CN109316469A - It is a kind of stable high to carry medicine Lidocaine transdermal patch and preparation method thereof - Google Patents
It is a kind of stable high to carry medicine Lidocaine transdermal patch and preparation method thereof Download PDFInfo
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- CN109316469A CN109316469A CN201811173470.2A CN201811173470A CN109316469A CN 109316469 A CN109316469 A CN 109316469A CN 201811173470 A CN201811173470 A CN 201811173470A CN 109316469 A CN109316469 A CN 109316469A
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- lidocaine
- pressure sensitive
- sensitive adhesive
- polymer matrix
- patch
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention discloses a kind of stable high load medicine lidocaine patch and preparation method thereof, and the patch includes back sheet, protective layer, and the polymer matrix layer among back sheet and protective layer.The polymer matrix layer includes active constituent lidocaine and the acrylate pressure sensitive adhesive without functional group.Active constituent lidocaine is evenly dispersed in polymer matrix in the form of fine particles in the patch, it is suppressed that the recrystallization of lidocaine can save steadily in the long term；And there is faster drug release express delivery and shorter onset time.Simple production process of the present invention, producing cost are cheap.
Description
Technical field
The invention belongs to percutaneous dosing technical fields, and in particular to it is a kind of it is stable it is high carry medicine Lidocaine transdermal patch and
Preparation method.
Background technique
Using transdermal delivery system (patch) active constituent by skin or mucous membrane enter in vivo to reach part or
System works, and is a kind of very common administration mode.Since first Scopolamine Patch in 1979
Since listing, people have done a large amount of trial to develop more transdermal delivery systems with therapeutic effect, existing at present more
A patch product successful commercialization.According to the combination of active constituent in patch and other auxiliary materials, patch can generally be divided into
Reservoir type patch (reservoir systems) and glue medicine mixed type patch (drug-in-adhesives).Wherein glue medicine mixes
Type is active constituent to be equably dissolved or dispersed in by one or more high molecular materials and other pharmaceutically available auxiliary
In the semi-solid combination for expecting composition, uniform drug containing polymer matrix is formed.If high molecular material used itself is pressure-sensitive
Glue then polymer matrix is the carrier function for playing the role of drug, and plays and sticks the gluing of area skin.
Lidocaine (Lidocaine) has anesthesia and analgesic activity, because rapid-action, effect is strong and persistently, penetration power
The features such as strong and safe range is larger, while without expansion blood vessel function, to tissue almost without irritation, therefore it is widely used in more
The local anaesthesia analgesic of kind form, such as treats postherpetic neuralgia, partial operation pain etc..
It is used for the lidocaine percutaneous dosing product of topical pain relief currently on the market, as U.S. FDA is successively ratified for band
Shape postherpetic neuralgia lidocaine patch, respectively lidocaine weight content are 5%Lidocaine weight
Measure the ZTLIDO that content is 1.8%TM.In the Japanese market, such as day east electrician (Nitto), help moral medicine company and Nip Lip river (Nipro)
It successively has listed patch product of the lidocaine concentrations from 10% to 60%, is mainly used for the analgesic of superficial surgical procedure, it is such as quiet
When vein punctures after pain relief, infectious software chondrectomy during pain relief and dermatological laser irradiation treatment
Pain relief etc..
For treating the lidocaine patch of the chronic aches such as postherpetic neuralgia, due to needing wear time long and
Effective dose is low, can reach therapeutic purposes by being slowly administered, therefore the weight content of active constituent lidocaine is general
Lower, being generally not more than 10% can meet the requirements.Crystallization risk caused by the lidocaine of low concentration is lower.It is shallow for alleviating
Lidocaine patch in terms of meter pain is designing local pain easing plaster agent in order to achieve the effect that topical pain relief
When, need in view of in patch system the concentration of lidocaine want sufficiently high, while to have suitable transmission efficiency so as to
Delivering has the dosage of therapeutic effect during sticking.Can be only achieved in the case where meeting the above two o'clock at the same time quickly work and
Lasting analgesic effect.But then, high concentration lidocaine patch system a possibility that there are active constituent recrystallizations.Patch
The crystallization of active constituent can bring the problem of series in agent system, and the safety such as used wears the change of performance, through efficiency
Reduction, the active constituent of crystalline state is to the irritation etc. for sticking area skin.
In order to solve the problems, such as that the lidocaine patch of high concentration is easy to recrystallize, Chinese Patent Application No.
It is 10% lidocaine lactate patch that CN200880115031.4, which discloses weight content, inhibits benefit using lactate
Crystallization of the cacaine in patch system is precipitated.Day eastern 60% lidocaine patch of electrician, in order to solve due to excessively high benefit card
Because crystallizing risk caused by drugloading rate, using the method for crystallization sustained release, lidocaine is pre-formed in patch preparation process
Microscopic grains, after patch is pasted on skin, preformed crystal gradates dissolution again, and gradually dissolution is inhaled by skin
It receives.But this method stability is not easy to control, and there are unpredictabilities for process, are unable to reach controllable administration mode.In patch
The control of crystal size and distribution is also a difficult point in the production process of patch, leads to complex process, and producing cost is high.Separately
On one side since crystallization redissolution process has also delayed the Transdermal absorption of lidocaine.Meanwhile active constituent is saving and is making
With period due to the presence of crystallization, crystal has the risk for further converting or growing.
Based on the above issues it is found that it is still necessary to exploitation lidocaine transdermal delivery system is for meeting clinically to superficial
The needs of analgesic.
Summary of the invention
The invention discloses a kind of stable high load medicine lidocaine patch.The patch includes back sheet, protective layer, with
And the polymer matrix layer among back sheet and protective layer.The polymer matrix layer include active constituent lidocaine and
Acrylate pressure sensitive adhesive without functional group.
It is an object of the invention to develop the high lidocaine patch for carrying medicine, and can be by lidocaine with fine particles
Form is evenly dispersed in polymer matrix, inhibits the recrystallization of lidocaine, so as to save steadily in the long term.
Another object of the present invention is to improve the penetration speed of lidocaine in patch, meets topical pain relief action
Fastly, the requirement of analgesic effect duration length.The study found that the present invention can be met using the acrylate pressure sensitive adhesive without functional group
Requirement.Product of the present invention simple production process, producing cost is cheap, has thus completed the present invention.
It should be noted that following description is only to this hair for this field has the technical staff of professional standards
Bright exemplary illustration can not limit the scope of the invention.
It is an object of the invention to improve the extracorporeal releasing speed of lidocaine, while increasing percutaneous penetration speed, reaches
To faster analgesic effect and duration.For glue medicine mixed type transdermal delivery system, active constituent generally pass through by
The form of dynamic diffusion penetrates skin, and the speed of Passive diffusion depends primarily on the saturation journey of active constituent in polymer matrix
Other component interactions in degree and active constituent and polymer matrix.In design glue medicine mixed type polymer matrix patch
When the main active ingredient of factor in need of consideration itself property and its drugloading rate, the physics of each component in polymer matrix
And the overall performance of chemical property and composition and active constituent, the external environment condition of patch production and preservation, patch
Using position and the time is used, needs drug delivery rate to be achieved and therapeutic effect etc..
For overcome the deficiencies in the prior art, so that quick release of the lidocaine in patch polymer matrix, is improved
Lidocaine percutaneous absorbtion efficiency, the present invention have made intensive studies.By numerous studies and experiment, present invention discover that using not
Pressure sensitive adhesive containing functional group is especially free of the acrylate pressure sensitive adhesive of functional group, is more preferably free of the propylene of carboxyl functional group
Sour pressure sensitive adhesive can reduce the interaction between active constituent lidocaine and pressure sensitive adhesive, increase lidocaine in macromolecule
Mobility in matrix can significantly improve the rate of release of lidocaine, increase the diffusion velocity of lidocaine.
In some embodiments, the present invention can directly adopt the acrylate pressure sensitive adhesive for being free of functional group.
In some embodiments, those also can be used by having the acrylic acid high score of pressure sensitive adhesive characteristic after processing in the present invention
Son, such as itself can not have pressure-sensitive colloidality some by the way that plasticiser, plasticizer, crosslinking agent or other auxiliary materials is added
The acroleic acid macromolecular of matter is adjusted to the macromolecule with pressure sensitive adhesive function.
Further, the functional group in the acrylate pressure sensitive adhesive of the present invention without functional group refer to not with lidocaine
The functional group to react, specifically include it is any one or several in carboxyl, hydroxyl, epoxy group, sulfonic group, amino etc., preferably
Carboxyl.
Specifically, the acrylate pressure sensitive adhesive without functional group refers in acrylate pressure sensitive adhesive without containing any carboxylic
The functional groups such as base, hydroxyl, epoxy group, sulfonic group, amino.
Further, the acrylate pressure sensitive adhesive without functional group include dimer macromolecule, tripolymer macromolecule and
Polymer macromolecule, such as including acrylate homopolymer, copolymer and polymer.
The monomer that can be used for preparing the acrylate pressure sensitive adhesive without functional group includes acrylate, is taken for example including nothing
For acrylate, methyl substituted acrylate.Specifically, it can be used for preparing the list of the acrylate pressure sensitive adhesive without functional group
Body includes methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, amyl acrylate, Hexyl 2-propenoate, propylene
Heptyl heptylate, 2-ethyl hexyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl ester, metering system
Sour methyl esters, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentylmethacrylate, methacrylic acid
Own ester, metering system heptyl heptylate, 2-Propenoic acid, 2-methyl-, octyl ester, nonyl methacrylate, decyl-octyl methacrylate, the methacrylic acid moon
Osmanthus ester, methacrylic acid myristin etc..
The monomer that can be used for preparing the acrylate pressure sensitive adhesive without functional group further includes acrylic acid amides, such as propylene
Sour amide and methacrylic.
Further, the acrylate pressure sensitive adhesive without functional group includes by acrylic monomers and non-acrylic monomers shape
At dimer or polymer.The non-acrylic pressure-sensitive adhesivee without functional group refers to that polymerized monomer is not acrylic compounds
Object is closed, such as the vinylacetate without functional group and the acrylic monomers without functional group form copolymerized macromolecule.
In some embodiments, the acrylate pressure sensitive adhesive without functional group only includes a kind of propylene without functional group
Sour macromolecule.In other embodiments, the acrylate pressure sensitive adhesive without functional group include two or more not
Acroleic acid macromolecular containing functional group.For the nonfunctionalized acrylate copolymer comprising two or more, can pass through
Physics and medicine of the ratio of each component to be met the requirements are adjusted for property, such as wears performance, the transmission of lidocaine
Speed etc..Since this kind of pressure sensitive adhesive does not have active function groups and crosslinking agent, active constituent lidocaine can be in colloid body
Resistance very little when moving in system so as to improve the rate of release of active constituent in vitro, while improving percutaneous through effect
Rate.
Further, in entire polymer matrix lidocaine and the acrylate pressure sensitive adhesive without functional group weight
Than being about 1:9 to about 2.5:1, preferably about 1:4 is more preferably about 2:3 to about 3 to being about 1.8:1:
2。
Further, lidocaine of the present invention includes: lidocaine hydrochloride, lidocaine free alkali, lidocaine
It is any one or several in lactate, lidocaine carbonate and lidocaine citrate etc.；Preferably lidocaine free alkali.
In some embodiments, the content of active constituent lidocaine is to account for about existing for entire polymer matrix dry weight
35% to about 65%, including about 35% to about 60%, about 45% to about 60%, such as about 35%, it is big
About 40%, about 45%, about 50%, about 55%, about 60%, about 65%.
In some embodiments, the content of the acrylate pressure sensitive adhesive without functional group is to account for entire polymer matrix to do
Weight about 35% to about 80%, including about 40% to about 65%, such as about 35%, about 40%, about
45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%.
The commercially available acrylate pressure sensitive adhesive without functional group has the Duro-Tak of Henkel Corp. (Henkel)
Series of products, for example, Duro-Tak 87-900A, Duro-Tak 87-9301 (it is non-crosslinked, be free of vinylacetate propylene acid fracturing
Quick glue, no functional group), Duro-Tak 87-4098 (non-crosslinked, vinylacetate acrylate pressure sensitive adhesive, no functional group)；Also wrap
Include Gelva GMS 3083, Gelva GMS 3253 (non-crosslinked, to be free of vinylacetate acrylate pressure sensitive adhesive, no functional group).
Further, the available other auxiliary materials of transdermal patch, example can also be contained in polymer matrix in some embodiments
Such as antioxidant, plasticizer, plasticiser, filler, crosslinking agent and transdermal enhancer.The content of other auxiliary materials accounts for dry matrices
About the 0.1%~about 1% of total weight, preferably approximately 0.1%~about 0.5%, further preferably about 0.1%~about
0.3%.
Another object of the present invention is to solve lidocaine in the crystallisation problems of patch system.Such as background technology part institute
It states, the lidocaine crystallized in patch can be with series of problems.In order to solve the problems, such as insoluble medicine, so-called solid dispersion skill is commonly used
Active constituent is dispersed in macromolecule by art in the form of fine particles, as a strategy for improving insoluble medicine solubility.
But be frequently the problem that and compared with crystal state, the active constituent in solid dispersion system due to higher energy,
It shows thermodynamic (al) unstability, there is the possibility recrystallized in long-term preservation.In order to reach evenly dispersed lidocaine
It avoids recrystallizing during preservation again simultaneously, by many experiments, having been surprisingly found that can incite somebody to action the present invention by heat fusing method
Lidocaine and acrylate pressure sensitive adhesive without functional group are prepared into stable evenly dispersed system, and lidocaine is with tiny micro-
The form of grain is dispersed in the polymer matrix of patch.The fine particles are exactly under an optical microscope, to be amplified to 400 times of sights
Examine the presence less than lidocaine crystal grain.In order to reach the dispersion in the form of fine particles, the present invention passes through many experiments
It was found that first mixing lidocaine and non-functional group acroleic acid macromolecular pressure sensitive adhesive, then temperature is increased to centainly
Range, such as about 60~80 DEG C, including about 65~75 DEG C, such as about 65 DEG C, about 68 DEG C, about 70 DEG C, about 72 DEG C,
The two is formed to the uniform fused matter dispersed mutually.Further, it due to the presence of not no crystal grain, eliminates directly and skin
Skin contact has point danger for leading to potential allergy, while not having an impact substantially to the performance of pressure sensitive adhesive, has enough wearing energy
Power.Therefore lidocaine is evenly dispersed into the acroleic acid macromolecular matrix of nonfunctionalized by the present invention in the form of fine particles
In, it can avoid recrystallizing for lidocaine.
In some embodiments, the present invention includes a back sheet and protective layer (such as release film).The back sheet
A face directly connected with polymer matrix layer, back sheet plays protection polymer matrix layer and peripheral ring when in use
The effect of the contact in border prevents the loss of drug.The material of back sheet generally comprise polyester, polyethylene polyvinylacetate resin,
The copolymer of polyethylene and vinylacetate, polyvinyl chloride, polyurethane, metal foil, non-woven fabrics etc., thickness is generally in 20~100 μ
M, such as the ScotchPak of 3M companyTM1109 or CotranTM9720.The protective layer (such as release film) and polymer matrix
The another side of layer is connected, such as the Scotchpak of 3M companyTM9744.In patch before use, needing to remove protective film.
The preparation of patch of the present invention can a variety of methods according to the literature carry out, experience can also be had based on this field
Technical staff known to technical solution.By the active constituent lidocaine of recipe quantity, the propylene acid fracturing without functional group
Quick glue, and/or further and pharmaceutically available other auxiliary materials such as antioxidant, plasticizer, filler or transdermal enhancer etc. add
Enter into suitable organic solvent, be applied on release film (at room temperature) after mixing evenly, then at a temperature of 60~80 DEG C
By the dry removal organic solvent of the polymer matrix coated, subsequent composite back lining.It is punched into as desired suitably sized.It needs
Prepare sequence involved in Lidocaine transdermal patch method to illustrate that above-mentioned, the additional amount of each component, stirring when
Between with the parameters such as speed can and actual needs different according to used particular compound property be adjusted.
In some embodiments, polymer matrix is prepared into after all components being mixed, the macromolecule that then will be prepared
Matrix is coated on release film, is placed at about 60~80 DEG C and is removed solvent, then compound with back sheet.Illustrative preparation side
Method is as follows:
1) preparation of polymer matrix: pressure sensitive adhesive described in formula ratio is weighed first and is added in suitable organic solvent, is stirred
It mixes uniformly；Mixing time determines according to whether being uniformly mixed, generally at about 15~30 minutes.Then it is being kept stirring situation
Under, solid lidocaine, stirring to whole dissolutions is added portionwise, until forming homogeneous transparent solution；Or further add medicine
Available other auxiliary materials on continue stirring to formation homogeneous transparent solution.
2) polymer matrix prepared by step 1) is coated on release film；Depending on coating thickness is as needed.
3) by the polymer matrix after coating by the baking oven with air-exhausting function, 5~15 points are dried at 60~80 DEG C
Clock removes organic solvent.Then compound with suitable backing film；Suitable size and shape is cut into according to the needs of use.
The organic solvent is the solvent that can dissolve lidocaine, the acrylate pressure sensitive adhesive without functional group, packet
Include ethyl acetate, methanol, ethyl alcohol, acetonitrile, acetone and isopropanol etc..
In some embodiments, the weight content range of the lidocaine contained in polymer matrix of the present invention about from
1.0mg/cm2To about 3.0mg/cm2, including from about 1.2mg/cm2To about 2.5mg/cm2, from about 1.2mg/cm2To big
About 2.0mg/cm2, such as about 1.2mg/cm2, about 1.4mg/cm2, about 1.6mg/cm2, about 1.8mg/cm2, about
2.0mg/cm2.According to application time range domestic demand blood concentration to be achieved, percutaneous administration patch area of the present invention about from
5cm2To about 50cm2, including from about 10cm2To about 40cm2, such as about 10cm2, about 15cm2, about 20cm2, greatly
About 25cm2, about 30cm2, about 40cm2.According to analgesic onset time to be achieved and duration, by regulating and controlling patch respectively
The area of agent, the thickness for carrying concentration and patch, can achieve the effect of needs.Lidocaine in patch by improving
Concentration, the thickness for reducing patch can achieve quick acting, but analgesia duration is short.Improving, the total lidocaine of patch is dense
While spending, also increase the thickness of patch, not only can be with quick acting, and also analgesia duration is long.It is mild in order to reach
Analgesic effect and slow onset time can reduce the thickness of the load concentration and patch of lidocaine in patch simultaneously.Dimension
The lidocaine for holding low concentration increases the thickness of patch, although onset time delay can reach more longlasting analgesic effect.
In some specific embodiments, by regulate and control lidocaine concentration (amount that unit area contains lidocaine) and
The thickness of patch patch of the present invention can continuously meet different onset times, while meet the continuous analgesia effect of different time
Fruit.
The application method of the obtained transdermal patch of the present invention for example takes patch protective layer off, is pasted on patient's administration portion
Position.According to patient's difference needs, different time can be sticked.The present invention can be used for the analgesia of operational pain, such as venous detaining needle
Pain relief when puncture, pain relief during pain relief and dermatological laser irradiation treatment after infectious software chondrectomy
Deng.
Active constituent lidocaine is evenly dispersed in polymer matrix in the form of fine particles in patch of the present invention
In, it is suppressed that the recrystallization of lidocaine can save steadily in the long term；And there is faster drug release express delivery and shorter action
Time.Patch of the present invention can be used for superficial analgesic, pain relief, infectious software chondrectomy when such as venous indwelling pin puncture
Pain relief etc. during pain relief and dermatological laser irradiation treatment afterwards.Simple production process of the present invention, producing cost are cheap.
Detailed description of the invention
Fig. 1 shows 1 stability experiment results of experimental example；
Fig. 2 indicates 2 extracorporeal releasing experiment result of experimental example.
Fig. 3 indicates 3 percutaneous penetration result of experimental example.
Specific embodiment
Following specific embodiment makes exemplary illustration with regard to the content that specification is illustrated, is not intended to limit model of the invention
It encloses.The experienced professional in this field can illustrate that illustrated content makes corresponding adjustment according to the present invention.
In the examples below, DURO-TAK 87-4098 is the acrylate pressure sensitive adhesive containing vinylacetate, no function
Group, cross-linking agent-free；DURO-TAK 87-2510 is acrylate pressure sensitive adhesive, contains hydroxy functional group, cross-linking agent-free；DURO-TAK
87-2074 is acrylate pressure sensitive adhesive, has carboxyl and hydroxy functional group, has crosslinking agent.It is purchased from Henkel Corp. (Henkel).
Antioxidant uses tertiary butyl-4-hydroxy methyl phenyl ethers anisole (BHA).
Embodiment 1
A kind of transdermal patch containing lidocaine, including polymer matrix layer；The polymer matrix layer include activity at
Divide lidocaine and the acrylate pressure sensitive adhesive without functional group.Further, the patch further includes back sheet and protective layer；Institute
Polymer matrix layer is stated between back sheet and protective layer.
After lidocaine and the acrylate pressure sensitive adhesive without functional group are mixed, about 60~80 DEG C are warming up to, is made
The two forms the uniform fused matter dispersed mutually, and the polymer matrix layer is made.
In the present embodiment, the weight of lidocaine and the acrylate pressure sensitive adhesive without functional group in the polymer matrix layer
Content is respectively 60% and 39.8%；Surplus is pharmaceutically other available auxiliary materials, such as contains the anti-of appropriate (such as 0.2%)
Oxygen agent (such as BHA).
In the present embodiment, the lidocaine is lidocaine free alkali；The acrylate pressure sensitive adhesive without functional group
Specially Duro-tak 87-4098.
The present embodiment also provides the preparation method of the transdermal patch containing lidocaine, specifically includes: weighing formula ratio pressure
Quick glue is added in organic solvent (such as ethyl alcohol), is stirred evenly；Mixing time determines according to whether being uniformly mixed, generally big
About 15~30 minutes.Then when being kept stirring, lidocaine is added portionwise, stirs to whole dissolutions, is eventually adding medicine
Other available auxiliary materials (such as antioxidant, BHA) on continue stirring to formation homogeneous transparent solution.It will be prepared molten
Liquid is coated on selected release film, and coating thickness determines according to the needs of use.By the polymer matrix after coating by having
The baking oven of air-exhausting function is dried 5~15 minutes at 60~80 DEG C, removes organic solvent.Then by after drying product and choosing
Fixed backing film is compound.Suitable size and shape is finally cut into according to the needs of use, is packaged into product.
Embodiment 2-4 and comparative example 1-2 is only that the constituent of polymer matrix layer is different from the difference of embodiment 1,
Be specifically shown in the following table 1 (in table content be it is dry after each component account for the weight percent of overall polymer matrix layer).It is recorded except table 1
Outside lidocaine and pressure sensitive adhesive, each polymer matrix layer can also be containing pharmaceutically other available auxiliary materials, such as contain appropriate (example
Such as antioxidant (such as BHA) 0.2%).
Table 1
(note: lidocaine is specially lidocaine for free alkali in table 1, and pharmaceutically other available auxiliary materials can be selected
BHA。)
In addition, lidocaine lactate, lidocaine carbonic acid can also be changed to for free alkali for lidocaine in embodiment 1-4
Salt or lidocaine citrate.
Comparative example 3 is the commercially available product (day east electrician) of the lidocaine patch containing 60%.
1 stability experiment of experimental example
By embodiment 1 and comparative example 2,3 patch of comparative example, be placed under identical preservation condition (30 ± 2 DEG C, 60% ±
10%RH), the result is shown in Figure 1 is periodically observed by electron microscope observation.
It is observed continuously the results show that patch active constituent within the observation period prepared by the embodiment of the present invention 1 and comparative example 2
Have no significant change, lidocaine is equably dispersed in polymer matrix in the form of molecule, and different multiples optics is aobvious
It has no that lidocaine particles (crystal) exist under micro mirror, has not observed crystalline polamer, illustrate patch stability of the invention
It is good.3 lidocaine patch of comparative example can be observed obviously under the crystal grain of lidocaine, especially high magnification numbe observation, bright
It shows as column crystal.
2 extracorporeal releasing experiment of experimental example
Release in vitro is a basic performance indices of patch, and reaction is other groups in active constituent and polymer matrix
The interaction divided.Overall performance, lidocaine and the polymeric pressure sensitive adhesive of polymer matrix and other components are shown in mutual
Such as hydrogen bond, ion pair, Van der Waals force are acted on, the behavior for causing lidocaine to flow in polymer matrix is different.It releases in vitro
Put be Transdermal absorption basis, only suitable releasability is just able to satisfy specific Transdermal absorption and requires.
According to dissolution rate and drug release determination method (Chinese Pharmacopoeia the 4th the 4th method of general rule 0931 of version in 2015 -- paddle dish
Method), using PBS as dissolution medium, medium temperature is 32 DEG C, 25 revs/min, operates according to methods, when through 20 minutes, takes solution 5ml, is filtered
It crosses, subsequent filtrate is taken to measure according to HPLC method (the 4th general rule 0512 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition: chromatographic column: octadecylsilane chemically bonded silica fills (250*4.6；5μm)；Detection wavelength: 230nm；
Sampling volume: 10 μ L；Column temperature: room temperature；Type of elution: Isocratic clution.As a result see Fig. 2.
The results show that the acrylate pressure sensitive adhesive system without functional group has faster extracorporeal releasing speed, such as embodiment
1, at first 15 minutes, completely, relatively 3 speed of example was faster for basic release.Acrylic pressure sensitive containing hydroxyl (- OH) functional group
The rate of release of glue is relatively slow with respect to embodiment 1 and comparative example 3, as shown in comparative example 1.Under identical drugloading rate, containing carboxyl (-
COOH) and the comparative example 2 of hydroxyl (- OH) has most slow rate of release.Reduce the load concentration of lidocaine, rate of release
It is corresponding slack-off, such as embodiment 2,4.
3 percutaneous penetration of experimental example
Percutaneous penetration is measured by Franz vertical proliferation pond.Healthy adult pig ear skin, skin used is according to standard
Thermal release method, obtain pig ear skin cuticula.Receiving liquid is the PBS solution that pH is 7.4, and acceptance pool volume is 7mL, if
Determine 32 ± 0.1 DEG C of temperature, mixing speed is 300 revs/min, respectively at 5,10,15,20,30,45,60,90,120,180 Hes
It samples within 240 minutes, then every sub-sampling 3mL adds the blank acceptable solution of isothermal.Every group of sample is 6 parts parallel, while parallel a
Blank is as control.The accumulation transmitance that each time point is calculated according to result, is as a result shown in Fig. 3.
The results show that patch embodiment 1 of the present invention compares comparative example 3, there is faster In vitro penetration ability, meaning
Have faster onset time.
4 healthy volunteer's human body of experimental example is through experiment
Healthy adult male 8 are chosen, everyone sticks embodiment 1 respectively and comparative example 3 each four pastes, and sticking position is upper arm
Inside, application time are 4 hours, judge lidocaine percutaneous absorbtion by calculating the residual rate of residual lidocaine in patch
Amount, concrete outcome is shown in Table 2.
Table 2
| Sample | Embodiment 1 | Comparative example 3 |
| Lidocaine is averaged residual rate % (4h) through patch | 75.2 | 86.5 |
| It calculates transmitance % (4h) | 24.8 | 15.5 |
The results show that patch embodiment 1 of the present invention than comparative example 3 has more percutaneous absorbtion amounts in the same time, it can
There is faster onset time with expected patch of the present invention, be more convenient clinical use.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of transdermal patch containing lidocaine, which is characterized in that including polymer matrix layer；The polymer matrix layer packet
Lidocaine containing active constituent and the acrylate pressure sensitive adhesive without functional group.
2. according to claim 1 containing the transdermal patch of lidocaine, which is characterized in that the functional group refer to not with benefit
The functional group that cacaine reacts；Preferably include carboxyl, hydroxyl, epoxy group, sulfonic group, amino.
3. the transdermal patch according to claim 1 or claim 2 containing lidocaine, which is characterized in that the acrylate pressure sensitive adhesive packet
Acroleic acid macromolecular is included, the acroleic acid macromolecular there can be pressure sensitive adhesive characteristic by processing.
4. the transdermal patch containing lidocaine described in -3 any one according to claim 1, which is characterized in that the acrylic pressure sensitive
Glue includes dimer macromolecule, tripolymer macromolecule and polymer macromolecule；
Alternatively, the monomer that can be used for preparing the acrylate pressure sensitive adhesive includes acrylate, acrylic acid amides；
Alternatively, the acrylate pressure sensitive adhesive includes the dimer formed by acrylic monomers and non-acrylic monomers or polymer.
5. according to claim 1 containing the transdermal patch of lidocaine, which is characterized in that the acrylate pressure sensitive adhesive includes
Duro-Tak 87-900A, Duro-Tak 87-9301, Duro-Tak 87-4098, Gelva GMS 3083, Gelva GMS
It is any one or several in 3253.
6. the transdermal patch containing lidocaine described in -5 any one according to claim 1, which is characterized in that the lidocaine packet
It includes: lidocaine hydrochloride, lidocaine free alkali, lidocaine lactate, lidocaine carbonate, lidocaine citrate
In it is any one or several.
7. the transdermal patch containing lidocaine described in -6 any one according to claim 1, which is characterized in that the polymer matrix
The weight ratio of lidocaine and the acrylate pressure sensitive adhesive is about 1:9 to about 2.5:1 in layer, and preferably about 1:4 is to greatly
About 1.8:1 is more preferably about 2:3 to about 3:2.
8. the transdermal patch containing lidocaine described in -7 any one according to claim 1, which is characterized in that the polymer matrix
The weight content of lidocaine is about 35% to about 65%, preferably about 45% to about 60% in layer；
Alternatively, the weight content of acrylate pressure sensitive adhesive described in the polymer matrix layer is about 35% to about 80%, it is excellent
It is selected as about 40% to about 65%.
9. the transdermal patch containing lidocaine described in -8 any one according to claim 1, which is characterized in that the patch further includes
Back sheet and protective layer；The polymer matrix layer is between back sheet and protective layer.
10. the preparation method of the transdermal patch containing lidocaine described in claim any one of 1-9 characterized by comprising will
After lidocaine and the acrylate pressure sensitive adhesive without functional group mix, it is warming up to about 60~80 DEG C and is preferably warming up to about
65~75 DEG C, so that the two is formed the uniform fused matter dispersed mutually, polymer matrix layer is made.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811173470.2A CN109316469B (en) | 2018-10-09 | 2018-10-09 | Stable high-drug-loading lidocaine transdermal patch and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811173470.2A CN109316469B (en) | 2018-10-09 | 2018-10-09 | Stable high-drug-loading lidocaine transdermal patch and preparation method thereof |
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| Publication Number | Publication Date |
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| CN109316469A true CN109316469A (en) | 2019-02-12 |
| CN109316469B CN109316469B (en) | 2022-02-22 |
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|---|---|---|---|
| CN201811173470.2A Active CN109316469B (en) | 2018-10-09 | 2018-10-09 | Stable high-drug-loading lidocaine transdermal patch and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021037199A1 (en) * | 2019-08-29 | 2021-03-04 | 江苏恒瑞医药股份有限公司 | Transdermal amide local anesthetic-containing pharmaceutical composition and preparation method therefor |
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|---|---|---|---|---|
| EP0488137B1 (en) * | 1990-11-30 | 1995-04-05 | Nitto Denko Corporation | Preparation for transdermal drug administration |
| JPH07233054A (en) * | 1994-02-21 | 1995-09-05 | T T S Gijutsu Kenkyusho:Kk | Percutaneous absorption type preparation |
| KR20030014779A (en) * | 2001-08-13 | 2003-02-20 | 아이큐어(주) | Transdermal system for local anesthesia |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0488137B1 (en) * | 1990-11-30 | 1995-04-05 | Nitto Denko Corporation | Preparation for transdermal drug administration |
| JPH07233054A (en) * | 1994-02-21 | 1995-09-05 | T T S Gijutsu Kenkyusho:Kk | Percutaneous absorption type preparation |
| KR20030014779A (en) * | 2001-08-13 | 2003-02-20 | 아이큐어(주) | Transdermal system for local anesthesia |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021037199A1 (en) * | 2019-08-29 | 2021-03-04 | 江苏恒瑞医药股份有限公司 | Transdermal amide local anesthetic-containing pharmaceutical composition and preparation method therefor |
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| Publication number | Publication date |
|---|---|
| CN109316469B (en) | 2022-02-22 |
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