rubber, butyl rubber, polyisobutylene, polystyrene, polyisoprene, polybutadiene, polyethylene/butylene, polyethylene/propylene and copolymer thereof." dextro-betoprofen preparation " (publication number: CN1260172A, open day: on July 19th, 2000) disclose dextro-betoprofen preparation with the different approaches administration, comprise injection, oral liquid (as syrup etc.), enteric hard wafer, external preparation multiple dosage forms such as (as ointment and percutaneous sticking plasters etc.), wherein percutaneous sticking plaster adopts rubber or acrylic resin substrate, makes with blend such as Colophonium, vaseline, lanoline, liquid paraffin." transdermal plaster of aryl propionic non-steroid antiphlogistic " (publication number: CN1387842A, open day: on January 1st, 2003) disclose a class aryl propionic non-steroid antiphlogistic (flurbiprofen, ketoprofen, ibuprofen, Russell Lip river sweet smell and naproxen) transdermal patch, the patch that the document relates to is made up of medicine and substrate, its substrate is made up of nonpolar sticky polymers and additive, and its non-polar polymer is selected from polyisobutylene, natural rubber, butyl rubber etc. and derivant thereof." a kind of transdermal patch and preparation method " (publication number: CN1565523A, open day: on January 19th, 2005) disclose a kind of transdermal patch and preparation method thereof, it is characterized in that the pressure sensitive adhesive that is adopted is that fusing point is 50～250 ℃ a thermoplastic elastomer (TPE), comprise a kind of in styrene-isoprene-phenylethene (SIS) triblock copolymer, s-B-S (SBS) triblock copolymer, SEBS (SEBS) triblock copolymer.
The common feature of the technical scheme that above-mentioned patent documentation provided is to adopt the pressure sensitive adhesive matrix of hydrophobic non-polar polymer (rubber type of material) as patch.
Pressure sensitive adhesive is that a class produces viscosity under pressure, does not stay the binding agent of residue after decompression, is the main adjuvant of percutaneous administration patch.Traditional pressure sensitive adhesive be mainly three types of polyisobutylene class rubber-type, silicone rubber kinds and polyacrylates (Liu Wei, Yang Xiangliang. percutaneous dosing is with composition, performance and the application of pressure-sensitive adhesive agent. Chinese adhesive, 2004,13 (2): 60-63.).There is variety of issue in above-mentioned pressure sensitive adhesive because hydrophilic is poor in the use.Only be applicable to low aqueous solubility and low polar medicine as nonpolar rubber-like pressure sensitive adhesive, owing to self hydrophobicity and forming process in need to add auxiliary agents such as gasoline, Colophonium reason, its water-permeable and air permeable extreme difference, life-time service causes and has the hydrops generation on the skin, make the skin whiting, also usually with allergic phenomena.Though the silicone rubber pressure sensitive adhesive increases than rubber-like pressure sensitive adhesives such as polyisobutylene aspect water vapor transmission, it can not absorb the moisture that body surface is discharged, and macerates phenomenon so skin still can appear in life-time service, and its another shortcoming is that viscosity is lower.The various aspects of performance of polyacrylate pressure sensitive adhesive is good than said two devices, but still is hydrophobic material, and is relatively poor with the biocompatibility of skin.In addition, the existence of residual monomer, the polyacrylate pressure sensitive adhesive can be produced skin to stimulate or toxic and side effects, has reduced its biocompatibility.Above-mentioned three class pressure sensitive adhesives also all exist simultaneously meets water and loses viscosity, and it is poor to take off subsides property repeatedly, and long-time use meeting stays residue on skin, and is difficult to shortcoming such as removing.In addition, rubber pressure-sensitive adhesive also exists viscosity and peel strength excessive, produces intensive pain when peeling off; In a large number with an organic solvent, equipment and labor protection are had relatively high expectations in the production, can cause problems such as environmental pollution.
Simultaneously, also used toxic solvents such as toluene among the patent documentation CN1181931A, toluene remains in and is difficult to eliminate in the hydrophobicity patch substrate, can cause damage to human body skin.Patent documentation CN1387842A then with patent documentation CN1181931A technical scheme basically identical.The hot melt pressure sensitive adhesive need be heated to more than 100 ℃ in the described patch preparation process of patent documentation CN1565523, can cause the thermal decomposition of medicines such as ketoprofen under this temperature.
The general drug loading of hydrophobic rubber pressure-sensitive adhesive is on the low side, though the dexketoprofen dosage is littler than ketoprofen, but still it is big (as oral 3-4 time of per day for adults, about each 25mg, be to need oral drugs 75-100mg every day), the pressure sensitive adhesive matrix in the technique scheme is difficult to satisfy the bigger dosage of dexketoprofen.
The clinical diseases such as treatment rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis that are mainly used in of dexketoprofen, the patient need accept long-term, heavy dose of Drug therapy.Therefore, be necessary characteristics at above-mentioned disease treatment, the novel dexketoprofen patch that exploitation is good with skin good biocompatibility, ventilative water permeability, can take off subsides repeatedly, drug loading is big, percutaneous penetration of drugs is effective satisfies the needs of dexketoprofen clinical treatment.
Summary of the invention
The object of the present invention is to provide a kind of gel type dexketoprofen plaster, this patch has with the skin good biocompatibility, drug loading is big, percutaneous penetration of drugs is effective, ventilative water permeability is good, adhibit quality is good, peel off characteristics such as suitable, can satisfy the needs of dexketoprofen clinical treatment.
A kind of gel type dexketoprofen plaster provided by the invention is made of back lining materials, gel-type Drug Storage material and adhesive, wherein,
Medicine-containing gel type Drug Storage material contains 0.5～30.0wt% (percetage by weight, dexketoprofen down together), the gel-type Drug Storage host material of 5.0～80.0wt%, 0.5 the drug solvent of～40.0wt%, 0.5 the wetting agent of～30.0wt%, and the transdermal absorption accelerator of 0.5～8.0wt%;
Transdermal absorption accelerator is at least a at least a or laurocapram and the propylene glycol at least a, carbamide at least a, Camphora in mixture, menthol and the butanols of ethyl acetate, oleic acid, linoleic acid, isopropyl myristate, α-pyrrolidone, N-N-ethyl pyrrole N-ketone, sodium laurylsulfate, N-N-methyl 2-pyrrolidone N-, glycerol, limonene, Oleum Terebinthinae, Borneolum Syntheticum, eucalyptus oil, Macrogol 200, salicylic acid and limonene or butanols and the butanols and the butanediol;
Described drug solvent and wetting agent are any in ethanol isopropyl alcohol, n-butyl alcohol, 2-enanthol, propylene glycol, glycerol, 2,2'-ethylenedioxybis(ethanol)., Macrogol 200, PEG400, Macrogol 600, sorbic acid, linoleic acid, Ethyl linoleate, butyl oleate, isopropyl myristate, isopropyl palmitate and the tri-n-butyl citrate;
Described gel-type Drug Storage host material comprises:
Ultra high molecular weight polyethylene base ketopyrrolidine or contain the unitary copolymer of vinyl pyrrolidone, its molecular weight M
1Be 200,000＜M
1≤ 250 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%;
Low-molecular-weight polyvinyl pyrrolidone or contain the unitary copolymer of vinyl pyrrolidone, its molecular weight M
2Be 0.3 ten thousand≤M
2≤ 20 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%;
Polyvinyl alcohol: its molecular weight M
3Be 1.0 ten thousand≤M
3≤ 20 ten thousand, the content in the Drug Storage host material is 1.0～50.0wt%; The perhaps mixture of polyvinyl alcohol and Polyethylene Glycol, polyvinyl alcohol molecular weight M
3Be 1.0 ten thousand≤M
3≤ 20 ten thousand, the molecular weight M of Polyethylene Glycol
4Be 0.08 ten thousand≤M
4≤ 10 ten thousand, the two content in the Drug Storage host material is 1.0～60.0wt%;
Cross-linking agent, content are 0.1～10.0wt%, and this cross-linking agent is glutaraldehyde, succinic acid, Biformyl, Azelaic Acid, acetic anhydride, maleic anhydride or succinic anhydride;
Surplus is a water;
Described back lining materials is elastic non-woven cloth, cotton, blended cloth or the paper material that hydrophobization is handled;
Described adhesive is paper, polyester, polyethylene, polypropylene, polystyrene or the silication polyester of surface through the silicone oil release treatment.
The step for preparing the method for above-mentioned gel type dexketoprofen plaster is:
(1) preparation gel-type Drug Storage host material: in the reactor that has stirring and heater, add the Drug Storage host material, comprise the polyvinyl pyrrolidone of high and low molecular weight or contain unitary copolymer of vinyl pyrrolidone and polyvinyl alcohol, perhaps polyvinyl alcohol and Polyethylene Glycol, and add entry, stir under 60～100 ℃ of temperature, make each component mix homogeneously, controlling temperature then is 40～45 ℃, adding its pH value of acid adjusting is 4～5, add cross-linking agent again, continue to stir 45～75min, mix homogeneously;
(2) preparation medicine-containing gel type Drug Storage material: have in the reactor of stirring and heater at another, add dexketoprofen, transdermal absorption accelerator, drug solvent and wetting agent, stir under 60～100 ℃ of temperature, make each component mix homogeneously and medicine is dissolved fully, treat that the Drug Storage host material that after medicine dissolves fully itself and step (1) is made stirs, fully mix homogeneously;
(3) adopt coating process that the medicine-containing gel type Drug Storage material of above-mentioned preparation is made patch.
Adopt patch provided by the present invention, dexketoprofen is by percutaneous dosing, and medicine directly infiltration reaches lesions position, increases the medicine local concentration of lesions position, effectively strengthens medicine to local arthritis and treatment of pain effect; After drug transdermal enters the body circulation, the effect of performance whole body therapeutic, thus improve the effect that dexketoprofen is treated diseases such as rheumatoid arthritis.Simultaneously, dexketoprofen is avoided the untoward reaction such as stimulation of the intestines and stomach of its generation by percutaneous dosing, increases the compliance of patient's long-term prescription, selects for all kinds of arthritics provide more excellent medication.
Describe process and the result that gel type dexketoprofen plaster of the present invention carries out performance test below in detail.
1, viscosity
Main adhering performance index comprises initial bonding strength, holds viscous force, 180 ° of peeling forces and take off the subsides performance repeatedly.According to " the regulation of Chinese pharmacopoeia (2005 editions), the GB4852-84 standard of pressing tack adopts CZY-G tack tester to measure, hold viscosity and adopt CZY-S to hold the measurement of viscosity tester by the GB4851-84 standard, 180 ° of peel strengths are measured and are pressed the measurement of GB2792-81 standard employing LANGUANG electron detachment testing machine.The initial bonding strength that generally requires patch is 10～20 (steel ball number), holds viscous force (separation time) greater than 10h, and 180 ° of peel strengths are 6～15N.Pressure sensitive adhesive in the patch (being the Drug Storage host material) requires to have suitable viscosity, viscosity to cross lowly can to cause patch to come off, viscosity is too high then cause patch from skin take off from the time can cause pain or injured skin.
For ideal percutaneous administration patch, should satisfy the requirement that administration at any time can be interrupted again at any time, this just requires the Drug Storage host material to have the good subsides of taking off repeatedly.Take off the measuring method of subsides property repeatedly and paste 50 times for taking off repeatedly continuously on the corrosion resistant plate after the clean, test its initial bonding strength, 180 ° of peel strengths then, above-mentioned adhering performance descends more little, represents that it takes off repeatedly that to paste performance good more.
According to test result as can be known, take off subsides repeatedly through 50 times after, the initial bonding strength of the gel type dexketoprofen plaster pressure sensitive adhesives of different prescriptions and 180 ° of peeling forces all have reduction in various degree, but they are still in operable scope.And the patch of rubber-like pressure sensitive adhesives such as polyisobutylene preparations is taken off repeatedly and is lost viscosity when pasting 5 times substantially.As seen, the gel type dexketoprofen plaster of the inventive method preparation has the good subsides performance of taking off repeatedly.
2, dampness through performance
Get the surface plate that a floor space is S, the distilled water of wherein packing into (be no more than 2/3 of surface plate volume, so as not to patch when putting into water diffuse out), the patch for preparing is cut out to onesize with surface plate, its glue faced down just seals up the above-mentioned surface plate that is filled with water, accurately weigh, weight W
1Be placed on temperature and be in 65% the constant temperature and humidity experimental box, accurately weigh behind the 24h for (25 ± 1) ℃, relative humidity, weight W
2Calculate patch 24h dampness transit dose as follows: dampness transit dose (g/cm
2)=(W
1-W
2)/S.
Traditional pressure sensitive glue can not absorb the body fluid that skin is discharged owing to hydrophilic, breathability are poor, is difficult to make body fluid to see through pressure sensitive adhesive again and oozes out.Body fluid is assembled at skin surface and is difficult to volatilization, causes skin to be turned white by immersion, even causes allergy or inflammation.Pressure sensitive adhesive in the prepared gel-type Drug Storage material of the present invention is hydrophilic gel section bar material, has excellent biological compatibility and air-and water-permeable performance.
Hydrophilic pressure sensitive adhesive (hydrophilic Drug Storage host material) in the prepared gel-type Drug Storage material of the present invention, 24h dampness transit dose is 500～750g/m
2, and traditional Polyisobutylene PSA 24h dampness transit dose only is 20g/m
2About, the hydrophilic gel type Drug Storage material prepared far below the present invention.
3, human body skin is observed
The not medicated patches of preparation is cut out to 10cm * 10cm, on experimenter's arm, attach 48h, observe skin and have or not whiting and anaphylactic reaction.
The result shows that experimenter's arm sticking portion skin does not have the immersion blushing, does not also have anaphylactic reaction and tangible zest.The prepared gel-type patch of experimental result explanation has advantages of good skin biocompatibility and air-and water-permeable performance (mainly being the effect that gel-type Drug Storage material plays).
4, percutaneous penetration of drugs performance
As the transdermal administration system, adopt improved Franz diffusion cell to carry out the test of isolated mouse skin transdermal to investigate the transdermal penetration performance of dexketoprofen patch the medicine carrying gel type dexketoprofen plaster, experimental technique is as follows:
Animal is male Kunming kind white mice (Hubei Province's preventive medicine academy Experimental Animal Center provides), and body weight is (22 ± 2) gram.Mouse web portion is lost hair or feathers with depilatory, and normal saline is cleaned abdominal part, raises disconnected two days later neck and puts to death, and gets the skin of abdomen that does not have hair, removes subcutaneous fat, washes repeatedly with distilled water, put preserve in 4 ℃ the normal saline standby.Clear and bright to washing liquid before using with the normal saline rinsing, blot with filter paper, stand-by.
Adopt improved Franz diffusion cell to carry out the transdermal test, diffusion cell is incubated with constant temperature (37 ℃) cyclic water jacket, and skin is fixed between supply chamber and the reception tank, and skin surface is towards supply chamber, and effectively infiltrating area S is 2.80cm
2, receive liquid for containing the alcoholic acid normal saline of 30% (v/v), carefully be fitted in skin surface in the supply chamber with cutting out dexketoprofen patch for suitable size, open the speed stirring of magnetic stirrer with 400rpm.In 1,2,3,4,5,6,7,8h takes out 0.5ml and receives liquid, mend simultaneously with blank and receive liquid with volume.The sample of obtaining is carried out centrifugal, get supernatant, reuse 0.45 μ m filtering with microporous membrane is got subsequent filtrate, and the HPLC method is measured wherein medicament contg.
The HPLC chromatographic condition is as follows.Chromatographic column: Hypersil C
18Post (250mm * 4.6mm, 5 μ m); It is 2.5～3.0 that the sodium dihydrogen phosphate of mobile phase: methanol-5mmol/L (30: 70) is regulated pH value with phosphoric acid; Flow velocity: 1.0mL/min; Detect wavelength: 260nm; Column temperature: 25 ℃; Sample size: 20 μ L.
Utilize the HPLC method to measure the concentration that different time receives the liquid Chinese medicine, according to receiving chamber volume, the effective diffusion area of skin, calculate unit are accumulation drug osmotic amount, the unit are accumulation drug osmotic amount and the time that will reach stable state return, and the collinear slope that obtains is as the transdermal penetration speed of medicine.
The percutaneous penetration of drugs performance of different prescription dexketoprofen patches is the detailed description among the row embodiment as follows.
The specific embodiment
Gel type dexketoprofen plaster is made of back lining materials, gel-type Drug Storage material and adhesive, wherein, medicine-containing gel type Drug Storage material is by 0.5～30.0wt% (percetage by weight, active pharmaceutical ingredient down together), the gel-type Drug Storage host material of 5.0～80.0wt%, 0.5 the drug solvent of～40.0wt%, 0.5 the wetting agent of～30.0wt%, the transdermal absorption accelerator of 0.5～8.0wt% is formed.Wherein, wetting agent/solvent plays skin care, promotes skin hydration, is beneficial to the effect that the active component percutaneous absorbs, and transdermal absorption accelerator plays the effect that promotes that the active component percutaneous absorbs.
Above-mentioned gel-type Drug Storage host material is by a kind of ultra high molecular weight polyethylene base ketopyrrolidine (PVP) or contain the unitary copolymer of vinyl pyrrolidone (NVP) and low-molecular-weight polyvinyl pyrrolidone or contain the unitary copolymer of vinyl pyrrolidone, polyvinyl alcohol (PVA) or polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG), cross-linking agent and water are formed.Wherein, ultra high molecular weight polyethylene base ketopyrrolidine or contain the molecular weight M of the unitary copolymer of vinyl pyrrolidone
1Scope is 200,000＜M
1≤ 250 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%.Low-molecular-weight polyvinyl pyrrolidone or contain the molecular weight M of the unitary copolymer of vinyl pyrrolidone
2Scope is 0.3 ten thousand≤M
2≤ 20 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%.The molecular weight M of polyvinyl alcohol
3Scope is 1.0 ten thousand≤M
3≤ 20 ten thousand, when share with Polyethylene Glycol, the molecular weight M of Polyethylene Glycol
4Be 0.08 ten thousand≤M
4≤ 10 ten thousand, the two content in the Drug Storage host material is 1.0～60.0wt%, and when using separately, the content of polyvinyl alcohol is 1.0～50.0wt%.The content of cross-linking agent is 0.1～10.0wt% in the Drug Storage host material, and surplus is a water.
Be suitable for drug solvent of the present invention and wetting agent and can be any one or two kinds of above mixture in aliphatic alcohol, fatty acid, the fatty acid ester.Other lipophilic solvent that also can use the well-known good biocompatibility in pharmaceutics field, dexketoprofen be had good solubility.Drug solvent and wetting agent can adopt with a kind of material.
Be suitable for that transdermal absorption accelerator of the present invention can be azone class, terpenes, aliphatic alcohols, organic acid and esters thereof, cutin is preserved moisture and any one or two kinds of above mixture of softening agent class, nonionic and ionic surfactant apoplexy due to endogenous wind, also can use well-known and other transdermal absorption accelerator that have excellent compatibility with medicine and Drug Storage host material in pharmaceutics field.
Be suitable for Drug Storage host material cross-linking agent of the present invention and can be dialdehyde, binary acid or anhydride, wherein preferred glutaraldehyde.
Be suitable for patch back lining materials of the present invention for soft comfortable, ventilative water permeability good and through elastic non-woven cloth, cotton, blended cloth or the paper material of hydrophobization processing, wherein preferred water prick nonwoven cloth.
Be suitable for patch adhesive of the present invention and be the film material of surface through high polymers such as the paper of silicone oil release treatment or polyester (PET), polyethylene (PE), polypropylene (PP), polystyrene, silication polyester.
The area size that is suitable for patch of the present invention wherein contains dexketoprofen 1～30mg for (5～10) cm * (8～16) cm, wherein, and preferred 5～20mg.
Being prepared as follows of above-mentioned medicine-containing gel type Drug Storage material is described:
In the reactor that has stirring and heater, add the Drug Storage host material, comprise the polyvinyl pyrrolidone of high and low molecular weight or contain unitary copolymer of vinyl pyrrolidone and polyvinyl alcohol, perhaps polyvinyl alcohol and Polyethylene Glycol, and add entry, stir under 60～100 ℃ of temperature, make each component mix homogeneously, controlling temperature then is 40～45 ℃, adding sour regulation system pH value is 4～5, add cross-linking agent, continue to stir 45～75min, make gel-type Drug Storage host material.
Have in the reactor of stirring and heater at another, add dexketoprofen (content 〉=98.5%), drug solvent and wetting agent, transdermal absorption accelerator, stir under 60～100 ℃ of temperature, make each component mix homogeneously and medicine is dissolved fully.Treat after medicine dissolves fully itself and the aforementioned Drug Storage host material that makes to be stirred, abundant mix homogeneously promptly makes the medicine-containing gel type Drug Storage material of gel type dexketoprofen plaster.
Be suitable for gel type dexketoprofen plaster of the present invention and can adopt coating process production, technology is easy, does not use any deleterious organic solvent, non-environmental-pollution.Concrete preparation method is seen " pressure sensitive adhesive goods technical manual " (Yang Yukun, Lv Fengting chief editor, Chemical Industry Press: 375～408).Gel-type Drug Storage material of the present invention also can be made into multiwalled form in patch, different layers can have different dexketoprofen Concentraton gradient, to reach the effect of controlled release, slow release.
The high-molecular weight unitary copolymer of vinyl pyrrolidone that contains can be selected vinylpyrrolidone/vinyl acetate copolymer 73, vinylpyrrolidone/vinyl acetate copolymer 64, vinyl pyrrolidone-dimethyl maleic acid copolymer or vinyl pyrrolidone-copolymers such as MAAm oxypropyl trimethyl ammonium chloride copolymer for use.
The low-molecular-weight unitary copolymer of vinyl pyrrolidone that contains can be selected vinylpyrrolidone/vinyl acetate copolymer 37, vinylpyrrolidone/vinyl acetate copolymer 55, vinyl pyrrolidone-styrol copolymer or vinyl pyrrolidone-copolymers such as the quaternary ammoniated copolymer of dimethylamino methyl ethyl acrylate for use.
Below described embodiment describe the solution of the present invention in detail, the prescription of embodiment 1～30 is formed and performance is listed in table 1, the table 2 respectively.
The present invention relates to the hydrophilic pressure sensitive patch, this patch has advantages such as side effect is little, hydrophilic, good biocompatibility.Disclosed content among the present invention, those skilled in the art can use to greatest extent.Therefore, specific embodiments preferred for this invention should be understood that only to illustrate, but not limits the present invention by any way.
Table 1 example 1～30 gel type dexketoprofen plaster prescription
| Example | High molecular PVP (*) | The high-molecular weight unitary copolymer of NVP (*) that contains | Low-molecular-weight PVP (*) | The low-molecular-weight unitary copolymer of NVP (*) that contains | PVA (*) |
| 1 | 20/60/46.2 | — | 15/1/0.8 | — | 18/10/7.7 |
| 2 | 20/50/39 | — | 14/2/1.6 | — | 20/12/9.4 |
| 3 | 30/50/32.5 | — | 20/4/2.6 | — | 15/15/9.8 |
| 4 | 40/43/29.2 | — | — | PVP-PSH，8/15/10.2 | 10/12/8.2 |
| 5 | — | PVP-VA73，50/40/ 28.8 | 13/8/5.8 | — | 12/20/14.4 |
| 6 | 50/35/7 | — | 10/20/4 | — | 14/25/5 |
| 7 | 50/37/6.7 | — | 8/28/5 | — | 17/20/3.6 |
| 8 | 70/32/24 | — | 9/30/22.5 | — | 13/20/15 |
| 9 | 80/28/22.4 | — | 7/40/32 | — | 15/18/14.4 |
| 10 | 80/25/20 | — | — | PVP-Q755N，10/30/24.0 | 12/15/12 |
| 11 | — | PVD，100/23/13.3 | 0.5/43/24.9 | — | 8/12/7 |
| 12 | 100/31/13 | — | 5/42/17.6 | — | 1/8/3.4 |
| 13 | 100/46/16.1 | — | 2/28/9.8 | — | 11/0.5/0.2 |
| 14 | 120/40/11.2 | — | 3/20/5.6 | — | 9/15/4.2 |
| 15 | 130/45/11.3 | — | 0.4/15/3.8 | — | 3.5/20/5 |
| 16 | 130/28/9.5 | — | 4/20/6.8 | — | 2/12/4.1 |
| 17 | 130/30/3.6 | — | 1/40/4.8 | — | 13/1/0.1 |
| 18 | — | PVP-Q100，150/25 /8.8 | 3/38/13.3 | — | 5/4/1.4 |
| 19 | 150/27/10 | — | — | PVP-VA55，0.8/42/15.5 | 2.5/8/3 |
| 20 | 180/16/0.8 | — | 2.5/45/2.3 | — | 3/15/0.8 |
| 21 | 180/13/4.9 | — | 1.5/52/19.8 | — | 2/7/2.7 |
| 22 | 200/18/7.2 | — | 1/60/24 | — | 3.5/4/1.6 |
| 23 | 210/15/7.8 | — | 2/45/23.4 | — | 3/22/11.4 |
| 24 | 220/4/1.5 | — | 0.5/50/19 | — | 2.5/35/13.3 |
| 25 | 220/2/0.8 | — | 3/6/2.4 | — | 1/50/20.0 |
| 26 | — | PVP-VA64，230/1/ 0.6 | 0.4/42/26 | — | 4/33/20.5 |
| 27 | 230/3/1.4 | — | 0.3/30/14.4 | — | 5/50/24.0 |
| 28 | 250/1/0.6 | — | — | PVP-VA37，2/60/33.0 | 6/18/10.0 |
| 29 | 250/2/0.9 | — | 1/50/23 | — | 4/20/9.2 |
| 30 | 250/1/0.6 | — | 5/30/18 | — | 1/5/3.0 |
| Example | PEG (*) | Cross-linking agent/content (gram)/ratio (%) | Dexketoprofen/content (gram)/ratio (%) | Drug solvent/content (gram)/ratio (%) | Wetting agent/content (gram)/ratio (%) |
| 1 | 8/7/5.4 | Glutaraldehyde/7/5.4 | 1.3/1 | N-butyl alcohol/14.9/11.5 | N-butyl alcohol/13.0/10.0 |
| 2 | 10/10/7.8 | Glutaraldehyde/8/6.2 | 0.6/0.5 | Isopropyl alcohol/13.5/10.5 | Isopropyl alcohol/11.5/9.0 |
| 3 | 9/12/7.8 | Succinic acid/9/5.9 | 3.1/2 | Glycerol/36.9/24 | N-butyl alcohol/12.3/8 |
| 4 | 2.5/12/8.2 | Biformyl/5/3.4 | 5.9/4 | 2-enanthol/11.8/8 | Ethanol/27.9/19 |
| 5 | — | Azelaic Acid/10/7.2 | 3.5/2.5 | Propylene glycol/25.0/18 | Propylene glycol/8.3/6 |
| 6 | 4.5/5/1.0 | Glutaraldehyde/4/0.8 | 15/3 | Butyl oleate/200/40 | Butyl oleate/150/30 |
| 7 | 7/3/0.5 | Biformyl/3/0.5 | 33.3/6 | 2,2'-ethylenedioxybis(ethanol) ./222.2/40 | 2,2'-ethylenedioxybis(ethanol) ./166.7/30 |
| 8 | 6.5/0.9/0.7 | Glutaraldehyde/0.1/0.1 | 9.3/7 | Propylene glycol/13.3/10 | Propylene glycol/6.7/5 |
| 9 | 5/2/1.6 | Succinic acid/4/3.2 | 11.3/9 | Isopropyl palmitate/6.3/5 | Isopropyl palmitate/2.5/2 |
| 10 | — | Acetic anhydride/12/9.6 | 13.8/11 | Glycerol/0.65/0.5 | Glycerol/0.65/0.5 |
| 11 | 2/3/1.7 | Glutaraldehyde/7/4.1 | 25.9/15 | Sorbic acid/31.0/18 | Sorbic acid/5.2/3 |
| 12 | 1/3/1.3 | Glutaraldehyde/5/2.1 | 19/8 | PEG400/40.5/17 | PEG400/71.4/30 |
| 13 | 3/0.5/0.2 | Succinic anhydride/10/3.5 | 34.3/12 | Glycerol/91.4/32 | Sorbic acid/45.7/16 |
| 14 | 1.5/5/1.4 | Azelaic Acid/7/2 | 60.7/17 | Linoleic acid/142.9/40 | Linoleic acid/35.7/10 |
| 15 | — | Glutaraldehyde/6/1.5 | 80/20 | Glycerol/120/30 | Isopropyl alcohol/80/20 |
| 16 | 0.25/15/5.1 | Glutaraldehyde/8/2.7 | 54.4/18.5 | Macrogol 200/88.3/30 | Macrogol 200/38.2/13 |
| 17 | — | Azelaic Acid/10/1.2 | 133.3/16 | Ethanol/333.3/40 | Propylene glycol/225.0/27 |
| 18 | — | Acetic anhydride/12/4.2 | 60/21 | Isopropyl myristate/85.7/30 | Isopropyl myristate/20.0/7 |
| 19 | — | Maleic anhydride/6/2.2 | 63.5/23.5 | Isopropyl alcohol/81.1/30 | Isopropyl alcohol/8.1/3 |
| 20 | — | Glutaraldehyde/8/0.4 | 440/22 | Macrogol 600/760/38 | Macrogol 600/600/30 |
| 21 | 0.75/6/2.3 | Succinic acid/6/2.3 | 65.8/25 | PEG400/68.5/26 | PEG400/10.5/4 |
| 22 | 1/6/2.4 | Glutaraldehyde/4/1.6 | 60/24 | Ethanol/65/26 | Ethanol/12.5/5 |
| 23 | — | Glutaraldehyde/6/3.1 | 51.9/27 | Glycerol/19.2/10 | Glycerol/8.7/4 |
| 24 | — | Succinic acid/3/1.1 | 59.2/22.5 | Macrogol 200/65.8/25 | Macrogol 200/26.3/10 |
| 25 | 0.08/10/4.0 | Glutaraldehyde/4/1.6 | 58.8/23.5 | 2-enanthol/70.0/28 | 2-enanthol/7.5/3 |
| 26 | 1.2/3/1.9 | Maleic anhydride/6/3.7 | 41.9/26 | Macrogol 600/8.1/5 | Macrogol 600/3.2/2 |
| 27 | — | Glutaraldehyde/6/2.9 | 57.3/27.5 | Ethyl linoleate/25.0/12 | Ethyl linoleate/14.6/7 |
| 28 | 2/5/2.8 | Succinic anhydride/7/3.9 | 54.5/30 | Glycerol/9.1/5 | Glycerol/5.4/3 |
| 29 | 1.2/6/2.8 | Glutaraldehyde/6/2.8 | 56.5/26 | Tri-n-butyl citrate/39.2/18 | Tri-n-butyl citrate/13.2/6 |
| 30 | 0.08/50/30 | Glutaraldehyde/4/2.4 | 50/30 | Glycerol/5/3 | 2,2'-ethylenedioxybis(ethanol) ./1.7/1 |
| Example | Water/content (gram)/ratio (%) | Transdermal absorption accelerator/content (gram)/ratio (%) | Back lining materials | Adhesive |
| 1 | 15/11.5 | Laurocapram/0.6/0.5 | Elastic non-woven cloth | Polyethylene film |
| 2 | 18/14 | Propylene glycol/2.6/2 | Elastic non-woven cloth | Polyester film |
| 3 | 10/6.4 | Ethyl acetate/1.5/1 | Elastic non-woven cloth | Polypropylene screen |
| 4 | 13/8.8 | Butanediol/1.5/1 | Cotton | Polyethylene film |
| 5 | 22/15.8 | Butanols/1.4/1, menthol/0.7/0.5 | Elastic non-woven cloth | Polyester film |
| 6 | 11/2.2 | Laurocapram/35/7 | Elastic non-woven cloth | The silication polyester film |
| 7 | 9/1.7 | Oleic acid/33.3/6 | Cotton | Silicon paper |
| 8 | 17/12.7 | Linoleic acid/4/3 | Oilpaper | Silicon paper |
| 9 | 8/6.4 | Carbamide/5/4 | Blended cloth | Polyethylene film |
| 10 | 18/14.4 | Isopropyl myristate/10/8 | Cotton | Silicon paper |
| 11 | 12/7 | Salicylic acid/5.2/3, limonene/5.1/3 | Elastic non-woven cloth | The silication polyester film |
| 12 | 11/4.6 | α-pyrrolidone/7.1/3 | Cotton | Polyethylene film |
| 13 | 15/5.2 | Isopropyl myristate/14.3/5 | Blended cloth | Polyester film |
| 14 | 13/3.6 | N-N-ethyl pyrrole N-ketone/17.9/5 | Elastic non-woven cloth | Polystyrene film |
| 15 | 14/3.4 | Sodium laurylsulfate/20/5 | Elastic non-woven cloth | Silicon paper |
| 16 | 17/5.8 | N-N-methyl 2-pyrrolidone N-/13.2/4.5 | Cotton | Polyethylene film |
| 17 | 19/2.3 | Butanols/41.7/5 | Elastic non-woven cloth | Silicon paper |
| 18 | 21/7.3 | Glycerol/20/7 | Cotton | Silicon paper |
| 19 | 17/6.3 | Menthol/17.6/6.5 | Elastic non-woven cloth | Polystyrene film |
| 20 | 16/0.7 | Camphora/100/5 | Elastic non-woven cloth | Polyethylene film |
| 21 | 16/6 | Limonene/18.4/7 | Elastic non-woven cloth | Silicon paper |
| 22 | 8/3.2 | Oleum Terebinthinae/12.5/5 | Blended cloth | Polypropylene screen |
| 23 | 12/6.3 | Carbamide/9.6/5, butanediol/3.9/2 | Cotton | Silicon paper |
| 24 | 8/3.1 | Borneolum Syntheticum/11.8/4.5 | Blended cloth | Silicon paper |
| 25 | 28/11.2 | Eucalyptus oil/13.8/5.5 | Elastic non-woven cloth | Polyethylene film |
| 26 | 15/9.3 | Camphora/4.8/3, butanols/3.3/2 | Oilpaper | Silicon paper |
| 27 | 11/5.3 | Macrogol 200/11.5/5.5 | Elastic non-woven cloth | Polyester film |
| 28 | 9/4.7 | Salicylic acid/5.5/3, butanols/7.2/4 | Blended cloth | Silicon paper |
| 29 | 16/7.3 | Sodium laurylsulfate/8.7/4 | Cotton | Polystyrene film |
| 30 | 10/6 | Laurocapram/6.7/4, propylene glycol/3.3/2 | Elastic non-woven cloth | The silication polyester film |
Annotate: 1. " * " expression " molecular weight (ten thousand)/content (gram)/ratio (%) ", "-" expression does not add this component;
2. each component molecular weight refers to mean molecule quantity in the table 1;
3.PVP: polyvinyl pyrrolidone, NVP: vinyl pyrrolidone, PVP-VA: vinylpyrrolidone/vinyl acetate copolymer, PVP-PSH: vinyl pyrrolidone one styrol copolymer, PVD: vinyl pyrrolidone-dimethyl maleic acid copolymer, PVP-Q100: vinyl pyrrolidone-MAAm oxypropyl trimethyl ammonium chloride copolymer, PVP-Q755N: the vinyl pyrrolidone-quaternary ammoniated copolymer of dimethylamino methyl ethyl acrylate, PVA: polyvinyl alcohol, PEG: Polyethylene Glycol;
4. indication ratio (%) accounts for the part by weight of Drug Storage material for this composition.
Table 2 embodiment 1～30 gel type dexketoprofen plaster performance
| Embodiment | Initial bonding strength/steel ball number | 180 ° of peeling force/N | Hold viscous force separation time/h | 24h dampness transit dose/(g/m 2) | The 48h human body skin is observed | Transdermal penetration speed (*) | The performance of noticing repeatedly * * | |
| Initial bonding strength/steel ball number | 180 ° of peeling force/N | |||||||
| 1 | 16 | 8.25 | 9.1 | 652.3 | No abnormal | 2.36 | 12 | 6.13 |
| 2 | 18 | 9.76 | 11.3 | 618.2 | No abnormal | 2.78 | 13 | 7.21 |
| 3 | 15 | 10.26 | 10.5 | 576.3 | No abnormal | 1.82 | 10 | 7.89 |
| 4 | 17 | 12.34 | 18.7 | 628.1 | No abnormal | 2.15 | 12 | 10.12 |
| 5 | 19 | 13.56 | 16.3 | 579.2 | No abnormal | 3.59 | 14 | 10.95 |
| 6 | 16 | 11.78 | 15.2 | 562.8 | No abnormal | 1.89 | 11 | 8.62 |
| 7 | 20 | 14.82 | 18.1 | 528.9 | Slight whiting | 4.63 | 16 | 11.38 |
| 8 | 15 | 10.93 | 10.3 | 615.4 | No abnormal | 2.54 | 11 | 7.95 |
| 9 | 17 | 13.18 | 17.5 | 532.7 | No abnormal | 3.62 | 13 | 10.82 |
| 10 | 13 | 9.82 | 16.2 | 623.6 | No abnormal | 13.7 | 8 | 7.17 |
| 11 | 19 | 14.15 | 19.1 | 547.9 | No abnormal | 4.83 | 14 | 12.03 |
| 12 | 18 | 13.26 | 15.2 | 585.3 | No abnormal | 2.69 | 13 | 11.57 |
| 13 | 20 | 14.05 | 17.8 | 506.2 | Slight whiting | 6.75 | 16 | 12.12 |
| 14 | 15 | 9.78 | 14.2 | 623.8 | No abnormal | 7.83 | 10 | 7.53 |
| 15 | 17 | 12.84 | 13.9 | 607.9 | No abnormal | 6.72 | 12 | 9.96 |
| 16 | 16 | 10.18 | 12.6 | 628.3 | No abnormal | 10.57 | 12 | 7.03 |
| 17 | 13 | 9.13 | 10.1 | 635.4 | No abnormal | 9.63 | 9 | 6.26 |
| 18 | 19 | 13.98 | 21.8 | 587.6 | No abnormal | 13.65 | 15 | 10.93 |
| 19 | 15 | 10.12 | 11.9 | 629.7 | No abnormal | 10.83 | 10 | 7.58 |
| 20 | 16 | 9.75 | 10.8 | 648.2 | No abnormal | 14.56 | 12 | 6.23 |
| 21 | 19 | 12.98 | 18.7 | 605.3 | No abnormal | 16.28 | 14 | 9.83 |
| 22 | 13 | 8.17 | 17.9 | 587.9 | No abnormal | 11.34 | 8 | 6.05 |
| 23 | 14 | 9.85 | 15.4 | 572.3 | No abnormal | 12.56 | 10 | 7.21 |
| 24 | 16 | 10.27 | 12.3 | 543.1 | No abnormal | 15.78 | 12 | 7.89 |
| 25 | 19 | 14.68 | 22.3 | 529.8 | No abnormal | 18.32 | 14 | 12.34 |
| 26 | 20 | 14.92 | 18.9 | 452.3 | Slight whiting | 20.68 | 16 | 12.05 |
| 27 | 18 | 13.89 | 17.6 | 503.2 | No abnormal | 17.92 | 14 | 10.76 |
| 28 | 17 | 12.65 | 13.8 | 589.7 | No abnormal | 16.83 | 13 | 10.28 |
| 29 | 15 | 10.27 | 15.6 | 615.3 | No abnormal | 14.38 | 11 | 7.95 |
| 30 | 18 | 12.89 | 17.9 | 542.8 | No abnormal | 16.78 | 13 | 10.36 |
Annotate: * μ gcm
-2H
-1The * test after 50 times of noticing repeatedly
Annotate: 1, respectively according to GB4852-84, GB4851-84 and GB2792-81 standard to embodiment 1～30 gel type dexketoprofen plaster carry out initial bonding strength, hold viscous force, the evaluation of 180 ° of peeling forces.
2,48h human body skin viewing test is mainly observed skin and is had or not whiting and anaphylactic reaction.
Example 31
Prescription is formed with embodiment 6, just intermediary medicine-containing gel type Drug Storage material is divided into three layers, and from the adhesive to the back lining materials, every layer contains different proportion and (accounts for the ratio of medicine total amount, down together) medicine: 25%, 30%, 45%.Preparation method is as follows: Drug Storage host material, drug solvent and wetting agent, transdermal absorption accelerator are pressed the technology mix homogeneously, this mixture is divided into three equal parts, each equal portions medicament mixed with corresponding proportion again are even, earlier the one deck on the back lining materials is spread, suitably repave the second layer after the drying, spread the 3rd layer with method.So make gel-type Drug Storage material and be divided into three layers and contain the gel type dexketoprofen plaster of different proportion medicine.
Example 32
Prescription is formed with embodiment 16, just intermediary medicine-containing gel type Drug Storage material is divided into four layers, from the adhesive to the back lining materials, and every layer of medicine that contains different proportion: 10%, 20%, 30%, 40%.Preparation method just according to corresponding drug ratios, is spread four layers with embodiment 31 successively from the adhesive to the back lining materials.
Example 33
Prescription is formed with embodiment 27, just intermediary medicine-containing gel type Drug Storage material is divided into five layers, from the adhesive to the back lining materials, and every layer of medicine that contains different proportion: 5%, 10%, 15%, 25%, 45%.Preparation method just according to corresponding drug ratios, is spread five layers with embodiment 31 successively from the adhesive to the back lining materials.
The present invention adopts hydrophilic high molecular material by blend and appropriately crosslinked, prepared hydrophilic gel type Drug Storage material with good voltage-dependent characteristic, adopt this Drug Storage material to prepare gel type dexketoprofen plaster as pressure sensitive adhesive, preparation technology is simple, need not high-temperature chemical reaction, thereby avoided the instability of dexketoprofen under the high temperature, do not used any deleterious organic solvent in the preparation process, non-environmental-pollution.Performance test and application result show, gel type dexketoprofen plaster has with skin good biocompatibility (non-stimulated and anaphylaxis), ventilative water permeability is good, adhibit quality is good, it is suitable to peel off, take off repeatedly that subsides property is good, percutaneous penetration of drugs is effective and drug loading characteristics such as big (the highest can reach 30%), can satisfy the needs of dexketoprofen clinical treatment.
Because gel-type Drug Storage material of the present invention all has well dispersing or dissolving property for hydrophilic medicament and lipophilic drugs, drug loading is big, therefore, thinking of the present invention also can be applicable to other hydrophilic medicament or lipotropy nonsteroidal antipyretic-antalgic and anti-inflammatory drug.
Claims (5)
1. a gel type dexketoprofen plaster is made of back lining materials, gel-type Drug Storage material and adhesive, wherein,
Medicine-containing gel type Drug Storage material contains the dexketoprofen of 0.5～30.0wt%, the gel-type Drug Storage host material of 5.0～80.0wt%, 0.5 the drug solvent of～40.0wt%, 0.5 the wetting agent of～30.0wt%, and the transdermal absorption accelerator of 0.5～8.0wt%;
Transdermal absorption accelerator is at least a at least a or laurocapram and the propylene glycol at least a, carbamide at least a, Camphora in mixture, menthol and the butanols of ethyl acetate, oleic acid, linoleic acid, isopropyl myristate, α-pyrrolidone, N-N-ethyl pyrrole N-ketone, sodium laurylsulfate, N-N-methyl 2-pyrrolidone N-, glycerol, limonene, Oleum Terebinthinae, Borneolum Syntheticum, eucalyptus oil, Macrogol 200, salicylic acid and limonene or butanols and the butanols and the butanediol;
Described drug solvent and wetting agent are any in ethanol, isopropyl alcohol, n-butyl alcohol, 2-enanthol, propylene glycol, glycerol, 2,2'-ethylenedioxybis(ethanol)., Macrogol 200, PEG400, Macrogol 600, sorbic acid, linoleic acid, Ethyl linoleate, butyl oleate, isopropyl myristate, isopropyl palmitate and the tri-n-butyl citrate;
Described gel-type Drug Storage host material comprises:
Ultra high molecular weight polyethylene base ketopyrrolidine or contain the unitary copolymer of vinyl pyrrolidone, its molecular weight M
1Be 200,000＜M
1≤ 250 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%;
Low-molecular-weight polyvinyl pyrrolidone or contain the unitary copolymer of vinyl pyrrolidone, its molecular weight M
2Be 0.3 ten thousand≤M
2≤ 20 ten thousand, the content in the Drug Storage host material is 1.0～60.0wt%;
Polyvinyl alcohol: its molecular weight M
3Be 1.0 ten thousand≤M
3≤ 20 ten thousand, the content in the Drug Storage host material is 1.0～50.0wt%; The perhaps mixture of polyvinyl alcohol and Polyethylene Glycol, the molecular weight M of polyvinyl alcohol
3Be 1.0 ten thousand≤M
3≤ 20 ten thousand, the molecular weight M of Polyethylene Glycol
4Be 0.08 ten thousand≤M
4≤ 10 ten thousand, the two content in the Drug Storage host material is 1.0～60.0wt%;
Cross-linking agent, content are 0.1～10.0wt%, and this cross-linking agent is glutaraldehyde, succinic acid, Biformyl, Azelaic Acid, acetic anhydride, maleic anhydride or succinic anhydride;
Surplus is a water;
Described back lining materials is elastic non-woven cloth, cotton, blended cloth or the paper material that hydrophobization is handled;
Described adhesive is paper, polyester, polyethylene, polypropylene, polystyrene or the silication polyester of surface through the silicone oil release treatment.
2. a kind of gel type dexketoprofen plaster according to claim 1 is characterized in that: the described high-molecular weight unitary copolymer of vinyl pyrrolidone that contains is: vinylpyrrolidone/vinyl acetate copolymer 73, vinylpyrrolidone/vinyl acetate copolymer 64, vinyl pyrrolidone-dimethyl maleic acid copolymer or vinyl pyrrolidone-MAAm oxypropyl trimethyl ammonium chloride copolymer.
3. a kind of gel type dexketoprofen plaster according to claim 1 and 2 is characterized in that: the described low-molecular-weight unitary copolymer of vinyl pyrrolidone that contains is: vinylpyrrolidone/vinyl acetate copolymer 37, vinylpyrrolidone/vinyl acetate copolymer 55, vinyl pyrrolidone-styrol copolymer or vinyl pyrrolidone-quaternary ammoniated copolymer of dimethylamino methyl ethyl acrylate.
4. a method for preparing the described gel type dexketoprofen plaster of claim 1 the steps include:
(1) preparation gel-type Drug Storage host material: in the reactor that has stirring and heater, add the Drug Storage host material, comprise the polyvinyl pyrrolidone of high and low molecular weight or contain unitary copolymer of vinyl pyrrolidone and polyvinyl alcohol, perhaps polyvinyl alcohol and Polyethylene Glycol, and add entry, stir under 60～100 ℃ of temperature, make each component mix homogeneously, controlling temperature then is 40～45 ℃, adding its pH value of acid adjusting is 4～5, add cross-linking agent again, continue to stir 45～75min, mix homogeneously;
(2) preparation medicine-containing gel type Drug Storage material: have in the reactor of stirring and heater at another, add dexketoprofen, transdermal absorption accelerator, drug solvent and wetting agent, stir under 60～100 ℃ of temperature, make each component mix homogeneously and medicine is dissolved fully, treat that the Drug Storage host material that after medicine dissolves fully itself and step (1) is made stirs, fully mix homogeneously;
(3) adopt coating process that the medicine-containing gel type Drug Storage material of above-mentioned preparation is made patch.
5. method according to claim 4 is characterized in that: the patch of described step (3) contains two layers or more gel-type Drug Storage material.
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| JP4879928B2 (en) * | 2008-03-25 | 2012-02-22 | 帝國製薬株式会社 | Aqueous patch containing ketoprofen lysine salt |
| CN101518520B (en) * | 2009-04-09 | 2011-07-27 | 浙江省医学科学院 | Framework-type transdermal patch with dextro ketoprofen accumulated in subcutaneous deep tissues |
| CN102068405A (en) * | 2010-12-16 | 2011-05-25 | 天津工业大学 | Ketoprofen gel and preparation method thereof |
| JP6151935B2 (en) * | 2013-03-11 | 2017-06-21 | 日東電工株式会社 | Transdermal absorption enhancing composition and patch preparation |
| CN106038515A (en) * | 2016-04-27 | 2016-10-26 | 邬春艳 | A self-heating transdermal drug delivery system having a heat-sensitive substrate and a preparing method thereof |
| CN108785286A (en) | 2017-04-28 | 2018-11-13 | 日东电工株式会社 | Transdermal absorption formulation |
| CN109432061B (en) * | 2018-11-09 | 2020-10-30 | 北京德默高科医药技术有限公司 | Multi-layer transdermal delivery system containing ibuprofen or structural analogs thereof |
| CN110693860B (en) * | 2019-11-26 | 2023-03-31 | 湖南九典制药股份有限公司 | Gel plaster containing ketoprofen and preparation method thereof |
| CN112870427A (en) * | 2021-03-12 | 2021-06-01 | 上海创始医疗科技(集团)有限公司 | Hydrogel elastic patch and preparation method thereof |
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| CN1260172A (en) * | 1998-12-18 | 2000-07-19 | 国家医药管理局上海医药工业研究院 | Dextro-betoprofen preparation |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
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| CN1260172A (en) * | 1998-12-18 | 2000-07-19 | 国家医药管理局上海医药工业研究院 | Dextro-betoprofen preparation |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
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