CN106822049A - Newcooperative medical system drug paste agent Ketoprofen paster and preparation method thereof - Google Patents

Abstract

The invention discloses a kind of Ketoprofen patch and preparation method thereof, SIS and styrene-isoprene di-block copolymer, tackifier, softening agent and antioxidant are contained in described patch.Patch of the invention have to skin stimulate very small, adhesive to skin without allergy, it is long-term preserve when medicine stability is good and stickups of skin is good, it is repeatable paste, meet that water is not inharmonious, be particularly splendid with the stickup at the position such as knee and ancon the features such as.Each component content of adhesive is by percentage to the quality in constituting above-mentioned patch：The summation of SIS and styrene-isoprene di-block copolymer is between 10%~55%, below high molecular weight polyisobutylene 22%, middle-molecular-weihydroxyethyl polyisobutene is below 30%, below low-molecular-weight polyisobutylene 25%, tackifier are between 10%~60%, between 12%~55%, antioxidant is between the 0.01%~2.5% of contained framework material total amount to softening agent.

Description

Newcooperative medical system drug paste agent Ketoprofen paster and preparation method thereof

Technical field

The present invention relates to adhesive and patche, in particular to a kind of medicinal adhesive and it is prepared from this Ketoprofen paster, be used to treat pain in waist and lower extremities, courbature, arthralgia etc..

Background technology

Ketoprofen or its solution are mixed with the adhesive containing styrene-isoprene-phenylethene based block copolymer class It is attached on backing cloth after closing uniformly, and is prepared into anti-inflammatory town after the another side covering release liners or mould release membrance of glue medicine layer The externally applied transdermal patch of pain effect is known.

But in the data such as existing patent document, there is the Ketoprofen paster for containing or not contain MENTHOL, it is related Respectively elaborate to contain or not contain the advantage and disadvantage of MENTHOL in patent document, its advantage can be to keep sustained drug to lead to Cross human body and keep needed for blood density of medicine, it has the disadvantage that the smell is awful, at the same MENTHOL it is readily volatilized and cause produce Menthol content is changed greatly during long-term preservation after product listing, and the saturating effect of rush to medicine can produce very big shadow Ring, and then have influence on drug quality and curative effect, while easily there is chemical reaction generation noval chemical compound with Ketoprofen in MENTHOL, And then have influence on content, drug quality and the medication validity of Ketoprofen in patch.

And shown in the data such as Ketoprofen Patents, the document of menthol are not contained, in order to without MENTHOL When, it is up to standard and play same therapeutic effect to play drug transdermal amount, is made with atoleine, olive oil, soybean oil, castor oil etc. The class adhesive containing styrene-isoprene-phenylethene is added after Ketoprofen is completely dissolved for the lytic agent of Ketoprofen In be prepared into percutaneous plaster or exist with the molecular state that is completely dissolved in such adhesive, but according in its Patent data Described content is tested, and discovery is tested by us, under the effective dose included in ketoprofen transdermal patch patent, In ultrasonic, stirring, lengthening dissolution time, roll up the above oils consumption（Explanation：It is added to when oils consumption is increased In the case that the cohesive force of adhesive is destroyed completely）Ketoprofen can not be completely molten in above-mentioned oil based solvent Deng under the conditions of Solution, when above oily substance is heated to more than the fusing point of Ketoprofen, Ketoprofen melts completely, and works as temperature less than Ketoprofen Fusing point when, Ketoprofen is separated out in above-mentioned oil, but, when the above-mentioned condition of high temperature is chronically at, above-mentioned oils destroys meeting Volatilization is more serious, does not ensure that the stability of product quality.If prepared under conditions of less than Ketoprofen fusing point foregoing special Oils in sharp data is the Ketoprofen paster of lytic agent, then Ketoprofen must be with scattered form rather than be completely dissolved point Sub- state is present in paster, this to the medicament contg uniformity, release performance, the transmitance through human body skin, paster it is effective Property have very big influence.

The content of the invention

In view of above-mentioned existing problem, the invention reside in a kind of paster containing Ketoprofen is provided, it does not contain L- peppermints Alcohol, while being prepared into Ketoprofen true solution from the solvent that can be completely dissolved Ketoprofen and containing styrene-isoprene-benzene The adhesive of ethene well mixed being attached to is prepared into ketoprofen transdermal paster on backing cloth, the release performance of its Ketoprofen, thoroughly Skin performance can reach prescribed limit, can steadily in the long term play the anti-inflammatory analgesic effect of medicine, and the stability of medicine is excellent, does not have There is unpleasant odor dispersion, attaching performance is excellent, it is without allergy, non-stimulated, painless during stripping, repeatable stickup, sweat is stagnant Stay disease to fall below sufficiently low level, greatly reduce light sensitivity of the skin to Ketoprofen.It is used to prepare transdermal patch simultaneously A kind of novel preparation process method of agent, can, medicine heated time relatively low in temperature it is extremely short（Between about 10s-60s） Under conditions of be prepared from, low temperature, in the short time farthest protect effective ingredient, it is to avoid high temperature is to medicine Destruction.

It is an object of the present invention to provide one kind with " SIS or/and Styrene-isoprene block copolymer " for framework material adhesive as host material, the external application for being used to prepare pastille is saturating Skin patch simultaneously selects Ketoprofen to be prepared for Ketoprofen paster for model drug.

The present inventor has carried out very deep system research to reach the above-mentioned purpose for preparing Ketoprofen paster, finds In the ketoprofen transdermal paster drug system for not using MENTHOL, if according to the selection phase described in Patents documents The oils such as plasticizer oil, particularly atoleine, olive oil, soybean oil, oil with hydrogenated soybean, epoxidized soybean oil, castor oil are closed, The consumption of above oils is in the case where ketoprofen transdermal paster adhesive is met with usable cohesive force requirement, you can in the above Ketoprofen is dissolved in the research on maximum utilized quantity of the above-mentioned oils in Ketoprofen paster, is found in above-mentioned various oil, Ketoprofen can only be located In dispersity rather than being completely dissolved state, this release performance to medicine, percutaneous abilities, uniformity of dosage units have very big shadow Ring.By substantial amounts of research experiment, have selected a kind of is framework material with " styrene-isoprene-phenylethene " to the present inventor Matrix adhesive there is excellent compatibility and the solvent of Ketoprofen can be completely dissolved and solve above-mentioned Ketoprofen in gluing Problems of dissolution in agent, and reached Ketoprofen paster there is the purpose of excellent release and percutaneous abilities, while also solving The Ketoprofen paster problem that the smell is awful containing MENTHOL, so as to complete the present invention.

That is, it is an object of the present invention to provide a kind of ketoprofen transdermal paster, the paster is main by with cementability Can pressure-sensitive adhesive, Ketoprofen and being used to dissolve the solvent of Ketoprofen, backing cloth, release liners group to adhesive attachment Into.The wherein above-mentioned adhesive with pressure-sensitive is with " SIS " and/or " benzene second The elastomer of alkene-isoprene block copolymer " is framework material, tackifier, caking property polymeric composition and above-mentioned each group Point oil with excellent compatibility is constituted as softening agent, the above-mentioned solvent for being used to dissolve Ketoprofen include butanediol, propane diols, Ethanol, ethyl acetate, Laurocapram（Low-molecular-weight polyisobutylene）Deng.Above-mentioned backing cloth includes polyesters（Such as PU classes）、 Elasticity manufacture cloth or stiff system with warp-wise or warp-weft two-way that at least one of polyethylene kind, PP type are made Make cloth, non-woven fabrics etc..Above-mentioned mould release membrance is including PET, PE, PP, PU, release liners etc..

Ketoprofen transdermal patch of the invention is characterised by following composition, that is, choose it is proper amount of with it is above-mentioned " styrene- The oils that isoprene-styrene block copolymer ", tackifier, caking property high molecular polymer have excellent compatibility softens Agent, simultaneous selection can be completely dissolved Ketoprofen and have the solvent of excellent compatibility with adhesive, it is possible thereby to reach institute Have the following effects：With excellent medicine-releasing performance, percutaneous absorbability high, excellent skin attachment and repetition stickup property , can effectively prevent that sweat is detained disease, medicine stability is excellent, the medicament contg uniformity is excellent, pain when being effectively reduced stripping Pain.

In Ketoprofen paster of the invention, as " SIS " of framework material With line style, preferably star-like, two block structures, linear structure and two block structures, as the bone for preparing Ketoprofen patche Frame material, adds the block of a certain amount of styrene-isoprene two in SIS Copolymer and select the amount with suitable combinated styrene content to be a need for, this release performance to medicine, percutaneous abilities, Processing characteristics has a very big impact, while tack, sweat the delay disease, repetition stickup performance to skin have significantly changing It is kind.

In ketoprofen transdermal paster of the invention, benzene is combined in above-mentioned SIS The content of ethene is 12%~30%, the number-average molecular weight Mn of SIS 70000~ Between 250000, preferred number average molecular weight Mn between 75000~200000, more preferably number-average molecular weight Mn 85000~ Between 160000.Selecting the SIS of this structure has appropriate cohesive force, such as Fruit its molecular weight Mn less than 70000 or combinated styrene content content be less than 12% when, the cohesive force of framework material is relatively Small, the pad pasting being prepared into is susceptible to strike-through, excessive glue, the problem using residual, if molecular weight is higher than 250000 and combines benzene The cohesive force of framework material is relatively large when the content of ethene is more than 30%, can cause that pad pasting applicating property is poor, drug ingedient release Putting poor performance, percutaneous abilities can further be deteriorated.SIS in matrix adhesive Weight/mass percentage composition between 10%~55%, between preferably 14%~50%, between more preferably 17%~42%, more preferably Between 20%~34%.When weight/mass percentage composition be less than 10% when matrix adhesive cohesive force become excessively poor, it is prepared into patch Film glue-line is susceptible to damaged, rotten glue, strike-through, the problem of excessive glue, and drugloading rate very little；When weight/mass percentage composition is more than 55% When, the cohesive force of matrix adhesive is excessive, and poor processability, processing temperature is too high, can be to heat sensitive drugs nutritional ingredient Damage, can also influence release and the percutaneous abilities of drug ingedient.

Combinated styrene content content is between 12%~30% in styrene-isoprene di-block copolymer, preferably in combination with benzene Ethylene contents are 14%~30%, number-average molecular weight Mn between 30000~200000, preferred number average molecular weight Mn 60000~ Between 160000.The styrene-isoprene di-block copolymer of this structure is selected to be advantageous in that and can either preferably adjust The processing characteristics of framework material styrene-isoprene-phenylethene is saved, its softening point is reduced, it is had well with skin Sticking performance, but the problem for destroying its cohesive force, the wherein quality hundred of styrene-isoprene block copolymer will not be caused Point content accounts for SIS and styrene-isoprene di-block copolymer gross mass Less than 35%, preferably less than 30%, more preferably less than 20%, when its weight/mass percentage composition is higher than the 35% of the two total content, hold Easily cause the cohesive force of framework material to be greatly reduced, easily produce excessive glue, backing strike-through, skin residual, drugloading rate reduction etc. Problem.

Ketoprofen transdermal patch in the present invention, is characterised by that the softening agent selected by pharmaceutical carrier adhesive therein includes Low-molecular-weight polyisobutylene of the molecular weight between 100~1000, naphthenic oil, atoleine, soybean oil and its derivative such as ring One or more in the mineral oil such as oxygen soybean oil and oil with hydrogenated soybean, castor oil or vegetable oil, preferably with framework material benzene Ethene-isoprene-styrene block copolymer and styrene-isoprene di-block copolymer compatibility are preferably and in temperature It is the grease type with good thermo-oxidative stability between 130 DEG C~200 DEG C to spend, and preferred molecular weight is between 600~1000 One or several in low-molecular-weight polyisobutylene, atoleine, soybean oil, epoxidized soybean oil, oil with hydrogenated soybean, more preferably One or two kinds of in the low-molecular-weight polyisobutylene and atoleine that are molecular weight between 600~1000.Softening agent exists Weight/mass percentage composition in pharmaceutical carrier adhesive between 12%~55%, between preferably 17%~45%, more preferably Between 20%~32%, through our experimental studies, when softening agent weight/mass percentage composition between when, pharmaceutical carrier adhesive tool There is preferable cohesive force, have to framework material styrene-isoprene-phenylethene and styrene-isoprene molten well Solution effect, while prepared adhesive has relatively low softening point, has preferable processing characteristics at a lower temperature, Low softening point and preferable processing characteristics has protective effect in the process of product to drug ingedient, especially for Hot oxygen is unstable or volatile drug ingedient, can substantially reduce its degree or drop for being oxidized due to high temperature or being decomposed The volatilization of low effumability drug ingedient, styrene-isoprene-benzene if the weight/mass percentage composition of softening agent is less than 12% The solute effect of ethene is poor, and dissolution time is greatly increased, and can destroy the structure of framework material, while the medicine being prepared into is carried The softening point of body adhesive is higher, and cohesive force is big, poor processability, and high temperature can destroy medicine nutritional ingredient, particularly hot Oxygen is unstable or effumability medicine nutritional ingredient, is not suitable for adding drug ingedient, while the release transdermal of drug ingedient can become Difference；When the weight/mass percentage composition of softening agent is more than 55%, then its cohesive force is deteriorated, and the embossability of adhesive is deteriorated, and easily occurs oozing The problems such as glue, excessive glue, skin are remained.

Ketoprofen transdermal patch in the present invention, is characterised by that the tackifier selected by pharmaceutical carrier adhesive therein are main Including rosin resin and its derivative species such as ester gum, hydrogenated rosin, C5 Petropols and its derivative, C9 oil trees Fat, terpene resin, low-molecular-weight polyisobutylene of the molecular weight between 1000~4900, molecular weight is between 16000~50000 Middle-molecular-weihydroxyethyl polyisobutene, high molecular weight polyisobutylene of the molecular weight between 50,000~200,000, polyurethanes is polyamide-based, Epoxy resin, polyacrylic, one or several in silicone.It is preferred that rosin resin and its derivative such as ester gum And hydrogenated rosin, C5 Petropols and its derivative, molecular weight low-molecular-weight polyisobutylene between 1000~4900, molecular weight Middle-molecular-weihydroxyethyl polyisobutene between 16000~50000, high molecular weight polyisobutylene of the molecular weight between 50,000~200,000, Polyurethanes, polyacrylic, one or more in silicone.More preferably rosin resin and its derivative such as rosin Glyceride and hydrogenated rosin etc., molecular weight between 1000~4900 low-molecular-weight polyisobutylene, molecular weight 16000~ One kind in the high molecular weight polyisobutylene of middle-molecular-weihydroxyethyl polyisobutene, molecular weight between 50000 between 50,000~200,000 or It is several, and added tackifier weight/mass percentage composition between 10%~60%, between preferably 15%~55%, further preferably Between 25%~45%, between more preferably 32%~45%.If the content of tackifier is less than the 10% of adhesive gross mass, Effective stickup performance can not be provided, it is impossible to the need for meeting as drug transdermal patch, when the content of tackifier is higher than 60% When, its peeling force is excessive, and skin has serious pain, heavy damage epidermal structure, while to the cohesion of adhesive during stripping Power has compared with havoc, has influence on its drugloading rate, there is excessive glue phenomenon when using around paster, and skin surface residual is serious, Er Qiehui Make the burst size of Ketoprofen in paster and rate of release reduction.

The polyisobutene of different molecular weight is especially have selected in the present invention as the stickup performance for changing adhesive, mainly with The polyisobutene of different molecular weight is used cooperatively to reach paster stickup requirement, and the polyisobutene of this kind of different molecular weight is mainly wrapped The molecular weight middle-molecular-weihydroxyethyl of low-molecular-weight polyisobutylene, molecular weight between 16000~50000 between 1000~4900 is included to gather One or more in the high molecular weight polyisobutylene of isobutene, molecular weight between 50,000~200,000.Its middle-molecular-weihydroxyethyl is 1000 Low-molecular-weight polyisobutylene accounts for less than the 25% of adhesive gross mass between~4900, between preferably 0.5%~17%, further Between preferably 1.5%~12%, the weight/mass percentage composition of the polyisobutene of above-mentioned low-molecular-weight is more than the 25% of adhesive total amount When, the drawbacks of easily trigger the destroyed problem of cohesive force and release amount of medicine to be reduced with rate of release.Above-mentioned molecular weight exists Middle-molecular-weihydroxyethyl polyisobutene between 16000~50000 accounts for less than the 30% of adhesive gross mass, preferably 0.5%~20% it Between, between more preferably 1.5%~11.5%, when the content of the polyisobutene of above-mentioned middle-molecular-weihydroxyethyl is higher than 30%, can trigger The drawbacks of Cohesive failure, the problem of skin residual and release amount of medicine and rate of release are reduced, while adherence force is excessive, can draw Hair peels off the problem of pain.High molecular weight polyisobutylene of the above-mentioned molecular weight between 50,000~200,000 accounts for adhesive gross mass Less than 22%, between preferably 0.5~15%, between more preferably 1.5%~12%, when the polyisobutene of above-mentioned HMW Content be higher than 22% when, adhesive viscosity can be triggered excessive, poor fluidity, it is not easy to process, can also make medicine burst size and Rate of release reduction, the problem of percutaneous rate reduction.

Ketoprofen transdermal patch in the present invention, is characterised by that pharmaceutical carrier adhesive therein can also include antioxidant, It is used to prevent framework material to be oxidized destruction, and then influences the drugloading rate of adhesive, cohesive force, stripping performance, skin to stick effect Really, it is also possible to have influence on the shelf-life of medicine, the quality problems of medicine are triggered, wherein antioxidant includes BHT264, antioxidant 1010 etc., weight/mass percentage composition shared by the antioxidant in pharmaceutical carrier adhesive be contained framework material gross mass 0.01%~ Between 2.5%, between preferably 0.1%~2%, between more preferably 0.4%~1.2%.

Ketoprofen transdermal patch in the present invention, is characterised by that pharmaceutical carrier adhesive therein is also an option that addition is water-soluble Property macromolecular material or hydroaropic substance further improve itself and the sticking performance of skin and the affine performance of medicine, this kind of Hydroaropic substance includes compound monomer, oligomer, high polymer.Can be to synthesize, or natural from the point of view of from source Such as various animals and plants extracts for extracting.Specifically have propane diols, glycerine, polyacrylate and its an esters, hyaluronic acid and Its esters, cellulose family, starch, poly-aspartic-acid, algin class such as sodium alginate etc., Aloe Vera Gel, polyvinyl alcohol, hydrolysis The water-soluble macromolecules such as polyacrylamide, polyvinylpyrrolidone, other natural plant gum, animal glue, also including crosslinked polypropylene One or more in the absorptive substances such as the copolymer of olefin(e) acid and its esters, acrylic acid and starch, vinyl alcohol etc..The above The weight/mass percentage composition of water-soluble high-molecular material and hydroaropic substance in carrier adhesive between 0~10%, preferably Between 0.5~5%.

Ketoprofen transdermal patch in the present invention, is characterised by that pharmaceutical carrier adhesive therein can also be added including other With the special auxiliary agent such as calcium carbonate, titanium white that improve the function demands such as its embossability, cohesive force, medicine dispersion effect and stability The fillers such as powder, zinc oxide, talcum powder, its weight/mass percentage composition in adhesive between 0~10%, between preferably 1%~6%, The weight/mass percentage composition of filler influences whether the effect that sticks of adhesive not above 10%, otherwise, and can make patch in itself Become harder.

Ketoprofen transdermal patch of the invention be characterised by the weight/mass percentage composition of wherein Ketoprofen 0.8%~3% it Between, between preferably 1.5%~2.5%, disclosure satisfy that the ketoprofen transdermal of q.s absorbs by making its content be in the scope, More preferably weight/mass percentage composition is 2%, and the haemoconcentration of enough Ketoprofens can be obtained under the concentration conditions, is played Extraordinary therapeutic effect.

Ketoprofen transdermal patch in the present invention is characterised by wherein also containing transdermal enhancer, and these transdermal enhancers include bay Azone, propane diols, menthol, oleic acid, isopropyl myristate etc., are preferably able to dissolve the transdermal enhancer of Ketoprofen, such as bay Azone, propane diols, menthol, further preferred Laurocapram select it to have following benefit as transdermal enhancer：One be can be molten Solution Ketoprofen, Ketoprofen solubility wherein is larger；Two is relatively good to the saturating effect of rush of Ketoprofen；Three is heat endurance phase To problem that is preferable, being not easy volatilization occur in process；Four be will not be with Ketoprofen chemically reactive, wherein transdermal enhancer Weight/mass percentage composition is preferable between 0.5%~4.5% between 0.1%~6%, between better than 1%~3%.

Ketoprofen transdermal patch of the invention is characterised by it is also an option that following backing cloth is used as supporter, including nothing Cloth is spun, weave cloth, bidirectional elastic cloth and unidirectional stretch fabric, polyurethanes film etc., the thickness of selected backing cloth is 5 μm~1500 Between μm, between preferably 100 μm~1000 μm, the backing cloth in thickness range is selected more than, preferably branch can be provided Will not seem " thick and heavy " again on the premise of support force, and the effect for preferably being sticked with skin can be provided.

Ketoprofen transdermal patch of the invention is characterised by that its coating is prepared into release membrane material bag used during pad pasting The mould release membrance and release liners of the non-papery class such as PET, PE, PP, PU, PC are included, these mould release membrances or release liners can be that one side is release Can also be it is two-sided release, the thickness of mould release membrance used between 0.01mm~0.5mm, preferably 0.03mm~0.3mm it Between.The interval mould release membrance more than of selection thickness has preferable advantage in the realization of product preparation process, while can also carry For enough support forces.

Ketoprofen transdermal patch in the present invention, be characterised by the contact area of its medicine layer and skin 70cm2~ Between 140cm2.

Ketoprofen transdermal patch in the present invention, when being characterised by that said medicine layer is contacted with skin, ketone in 0~72 hour The blood concentration versus time area under a curve AUC of ibuprofen（0~72hr）It is 1100~3000nghr/ml, its highest blood is dense Degree Cmax is 50~150ng/ml.

The present invention also aims to provide a kind of novel preparation process for preparing ketoprofen transdermal paster in the present invention, this The method that kind prepares medicine patch has medicine heated time short, it is only necessary to which 10s~60s, medicine heating temperature is relatively It is low, below 120 DEG C, this low temperature and short process conditions of medicine heated time are to effumability therein and the medicine of thermal sensitivity Thing composition has extraordinary protective effect, can to greatest extent avoid these compositions from being destroyed, and improves the validity of medicine And safety in utilization, concrete technology flow process is as follows：

1）The adhesive that will be prepared is added in the glue melting box with precision metering pump, sets appropriate melt adhesive temperature, treats glue Glutinous agent is standby after melting completely；

2）Ketoprofen is stirred to being completely dissolved and be well mixed according to Laurocapram is added to after determination amount accurate weighing, and It is added in the explosive box with precision metering pump and agitating paddle and stirs liquid according to certain requirement, it is standby；

3）Coating machine is opened, during drug extract and glue accurately pumped into screw machine respectively through glue pump and Teat pipette, in a constant temperature Glue and drug extract are quickly well mixed under degree, incorporation time is between 20s~80s；

4）The glue medicine mixture that will be mixed uniformly is applied on backing cloth and covers mould release membrance according to the standard of regulation, is die-cut to one The paster of set pattern lattice.

Specific embodiment

Some embodiments of the present invention are described below, to be further understood that the present invention.

Description of test：1）Release test in this patent embodiment is according to the slurry described in China national pharmacopeia relief test method Method is tested, and condition determination is as follows：

Experimental liquid：0.9% physiological saline；32 ± 0.5 DEG C of test temperature；Revolution 50rpm,

Transdermal test in this patent embodiment is carried out according to China national pharmacopoeial requirements, and selection isolated mouse skin is tested, Experiment reception liquid is 0.9% physiological saline or alcohol water blend.

Embodiment 1

This experiment with SIS that combinated styrene content content is 15% as framework material, Atoleine is softening agent, and hydrogenated rosin glyceride is prepared for ketoprofen transdermal patch matrix adhesive for tackifier, specifically It is as follows：

Gluing agent prescription used：

Ingredient names	SIS	Hydrogenated rosin glyceride	Atoleine	Antioxidant	Other function additives
						Content Wt/%	29.9	22.4	42.7	0.2	4.8

It is that framework material prepares medical transdermal patch adhesive with " SIS ", adds Plus tackifier, softening agent, antioxidant, other specific function auxiliary agents such as inorganic filler, hydroaropic substance etc..Specific auxiliary agent raw material is such as Under：

Tackifier：In the present embodiment tackifier used can also be it is following in use cooperatively for one or more, including：Rosin tree Lipid, hydrogenated rosin resin class, C5 Petropols class, hydrogenation C5 Petropols class, terpene resin class, C9 resinaes, C5-C9 Resinae, polyisobutene, middle-molecular-weihydroxyethyl polyisobutene, low-molecular-weight polyisobutylene of HMW etc..

Softening agent：In the present embodiment softening agent used can be it is following in use cooperatively for one or more, including：Liquid Body paraffin class, cycloalkanes oils, hydrogenated soybean oils, epoxy soybean oils, low-molecular-weight polyisobutylene, other suitable mineral oil Class.

Other function additives have：The inorganic fillers such as calcium carbonate, talcum powder, zinc oxide, hydrophilic macromolecule, water imbibition thing Matter, amphiphilic macromolecular, the surfactant of small molecule, inorganic filler, specific function auxiliary agent are as improving certain performance Nanometer materials, synthetic rubber class etc..Other function additives are used cooperatively comprising one or more following materials：It is hydrophilic Property macromolecule, absorptive substance, amphiphilic macromolecular, the surfactant of small molecule, inorganic filler, specific function auxiliary agent as use In nanometer materials, synthetic rubber class for improving certain performance etc., such as 1）Water-soluble macromolecule：It is with natural animal-plant Raw material is extracted and obtained：Such as starch, cellulose, natural plant gum, animal glue；2）Naturally（Or chemical modification）Polymer：Mainly have Biogum such as algin etc., modified starch and modified cellulose, such as algin, Aloe Vera Gel, chitin, CMS, acetic acid Starch, hydroxymethyl cellulose, carboxymethylcellulose calcium, cyclodextrin etc.； 3）Synthetic polymer：There are polymer resin and condensation class tree The class of fat two, such as polyacrylamide (PAM), hydrolyzed polyacrylamide (HPAM)), polyvinylpyrrolidone (PVP), methacrylic acid Beta-hydroxy ethyl ester (HEMA), long-chain aliphatic acrylate (RA), super absorbent resin（Such as crosslinked salt polyacrylate class, starch-poly- Acrylate copolymer, acrylic acid-ethenol copolymer, polyoxyethylene crosslinked, cross-linked isobutylene-maleate copolymer System etc.）Deng；

The specific preparation method of adhesive is as described below：

1）To adding SIS in reactor, and stirring is opened simultaneously；

2）By auxiliary agent powder（Antioxidant etc.）Add in atoleine, added after homogeneous in a reservoir in reactor, continue to stir；

3）Continuously add hydrogenated rosin glyceride Petropols；

4）After charging is finished, the temperature for setting oil bath pan is 160 DEG C, starts clock reaction 3.5h, rear plastic emitting, you can.

Embodiment 2

This experiment is with SIS that combinated styrene content content is 15% and styrene-different Pentadiene di-block copolymer is framework material, molecular weight be 400 low-molecular-weight polyisobutylene for softening agent, hydrogenated rosin is sweet The polyisobutene of grease and different molecular weight is prepared for cervicodynia patch pharmaceutical carrier adhesive for tackifier, specific as follows：

Gluing agent prescription used：

Ingredient names	SIS and styrene-isoprene di-block copolymer	Hydrogenated rosin glyceride	Middle-molecular-weihydroxyethyl polyisobutene	Polyisobutene Mn=400	Antioxidant	Other function additives
							Content Wt/%	29.8	13.6	18.1	32.7	0.1	5.7

With SIS and styrene-isoprene di-block copolymer as framework material Prepare medical transdermal patch adhesive, addition tackifier, softening agent, antioxidant, inorganic filler, other specific function auxiliary agents Deng the preparation method of other specific auxiliary agent raw material type compositions and its adhesive is as described in example 1 above.

Embodiment 3

Ketoprofen solute effect is tested：The lytic agent to Ketoprofen with excellent dissolution effect has been investigated and have selected in this experiment, Focal selection have simultaneously promote permeability can Ketoprofen lytic agent, also high spot reviews other patents such as ZL Patent No.s in experiment 01808284.X and patent publication No. be in CN101137356A it should be particularly mentioned that with atoleine, olive oil, soybean oil, castor-oil plant The solute effect of Ketoprofen when oil etc. are for Ketoprofen lytic agent, concrete outcome is as follows：

The solute effect of table, Ketoprofen in different lytic agents

Solvent species	Ketoprofen content/%	Normal-temperature dissolution effect	60 DEG C of solute effects	85 DEG C of high-temperature digestion effects
					Atoleine	20	It is insoluble	It is insoluble	Dissolving, is down to normal temperature and crystallization Ketoprofen occurs
Olive oil	20	It is insoluble	It is insoluble	Dissolving, is down to normal temperature and crystallization Ketoprofen occurs
					Apricot kernel oil	20	It is insoluble	It is insoluble	Dissolving, is down to normal temperature and crystallization Ketoprofen occurs
Peanut oil	20	It is insoluble	It is insoluble	Dissolving, is down to normal temperature and crystallization Ketoprofen occurs
					Oleic acid	20	It is insoluble	It is insoluble	Dissolving, is down to normal temperature and crystallization Ketoprofen occurs
Propane diols	20	Dissolving is complete	Dissolving is complete	Dissolving, is down to normal temperature and crystallization Ketoprofen does not occur, but propane diols is volatile during high temperature
					Laurocapram	20	Dissolving is complete	Dissolving is complete	Dissolving, is down to normal temperature and crystallization Ketoprofen does not occur

From the point of view of dissolving situation from above Ketoprofen in different lytic agents, ZL Patent No.s 01808284.X and patent are disclosed Number in CN101137356A it should be particularly mentioned that the lytic agent with atoleine, olive oil, soybean oil, castor oil etc. as Ketoprofen It is at normal temperatures infeasible, the Ketoprofen dissolving when temperature is higher than more than 85 DEG C, but because the temperature of solvent reaches The fusing point of Ketoprofen, caused by Ketoprofen fusing, after temperature reduction, Ketoprofen starts again to be in crystalline state.But this for It is unfavorable to need Ketoprofen to be chronically under high temperature to its stability and Drug safety in production, so in patent 01808284.X and patent publication No. are that the lytic agent mentioned with atoleine etc. as Ketoprofen in CN101137356A at least exists 60 DEG C the following is irrealizable, unless be always held at a high temperature of more than 80 DEG C.Consider, in the present invention selection tool The Laurocapram for having rush permeability energy is the solvent of Ketoprofen.

Embodiment 4

This experiment is investigated to the heat endurance of Ketoprofen：Be have selected in experiment at 120 DEG C to better heat stability Laurocapram is the solvent of Ketoprofen, has investigated Ketoprofen stability at high temperature, is mainly carried out in terms of following two Investigate：One is the situation of change of the Ketoprofen content in different heated times under certain high temperature；Two is not within a certain period of time not With the changes of contents situation of Ketoprofen under high temperature, specific experiment and result are as described below：

Table, 110 DEG C when different heated times in Ketoprofen changes of contents situation

Ketoprofen changes of contents under different heating temperatures when table, 30min

Be can be seen that temperature is too high by above experimental result, the stability of Ketoprofen becomes in the case that heated time is long Difference, this can badly influence drug quality, therefore can realize quickly being well mixed glue medicine at low temperature using one kind And be coated with the ketoprofen transdermal patch preparation method of production and be necessary.

Embodiment 5

This experiment provides a kind of novel processing step for preparing ketoprofen transdermal patch, and this new transdermal patch prepares work Skill has medicine heated time extremely short, is between 30 seconds~60 seconds, the characteristics of homogeneous is quick, processing temperature is low, can effectively protect Drug ingedient, it is ensured that product quality.Pharmaceutical carrier adhesive used is preparation gained in embodiment 2, and specific preparation technology is as follows：

1）The adhesive prepared in embodiment 2 is added in the glue melting box with precision metering pump, melt adhesive temperature as 115 is set DEG C, it is standby after adhesive is completely dissolved；

2）Ketoprofen is added in azone according to the ratio for determining to be made its dissolving completely and is well mixed, and is added to precision Liquid is stirred in the explosive box of measuring pump and agitating paddle and according to certain requirement, it is standby；

3）Coating machine is opened, during the azone solution and glue of Ketoprofen accurately pumped into screw machine respectively through glue pump and Teat pipette, Glue and ketoprofen solution are quickly well mixed at a certain temperature, incorporation time is about 30s；

4）The glue medicine mixture that will be mixed uniformly is applied on backing cloth according to the standard of 150g/ ㎡ and covers mould release membrance, and mould It is cut into the paster of certain specification.

Embodiment 6

This experiment is prepared for ketoprofen transdermal paster, experimental selection with the adhesive for preparing in embodiment 2 as drug-carrier matrix, Laurocapram is the lytic agent and transdermal enhancer of Ketoprofen, and the addition of Ketoprofen is the 2% of glue medicine mixture gross mass, and with The preparation method of the ketoprofen transdermal paster described in embodiment 5 is prepared for containing menthol and does not contain menthol respectively Ketoprofen transdermal patch.

Table, ketoprofen transdermal patch pharmaceutical formulation table

Pharmaceutical formulation is numbered	Ketoprofen/g	Azone/g	Menthol/g
				Formula one	2.0	4.0	0
Formula two	2.0	4.0	2.0

Explanation：Dissolving is well mixed in only menthol need to being added to the azone solution of Ketoprofen when menthol is added.

Embodiment 7

Glue medicine in the case of being completely dissolved in the case of this measuring Ketoprofen is scattered in the atoleine and in azone The uniformity of dosage units of Ketoprofen in mixture.The Ketoprofen actual content in 1g glue medicine mixtures is determined in experiment, in 1g glue The theoretical content of Ketoprofen is 20mg in medicine mixture, and specific test result is as follows：

Ketoprofen under table, the different dissolved state uniformity of dosage units in glue medicine mixture compares

Test group number	Content/mg when disperseing in atoleine	Content/mg when being completely dissolved in azone
			1	18.2756	19.8302
2	19.8342	19.6982
			3	21.0557	20.0357
4	18.0202	19.9202
			5	22.0790	20.0266
6	20.2479	19.9849
			7	17.2447	19.9637
8	19.4942	20.0242
			9	18.1961	20.0661
10	23.1362	19.7482

The dissolved state of above experimental result explanation Ketoprofen is influential on the uniformity of Ketoprofen content in paster.

Embodiment 8

Ketone Lip river in the case of being completely dissolved in the case of this measuring Ketoprofen is scattered in the atoleine and in azone The comparing of Ketoprofen release performance stability in fragrant transdermal patch.Ketoprofen transdermal paster used is determined in experiment according to implementation Prepared by preparation method described in example 5, carry medicine adhesive according to prepared in embodiment 2, and paster specification is 5cm × 5cm, ketone Ibuprofen theoretical content is pasted for 7.143mg/, and release test reception liquid is 10% ethanol water, and specific test result is as follows：

The release that can be seen that the scattered Ketoprofen in atoleine from above experimental result is unstable, not in regularity, The Ketoprofen release being completely dissolved in azone is in certain regularity.The solute effect of Ketoprofen is released Ketoprofen in percutaneous plaster The stability for putting performance is influential, and the Ketoprofen being completely dissolved can provide more stable insoluble drug release effect, this for The quality and therapeutic effect of medicine are very important.

Embodiment 9

This experiment has carried out the test of related stickup performance to the ketoprofen transdermal paster prepared by formula one in embodiment 6, main To include initial bonding strength, holding power, the aspect of peel strength three, it is specific as follows：

Adhesive property index	Initial bonding strength/steel ball number	Holding power/h	Peel strength/（N/mm）
				Initial test result	14	＞ 16	0.47
Test result after 6 months	12	＞ 16	0.43

From the point of view of test data of experiment result, the Ketoprofen paster in the present invention have preferably paste performance and stripping performance and Cohesive force.

Embodiment 10

This experiment cuts into the paster that specification is 7cm × 10cm and carries out to Ketoprofen paster prepared in the formula of embodiment 6 one Human body pastes performance test, and specific method of testing and result be as follows：

Table, Ketoprofen paster human body adhesiveness and pain test result when peeling off

Drawn by above experimental result, the Ketoprofen paster in the present invention has preferable affine performance and stickup with human body skin Performance, peel strength is moderate, will not cause stronger pain, and also without allergic stimulated phenomenon, its combination property is preferable.Have Relatively preferably, there is not excessive glue yet in preferably adhesive property, cohesive force, does not occur residual after use, repeats to paste property reachable To more than 5 times, comfort is relatively preferable.

Embodiment 11

This experiment has carried out heat stabilization test method with Ketoprofen paster prepared by formula one in embodiment 6（Prove tack are tested Method）Test and place in the stability test case under certain heating temperature excessive glue situation around 6 months bak stays and contain with Ketoprofen Amount situation of change, Ketoprofen paster specification used is 7cm × 10cm/ patches in experiment, and Ketoprofen theoretical content is that 20mg/ is pasted.

1）Experiment condition：

Temperature：40±2℃；Humidity：75%±5% .

2）Test method：By test sample requirement three batches, packed by commercial standard, placed 6 months under prescribed conditions, in examination It is separately sampled to test period the 0th, 4, the 5, the end of month in June, tests Ketoprofen changes of contents situation.

Test period/month	0	4	5	6
					Ketoprofen content/mg	20.2058	19.8386	19.6239	19.3656
Sample appearance	Overflow adhesive, backing are without strike-through	Overflow adhesive, backing are without strike-through	Overflow adhesive, backing are without strike-through	Overflow adhesive, backing are without strike-through

Result is investigated by above stability experiment and can be seen that the stability for making ketoprofen transdermal paster by oneself preferably, energy Enough meet medicine quality standard requirement.

Embodiment 12

This experiment has investigated human body of the ketoprofen transdermal paster after normal temperature is preserved 6 months and has pasted performance, experiment Ketoprofen used Percutaneous plaster is prepared according to formula one in embodiment 6, and experiment sample specification is 7cm × 10cm, specific method of testing and result It is as follows：

Table, ketoprofen transdermal paster human body adhesiveness and pain test result when peeling off after 6 months

From above experimental result can be seen that the present invention in ketoprofen transdermal paster at normal temperatures for a long time place still have Performance is pasted well.

Embodiment 13

This experiment uses ketoprofen transdermal paster prepared by new transdermal patch preparation technology as experiment with formula one in embodiment 6 Sample, has investigated the stability of new-type heat-melting method moulding process, is with the Ketoprofen content tested in different phase paster specifically Index, the specification of Ketoprofen paster is 7cm × 10cm/ patches in experiment, and Ketoprofen theoretical content is that 20mg/ is pasted, specific experiment knot Fruit is as follows：

Medicine paste prepared by table, new transdermal patch preparation technology and Ketoprofen uniformity of dosage units test result in piece

The technology stability that can be seen that transdermal patch novel preparation process from above experimental result is extraordinary, and it can Meet uniformity of dosage units requirement of the pharmacopeia to percutaneous plaster.

Embodiment 14

This experiment is prepared for containing menthol and the ketoprofen transdermal paster for not containing menthol according to the formula in embodiment 6, It it is 40 ± 2 DEG C in temperature, humidity tests the content of wherein Ketoprofen after being placed 4 months for 75% ± 5%, investigation contains hydroxyl Influence of the menthol to Ketoprofen stability, specimen in use specification is 7cm × 10cm/ patches in experiment, and Ketoprofen theoretical content is 20mg/ is pasted, and specific experiment is as follows：

In an experiment it also will be understood that one is tested precondition, i.e., in this experiment, in order to reduce Ketoprofen content as far as possible Difference may exist on experimental result to be influenceed, so the paster sample employed in experiment is existed from difference in thickness 0.01mm, sample gross weight（The weight of cloth containing backing and mould release membrance）Paster of the difference within 0.02g, has carried out 15 groups altogether Test comparison has carried out the experimental analysis of early stage, right to infer the menthol of hydroxyl and Ketoprofen esterification may occur There is influence in the stability of medicine, carry out theoretical implications from the chemical constitution of each constituent in addition, the alcoholic extract hydroxyl group in menthol with Esterification can occur between the carboxyl in Ketoprofen.Simultaneously in order to discharge the test error and content difference factor in experiment, Therefore result is accumulated according to experimental data, can be seen within 3% if judging the changes of contents of Ketoprofen after placement certain hour Work is that the above factor is caused rather than esterification causes, if Ketoprofen changes of contents rate in two groups of experimental datas with The rate of change significant difference for increasing both of time is prevented, then can be determined that to be the presence of esterification.

Be can be seen that with the increase of patche standing time from above experimental result, be ketone in paster containing menthol The relative Ketoprofen content that be less than in the paster without menthol of the content of ibuprofen, so menthol and ketone containing alcoholic extract hydroxyl group There is esterification in ibuprofen, this is very unfavorable for the stability of medicine, so in the preparation of ketoprofen transdermal paster, It is best that selected various components should not contain alcoholic extract hydroxyl group, and the ketoprofen transdermal paster in the present invention can be good at preventing The esterification of Ketoprofen.

Embodiment 15

The present embodiment has investigated the in vitro transdermal effect of animal of Ketoprofen, and isolated mouse skin is used in experiment, and reception liquid used is 0.9% sodium-chloride water solution, test period is 24h, and sample is prepared according to the formula one in embodiment 6, and sample specification is diameter The circular patch of d=1.5cm, the wherein theoretical content of Ketoprofen are 0.5049mg（Pastille percentage is 2%）.

Table, self-control Ketoprofen paster 24h accumulation transdermal amounts

Time/h	Ketoprofen accumulated transdermal amount/mg	Ketoprofen accumulated skin permeation rate/%
			0.25	0.0024	0.48
0.5	0.0055	1.09
			0.75	0.0093	1.84
1	0.0135	2.67
			2	0.0316	6.26
4	0.0705	13.96
			6	0.1205	23.87
8	0.168	33.27
			10	0.2236	44.29
12	0.2776	54.98
			24	0.4485	88.83

As can be seen from the above table, the ketoprofen transdermal paster in the present invention has good transdermal effect, disclosure satisfy that treatment will Ask.

Embodiment 16

Be have selected in this experiment has carried out 20 person-portions and has faced using the ketoprofen transdermal patch prepared by new-type heat-melting method moulding process Bed examination patch Contrast on effect, concrete outcome is as follows, and experiment ketoprofen transdermal paster used is made according to formula one in embodiment 6 It is standby：

Table, the person-portion clinical therapeutic efficacy of self-control ketoprofen transdermal paster 20

As can be seen from the above results, the ketoprofen transdermal paster in the present invention has the therapeutic action that relieves the pain well, for one As pain all there is obvious relieving the pain effect, after the ketoprofen transdermal paster in 3 present invention of use, to pain therapy Effective percentage has reached 90%.

Embodiment 17

The security of the ketoprofen transdermal paster in the present invention has been investigated in this experiment, and used test sample is according to embodiment in experiment Formula in 6 is prepared for, containing menthol and the ketoprofen transdermal paster for not containing menthol, having carried out the skin of rabbit and cavy Skin irritation test, it is specific as follows in experiment：

Experimental animal：Rabbit, 1.8~2.0kg, cavy, 250~300g selects male and female half and half.

Animal feeding requirement：Animal House room temperature should be controlled at 22 ± 2 DEG C, and humidity 55% or so, ammonia density is less than 20ppm, Using 12h：12h occulting lights shine, timing ventilation.All animals are fed with full nutrition feed, every independent label of animal, raise In in Rotating Stainless Steel Cage, animal ad lib is drunk water.

Rabbit intact skin and damaged skin single skin irritatin：Healthy rabbits, are divided into normal skin group and damaged skin Group is each 4, using consubstantiality left and right sides self-contrast method, male and female half and half.24h carries out depilation treatment to administration area before experiment, left Each one piece, the unhairing scope 3cm × 3cm in the right side.Damaged skin group draws " well " word in agents area, to ooze out blood as degree.Every group of left side The ketoprofen transdermal paster prepared in this present invention is sticked at depilation, right side is fixed as control with gauze, is removed after 24 hours Ketoprofen transdermal paster.Examine skin at coating whether there is erythema, oedema respectively at 1h, 24h, 72h, by new drug toxicity technology The requirement of specification carries out skin irritation evaluation.

Skin irritation is evaluated：

（1）Standards of grading：Erythema：Without 0 point of erythema；Slight erythema（It is visible reluctantly）1 point；Moderate erythema（It is clearly visible）2 points；Weight 3 points of erythema of degree；Aubergine erythema forms 4 points to slight eschar.Oedema：Without 0 point of oedema；Mild edema（It is visible reluctantly）1 point；In Degree oedema（Substantially swell）2 points；Severe edema（Cutaneous protuberance 1mm, profile understands）3 points；Severe edema（Cutaneous protuberance ＞ 1mm simultaneously has expansion）4 points.8 points of highest point total value.

（2）Skin irritatin intensity evaluation standard：0~0.49 point nonirritant；0.50~2.99 point of slight stimulation；3.00 ~5.99 points of moderate excitants；6.00~8.00 points of strong and stimulatings.

Administration terminates rear check plot and the tested area's comparative observation of ketoprofen transdermal paster, the ketoprofen transdermal without menthol Patch is in recipient site without IRs such as erythema, dry skin, furfurs, and skin wound repair intensity is equal<0.5 point；Containing There are the IRs such as dry skin, furfur in the recipient site of the ketoprofen transdermal paster of menthol, or even occurs in that slight Or the erythema of moderate strength, skin wound repair intensity is 3.78 points, 3.00~5.99/, belong to moderate excitant.

Illustrated by above experimental result, the ketoprofen transdermal paster in the present invention can be substantially prevented from causing skin irritatin The drawbacks of occur, the addition of menthol may cause skin irritatin and discomfort.

Embodiment 18

Different backing cloth are have selected in this experiment, the experiment of skin applicating property has been carried out, different backing cloth has been investigated to transdermal patch The influence of the stickup performance of agent, sample used is prepared according to the formula one in embodiment 6 in experiment, and be have selected grammes per square metre and be The non-woven fabrics of 50g/ ㎡, the common weaving cloth without elastic force, unidirectional elastic force weaving cloth, bidirectional elastic weaving cloth are compared Compared with specific experiment result is as follows：

Table, different backing cloth paste the influence of performance to human body

Backing cloth species	Shoulder back examination patch result	Joint examination patch result	Peel off pain
				The non-woven fabrics of 50g/ ㎡	Edge is easy to inharmonious	It is overall easily to come off	Peel off pain stronger
Common inelastic weaving cloth	Patch edges are easy to inharmonious	It is overall easily to come off	Peel off pain stronger
				Unidirectional elastic force weaving cloth	The inharmonious phenomenon of patch edges makes moderate progress	Patch portion comes off	Peel off pain lighter
Bidirectional elastic weaving cloth	There is not the inharmonious phenomenon of patch edges, the coating performance with skin is excellent	Do not occur coming off and inharmonious phenomenon	Without stripping pain

As can be seen from the above test results, backing cloth has a significant impact to paster with the effect that sticks of skin, and peel off pain Pain also has relation with backing cloth, and this is probably because different backing cloth should at the edge during sticking and in stripping process Power difference causes.In general, selection bidirectional elastic weaving cloth is optimal, and unidirectional elastic force weaving cloth takes second place, common inelastic spinning Combination property of weaving cotton cloth is general, and non-woven fabrics is worst.

Embodiment 19

Heat resistance is tested：Cervicodynia 2, the sample of patch prepared in Example 6（Specification is 7cm × 10cm）, mould release membrance is removed, 60 DEG C are heated 2 hours, and after letting cool naturally, without permeability phenomenon, sense that cream face is glossy touches still toughness, still with finger at the back side high Repeatability is noticed more than 5 times.Meet《Chinese Pharmacopoeia》To the quality requirement of rubber ointment.

Embodiment 20

Plastic property is tested：Cervicodynia 2, the sample of patch prepared in Example 6（Specification is 7cm × 10cm）, 37 DEG C, it is relatively wet 30min is placed in the climatic chamber of degree 64%, is taken out, sample is fixed on a smooth steel plate, the inclination angle of steel plate and horizontal plane It is 60 DEG C, places 24 hours, cream face is without trickling phenomenon.Meet《Chinese Pharmacopoeia》To the quality requirement of rubber ointment.

Illustrated according to above example, the lytic agent containing alcoholic extract hydroxyl group without menthol etc. or rush in the present invention are saturating Agent, has protective effect to anti-inflammatory class drug paste such as Ketoprofen containing carboxyl etc., it is to avoid the drug ingedient containing carboxyl occurs Esterification, while this anti-inflammatory percutaneous plaster can long-time be sufficient, play consistently the anti-inflammatory analgesic action of anti-inflammatory agent, no The drawbacks such as skin irritatin are brought, and with excellent stickup performance, is mitigated and is peeled off pain, the stability of medicine patch is also excellent It is good, therefore, it is proposed, according to the invention, a kind of externally applied transdermal patch such as ketone containing anti-inflammatory agent for the purpose of anti-inflammatory analgesic can be provided Ibuprofen percutaneous plaster etc..

The above is the embodiment for embodying research process of the present invention and result, it is noted that for the art For those of ordinary skill, on the premise of principle of the present invention is not departed from, some improvements and modifications can also be made, these Improvements and modifications also should be regarded as protection scope of the present invention.

Claims (20)

1. a kind of ketoprofen transdermal paster, it includes adhesive and Ketoprofen；Contain wherein in adhesive and account for the total matter of adhesive SIS and styrene-isoamyl two of the amount percentage composition between 10%~55% Alkene di-block copolymer accounts for benzene as framework material, the weight/mass percentage composition of wherein styrene-isoprene di-block copolymer Less than the 35% of ethene-isoprene-styrene block copolymer and styrene-isoprene di-block copolymer gross mass is high The weight/mass percentage composition of molec weight polyisobutylene accounts for less than the 22% of adhesive gross mass, the quality hundred of middle-molecular-weihydroxyethyl polyisobutene Point content accounts for less than the 30% of adhesive gross mass, and the weight/mass percentage composition of low-molecular-weight polyisobutylene accounts for adhesive gross mass Less than 25%, the weight/mass percentage composition of tackifier is accounted between the 10%~60% of adhesive gross mass, the weight/mass percentage composition of softening agent Account between the 12%~55% of adhesive gross mass, weight/mass percentage composition shared by antioxidant is contained framework material gross mass Between 0.01%~2.5%, Ketoprofen weight/mass percentage composition is 1-3% in above-mentioned Ketoprofen paster；Preferred Ketoprofen quality percentage Content is 2%, is attached on backing cloth after described adhesive and Ketoprofen are well mixed and is covered with release liners.

2. ketoprofen transdermal paster according to claim 1, wherein SIS Molecular weight Mn between 70000~250000, between 75000~200000, more preferably number is equal for preferred number average molecular weight Mn Molecular weight Mn is between 75000~160000.

3. SIS according to claims 1 to 2, it is characterised in that number is divided equally Son amount Mn 75000~85000,85000~95000,95000~105000,105000~115000,115000~ 125000th, between 125000~135000,135000~145000,145000~155000,155000~160000.

4. ketoprofen transdermal paster according to claim 1, the number of wherein styrene-isoprene di-block copolymer is equal Between 30000~200000, preferred number average molecular weight more preferably counts equal molecule to molecular weight Mn between 40000~180000 Amount is between 50000~140000.

5. the SIS and benzene in Ketoprofen paster according to claims 1 to 4 In ethene-isoprene block copolymer, combinated styrene content content be 12%~30%, preferably in combination with styrene-content be 13%~ 30%th, more preferably combinated styrene content content is 14%~23% or 26%~30%,.

6. Ketoprofen paster according to claims 1 to 5, wherein SIS and benzene The combinated styrene content content of ethene-isoprene block copolymer be 14%~15%, 15%~16%, 16%~17%, 17%~18%, 18%~19%, 19%~20%, 20%~21%, 21%~22%, 22%~23%, 26%~27%, 27%~28%, 28%~29%, 29%~ Between 30%.

7. Ketoprofen paster according to claims 1 to 6, wherein SIS and The preferred linear structure of styrene-isoprene block copolymer.

8. Ketoprofen paster according to claims 1 to 7, wherein SIS And the total weight/mass percentage composition of styrene-isoprene di-block copolymer is between 10%~55%, between preferably 14%~50%, Between more preferably 17%~42%, between more preferably 20%~34%, wherein styrene-isoprene di-block copolymer Weight/mass percentage composition account for SIS and styrene-isoprene di-block copolymer Less than the 35% of gross mass, preferably less than 30%, more preferably less than 20%.

9. Ketoprofen paster according to claims 1 to 8, the wherein molecular weight of high molecular weight polyisobutylene 61000~ Between 119000 or 121000~190000, molecular weight preferred scope be between 75000~115000 or 130000~180000, Between more preferably 80000~115000 or 130000~160000, more specifically 80000~90000,90000~ 100000th, 100000~110000,110000~115000, or 130000~140000,140000~150000,150000~ Between 160000, the weight/mass percentage composition of the high molecular weight polyisobutylene accounts for less than the 22% of adhesive gross mass, preferably 0.5 Between~15%, between more preferably 1.5%~12%.

10. Ketoprofen paster according to claims 1 to 9, the wherein molecular weight of middle-molecular-weihydroxyethyl polyisobutene 16000~ Between 49000, more specifically 16000~19000,19000~22000,22000~25000,25000~28000, 28000~31000,31000~34000,34000~37000,37000~41000,41000~44000,44000~ 47000th, between 47000~49000, the middle-molecular-weihydroxyethyl polyisobutene weight/mass percentage composition accounts for less than the 30% of adhesive total amount, excellent Elect as between 0.5%~20%, between more preferably 1.5%~11.5%.

11. Ketoprofen pasters according to claims 1 to 10, wherein the molecular weight of the polyisobutene of low-molecular-weight is 1000 Between~4900, more specifically 1000~1400,1400~1800,1800~2200,2200~2600,2600~ 3000th, between 3000~3400,3400~3800,3800~4200,4200~4500,4500~4900, the low-molecular-weight is gathered The weight/mass percentage composition of isobutene accounts for less than the 25% of adhesive gross mass, between preferably 0.5%~17%, more preferably Between 1.5%~12%.

The 12. Ketoprofen paster according to claim 1~11, wherein the species of tackifier used includes rosin, hydrogenation Rosin, rosin esters, C5 Petropols, C9 Petropols, terpene resin, epoxy resin, polyamide-based, polyurethanes and with One or several in the modified resin of upper species tackifier, preferably ester gum, hydrogenated rosin glyceride, wherein viscosifying The weight/mass percentage composition of agent between 10%~60%, between preferably 15%~55%, between more preferably 25%~45%, more Between preferably 32%~45%.

The 13. Ketoprofen paster according to claim 1~12, wherein softening agent used includes that naphthenic oil, molecular weight exist Low-molecular-weight polyisobutylene, atoleine between 100~1000, olive oil, soybean oil, epoxidized soybean oil, oil with hydrogenated soybean In one or several, the preferred low-molecular-weight polyisobutylene of naphthenic oil, atoleine, molecular weight between 100~1000, One or two more preferably in the low-molecular-weight polyisobutylene of atoleine, molecular weight between 600~1000, should The weight/mass percentage composition of softening agent between 12%~55%, between preferably 17%~45%, more preferably 20%~32% it Between.

The 14. Ketoprofen paster according to claim 1~13, wherein antioxidant used includes BHT264, antioxidant 1010 etc., weight/mass percentage composition shared by the antioxidant in pharmaceutical carrier adhesive be contained framework material gross mass 0.01%~ Between 2.5%, between preferably 0.1%~2%, between more preferably 0.4%~1.2%.

In the 15. Ketoprofen paster according to claim 1~14, wherein the weight/mass percentage composition of Ketoprofen 0.8%~ Between 3%, between preferably 1.5%~2.5%, more preferably 2%.

The 16. Ketoprofen paster according to claim 1~15, medicine lytic agent used, transdermal enhancer include that bay nitrogen is tall and erect Ketone, propane diols, menthol, oleic acid, isopropyl myristate etc., are preferably able to dissolve the transdermal enhancer of Ketoprofen, and such as bay nitrogen is tall and erect Ketone, propane diols, menthol, further preferred Laurocapram, wherein can be used as the quality hundred of the transdermal enhancer of Ketoprofen lytic agent Divide content between 0.1%~6%, be preferable between 0.5%~4.5%, between better than 1%~3%.

Accompanying the claims 1 on the 17. Ketoprofen paster according to claim 1~16, wherein backing cloth~ The glue medicine mixed layer that the mixture of adhesive and medicine described in 16 any one is formed, its glue medicine mixture layer be 70 g/ ㎡~ 230g/ ㎡, preferably 100 g/ ㎡~190g/ ㎡, more preferably 135 g/ ㎡~150g/ ㎡.

The 18. Ketoprofen paster according to claim 1~17, during the contact area of its medicine layer and skin is the present invention Ketoprofen transdermal patch, is characterised by the contact area of its medicine layer and skin between 70cm2~140cm2.

The 19. ketoprofen transdermal patch according to claim 1~18, when being characterised by that said medicine layer is contacted with skin, 0 The blood concentration versus time area under a curve AUC of Ketoprofen in~72 hours（0~72hr）It is 1100~3000nghr/ml, Its highest haemoconcentration Cmax is 50~150ng/ml.

A kind of 20. techniques for preparing the Ketoprofen paster in claim 1-19 described in any one, concrete technology flow process is as follows：

1）The adhesive that will be prepared is added in the glue melting box with precision metering pump, sets appropriate melt adhesive temperature, treats glue Glutinous agent is standby after melting completely；

2）Ketoprofen is stirred to being completely dissolved and be well mixed according to Laurocapram is added to after determination amount accurate weighing, and It is added in the explosive box with precision metering pump and agitating paddle and stirs liquid according to certain requirement, it is standby；

3）Coating machine is opened, during drug extract and glue accurately pumped into screw machine respectively through glue pump and Teat pipette, in a constant temperature Glue and drug extract are quickly well mixed under degree, incorporation time is between 20s~80s；

4）The glue medicine mixture that will be mixed uniformly is applied on backing cloth and covers mould release membrance according to the standard of regulation, is die-cut to one The paster of set pattern lattice.