CN117899056A - Transdermal patch containing lidocaine, and preparation method and application thereof - Google Patents
Transdermal patch containing lidocaine, and preparation method and application thereof Download PDFInfo
- Publication number
- CN117899056A CN117899056A CN202311839093.2A CN202311839093A CN117899056A CN 117899056 A CN117899056 A CN 117899056A CN 202311839093 A CN202311839093 A CN 202311839093A CN 117899056 A CN117899056 A CN 117899056A
- Authority
- CN
- China
- Prior art keywords
- lidocaine
- sensitive adhesive
- transdermal patch
- patch
- transdermal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 132
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims abstract description 14
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- 229940065472 octyl acrylate Drugs 0.000 description 1
- ANISOHQJBAQUQP-UHFFFAOYSA-N octyl prop-2-enoate Chemical compound CCCCCCCCOC(=O)C=C ANISOHQJBAQUQP-UHFFFAOYSA-N 0.000 description 1
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- 150000002989 phenols Chemical class 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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- ATZHWSYYKQKSSY-UHFFFAOYSA-N tetradecyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCCCCCOC(=O)C(C)=C ATZHWSYYKQKSSY-UHFFFAOYSA-N 0.000 description 1
- XZHNPVKXBNDGJD-UHFFFAOYSA-N tetradecyl prop-2-enoate Chemical compound CCCCCCCCCCCCCCOC(=O)C=C XZHNPVKXBNDGJD-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a transdermal patch containing lidocaine, which comprises a high polymer matrix layer, wherein the high polymer matrix layer comprises active ingredients of lidocaine, acrylic acid pressure-sensitive adhesive and a transdermal enhancer, the weight content of the lidocaine is 21-33%, the weight content of the acrylic acid pressure-sensitive adhesive is 45-75%, and the weight content of the transdermal enhancer is 3-25% based on the weight of the high polymer matrix layer. The transdermal patch has the advantages of simple prescription and process, good drug permeability and colloid application performance, high stability, long-term use without causing skin irritation, and suitability for treating peripheral nerve related pain, in particular to patients needing long-term administration such as postherpetic neuralgia and the like.
Description
Technical Field
The invention belongs to the technical field of transdermal drug delivery, and particularly relates to a transdermal patch containing lidocaine, and a preparation method and application thereof.
Background
Transdermal delivery systems (transdermal patches) are a common mode of administration for delivering active ingredients into the body through the skin or mucosa to achieve local or systemic effects. Scopolamine patch since 1979) Since the market, numerous attempts have been made to develop more transdermal drug delivery systems with therapeutic effects, and a number of patch products have been successfully commercialized. The patches can be generally classified into a depot type (reservoir) and a drug-in-adhesives type (drug-in) patch according to the combination of the active ingredient and other excipients in the patch. Wherein the adhesive and drug mixed patch is prepared by uniformly dissolving or dispersing active ingredients in a semisolid composition composed of one or more polymer materials and other pharmaceutically acceptable auxiliary materials to form a uniform drug-containing polymer matrix. If the polymer material is pressure sensitive adhesive, the polymer matrix not only plays a role of a carrier of the medicine, but also plays a role of adhesion with the skin of the application part.
Lidocaine is an amide local anesthetic, plays roles in stabilizing nerve cell membranes and blocking nerve excitation and conduction by inhibiting sodium ion channels of the nerve cell membranes, and is widely used for treating various acute and chronic pains, especially neuropathic pains in clinic. The common dosage forms include injection, ointment, spray, plaster, etc. Lidocaine gel patch is useful for the treatment of localized pain with neuropathic and inflammatory characteristics, such as post-traumatic, post-operative pain or musculoskeletal pain, and has become a first line treatment for postherpetic neuralgia (postherpetieneuralgia, PHN).
5% Lidocaine gel plaster (trade name) In 1999, PHN was marketed in the United states as an indication, 14.0cm by 10.0cm per patch, containing 700mg of lidocaine, and further containing the following inactive ingredients: dihydroxyaluminum aminoacetate, disodium edetate, gelatin, glycerin, kaolin, methyl paraben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propyl paraben, sodium carboxymethyl cellulose, sodium polyacrylate, sorbitol, tartaric acid, and urea. /(I)Although the medicine is used as a first-line medicine for treating PHN, the pain relieving rate of moderately severe patients is low, the adhesive property of the patch is poor, the patch can only be applied for 12 hours, the pain treatment of the patients is unfavorable, the prescription is complex, the medicine loading rate of lidocaine is too large, the medicine utilization rate is low, and the medicine residues are more.
60% Lidocaine patch (product name is obtained from Nissin Denshidong electric Co., ltd.)) The hot melt adhesive patch is mainly used for treating operation pain, is a short-acting preparation, cannot meet the application requirement due to weak adhesion after long-time application, and has the phenomenon of crystallization of raw materials. In order to address the crystallization risk due to excessive lidocaine drug loading,The method of crystallization slow release is utilized, tiny crystals of lidocaine are preformed in the preparation process of the patch, and after the patch is applied to the skin, the preformed crystals are gradually converted and dissolved again, and gradually dissolved out and absorbed by the skin. However, the stability of the method is not easy to control, the process is unpredictable, the method can not achieve the administration in a controllable mode, and the risk of fluctuation of the drug effect exists. The control of the crystal size and distribution in the patch is also a difficulty in the production process of the patch, resulting in complicated process and high production cost. On the other hand, the transdermal absorption of lidocaine is also delayed by the crystallization redissolution process. At the same time, due to the presence of crystals, the active ingredient crystals risk further transformation or growth during storage and use.
The present inventors have previously disclosed a stable transdermal patch of lidocaine with high drug loading and a preparation method thereof, wherein a polymer matrix layer of the transdermal patch contains lidocaine with a weight content of 35% to 65%, and the lidocaine and an acrylic acid pressure sensitive adhesive without functional groups are uniformly mixed and then heated to 60 to 80 ℃ to form a uniform blend of the lidocaine and the acrylic acid pressure sensitive adhesive with no functional groups, so that the lidocaine and the acrylic acid pressure sensitive adhesive are dispersed with each other to form a polymer matrix layer, thereby inhibiting recrystallization of the lidocaine and enabling the lidocaine to be stably stored for a long time. The patent adopts a special process means to improve the crystallization stability, but the high drug concentration affects the adhesive property of the pressure-sensitive adhesive, so that the adhesive application property can not meet the application requirement of 24 hours.
Compositions and methods for transdermal delivery of lidocaine are disclosed in U.S. patent No. 10307380B1, wherein the adhesive matrix layer contains about 3.0 to about 5.0 parts by weight of lidocaine base and a polyisobutylene adhesive is used. However, the lidocaine transdermal composition disclosed in this patent still has the problem of poor drug permeation performance and the like, and cannot meet clinical demands. In particular, in example 2 of this patent, it is disclosed that: while acrylic adhesives do allow for easy release from release films and have adequate adhesive properties, the solubility of the drug in the adhesive is considered to be very high, which is considered to be disadvantageous because more drug must be used to achieve the same drug delivery to the skin, as seen, the patent teaches that acrylic pressure sensitive adhesives are disadvantageous for transdermal delivery of lidocaine. Furthermore, it is well known in the art that to achieve faster passive penetration, it is desirable to meet the near or reaching saturation solubility of the active ingredient in the adhesive matrix, whereas in acrylic adhesive systems, higher solubility requires higher drug levels to approach or reach saturation, while lidocaine acts as a tackifier, higher levels leading to a greater prescription tack, resulting in reduced adhesive application performance. Therefore, there is technical difficulty in developing a product which satisfies both the clinical therapeutic requirements of drug permeation and the long-term application properties, and a commercially available product satisfying the above requirements has not been successfully developed yet in the art.
Based on the above-mentioned problems, there is still a need to develop a percutaneous administration system of lidocaine, which solves the problem of good application performance during application for at least 24 hours while satisfying the amount of drug permeation reaching clinical treatment requirements, and is thus suitable for treating patients requiring long-term administration such as PHN.
Disclosure of Invention
Therefore, the invention aims to provide a lidocaine transdermal patch which can simultaneously meet the clinical treatment requirement of drug permeation quantity, has good colloid application performance during long-term application and good stability, and a preparation method and application thereof.
It is another object of the present invention to provide a lidocaine-containing transdermal patch having improved product stability, and a method of preparing the same and use thereof.
In order to improve the drug permeability of the patch, a common technical means may increase the passive diffusion of the drug by increasing the drug content. However, as reported in the prior art, too high content of the drug not only easily causes the risk of crystallization of lidocaine in the process of placement, which affects drug release and permeation, but also causes the problems of poor adhesive properties (such as unsuitable peeling viscosity, easy falling off, etc.) and the like. The present inventors have attempted to improve problems such as crystallization and colloidal application properties by adding various excipients commonly used in the field of transdermal drug delivery technologies, such as crystallization inhibitors, tackifiers, plasticizers and/or fillers, but have failed to obtain satisfactory results in all aspects. In addition, it was found during the course of the study that the permeation enhancer was added at a lower lidocaine content without significant improvement in permeation capacity. Later experiments and researches unexpectedly show that by adjusting the lidocaine in the polymer matrix layer to a proper content and simultaneously adding a certain amount of permeation enhancer, the release and permeation capabilities of the lidocaine can be obviously improved, and the problems of poor colloid application performance, easiness in crystallization, high skin irritation and the like in the prior art are solved, so that the invention is completed.
In addition, the impurity content needs to be strictly controlled in the medicine development, so that the impurity overrun is avoided. The inventor finds that the lidocaine free alkali in the patch exists and the residual monomer, active functional groups such as carboxyl, cross-linking agent and the like in the pressure-sensitive adhesive are subjected to potential reaction risks in the process of storage under high temperature conditions, so that the quality of the product is not qualified. Further studies have found that the object of controlling impurities can be easily achieved by controlling the content of the crosslinking agent in the pressure-sensitive adhesive, thereby completing the present invention.
The aim of the invention is realized by the following technical scheme:
In one aspect, the present invention provides a lidocaine-containing transdermal patch comprising a polymeric matrix layer containing lidocaine as an active ingredient, an acrylic pressure-sensitive adhesive and a permeation enhancer, wherein the weight content of lidocaine is 21% to 33%, preferably 25% to 30%, the weight content of acrylic pressure-sensitive adhesive is 45% to 75%, preferably 55% to 68%, and the weight content of permeation enhancer is 3% to 25%, preferably 5% to 15%, based on the weight of the polymeric matrix layer.
The active ingredient lidocaine used in the present invention is lidocaine free base. The use of lidocaine free base can significantly increase drug permeation capacity compared to the salt of lidocaine.
Preferably, the weight content of lidocaine in the polymer matrix layer is lower than that when it reaches saturated solubility in the acrylic pressure-sensitive adhesive.
The saturated solubility of lidocaine in acrylic pressure sensitive adhesives can be determined using methods conventional in the art. By using an acrylic pressure-sensitive adhesive with proper saturation solubility for lidocaine, the risk of drug crystallization can be effectively reduced.
Preferably, the acrylic pressure sensitive adhesive is a crosslinked acrylic pressure sensitive adhesive,
The viscosity of the acrylic pressure-sensitive adhesive at room temperature is 1500-8000 mPas, preferably 1500-6500 mPas;
the Tg value of the acrylic pressure-sensitive adhesive is-50 ℃ to-10 ℃, preferably-40 ℃ to-20 ℃; and/or
The acrylic pressure sensitive adhesive is selected from one or more of DURO-TAK 87-2852、DURO-TAK 87-900A、DURO-TAK 87-2074、DURO-TAK 387-2510/87-2510、DURO-TAK387-2052/87-2052、DURO-TAK 87-2196、DURO-TAK 387-2051/87-2051 and DURO-TAK 87-4098.
By using a crosslinked acrylic pressure-sensitive adhesive and/or selecting an acrylic pressure-sensitive adhesive having a viscosity and Tg value within the scope of the preferred embodiment of the present invention, the permeation performance and the colloid application performance of the lidocaine patch can be significantly improved, the resulting patch has good peel viscosity, and the residual adhesive, cold flow, and crystallization phenomena are greatly reduced.
It is particularly surprising that, within the content range of the present invention, when the acrylic pressure-sensitive adhesive is selected from DURO-TAK 87-2852 and DURO-TAK 87-2074, the resulting patch has excellent drug release and permeation properties as well as colloid application properties. Wherein DURO-TAK 87-2852 and DURO-TAK 87-2074 are acrylic pressure-sensitive adhesives having-COOH and-COOH/-OH functional groups, respectively, and amino groups contained in the active ingredient lidocaine can interact with-COOH and/or-OH functional groups in the pressure-sensitive adhesives according to the conventional understanding in the art, which is unfavorable for the mobility of the lidocaine in a polymer matrix, thus affecting the release rate of the drug, so that for pharmaceutically active molecules containing basic groups, it is conventional practice to avoid the use of pressure-sensitive adhesives containing-COOH and/or-OH functional groups as much as possible.
Without wishing to be bound by theory, the unexpected result in the present invention is due, on the one hand, to the higher solubility of lidocaine in the pressure sensitive adhesive described above, which allows for the inclusion of higher levels of drug in the pressure sensitive adhesive, thereby facilitating passive diffusion of the drug while reducing the risk of drug crystallization; on the other hand, in the content range of the present invention, by combining the pressure-sensitive adhesive with the permeation enhancer, a microenvironment favorable for permeation of lidocaine is generated; in addition, the acrylic pressure-sensitive adhesive has proper physical properties, so that the adhesive prepared by using the acrylic pressure-sensitive adhesive and the permeation enhancer has proper initial adhesion, holding adhesion, cohesion, stripping force and other properties on the whole within the content range of the invention, thereby having good release and permeation properties and application properties on the whole.
Preferably, the permeation enhancer is selected from one or more of fatty alcohols, monohydric alcohol esters, glycerol esters and polyethylene glycol esters; more preferably, the permeation enhancer is selected from one or more of isopropyl palmitate, glycerol monooleate, ethyl oleate, octyldodecanol, triethyl citrate, terpineol, azone, cocoyl caprylyl caprate, basf crospovidone PVPCL-M, glyceryl triacetate and isopropyl myristate.
Preferably, the transdermal patch containing lidocaine further comprises other pharmaceutically acceptable auxiliary materials; preferably, the other pharmaceutically acceptable auxiliary material is an antioxidant; more preferably, the antioxidant is present in an amount of 0.01 to 0.1%, preferably 0.02 to 0.05% by weight based on the weight of the polymeric matrix layer; further preferably, the antioxidant is selected from one or more of dibutyl hydroxytoluene, tocopherol, sodium metabisulfite, ascorbyl palmitate.
Preferably, the polymeric matrix layer does not contain other crystallization inhibitors, tackifiers, plasticizers, and/or fillers.
In order to improve the problems of the adhesive application property and crystallization, the inventors have tried to adjust by various methods such as adding auxiliary materials such as crystallization inhibitors, tackifiers, plasticizers and/or fillers, however, since it is possible to optimize one aspect of properties (such as one or more of crystallization, peeling viscosity, residual gum or cold flow, etc.) while adversely affecting other aspects of properties (such as other adhesive application properties and skin irritation, drug release and permeation properties, formulation stability, etc.), the present invention preferably does not include crystallization inhibitors, tackifiers, plasticizers and/or fillers.
Preferably, the transdermal patch contains lidocaine in an amount of 0.20mg to 2.0mg per square centimeter; preferably, the transdermal patch has a delivery area of 5cm 2～100cm2.
Preferably, the lidocaine-containing transdermal patch further comprises a backing layer and a protective layer; the polymer matrix layer is positioned between the backing layer and the protective layer.
Preferably, the transdermal patch has a weight ratio of the compound of formula (I) and/or acetylacetone to lidocaine of less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%;
In the crosslinked acrylic pressure-sensitive adhesive, there is a residual acetylacetone crosslinking agent, although the content thereof is low, which reacts with lidocaine during the patch placement to generate impurities of the structure represented by formula (I), and the presence of the impurities may affect the product quality. The invention prevents the overrun of related substances generated in the long-term placement process of the transdermal patch by controlling the content of acetylacetone in the transdermal patch, thereby controlling the quality of the product.
More preferably, the transdermal patch is prepared by a method comprising the steps of: uniformly mixing the lidocaine, the acrylic acid pressure-sensitive adhesive and the penetration enhancer in the prescription amount to obtain clear glue solution, and then drying the glue solution under the ventilation condition at 50-60 ℃, preferably at 55-60 ℃.
The inventors have unexpectedly found that the residual cross-linking agent acetylacetone in the pressure-sensitive adhesive can be volatilized with the solvent when dried at 50-60 ℃, preferably 55-60 ℃, and under ventilation conditions, thereby greatly reducing the generation of related substances during the placement process. The invention controls the content of acetylacetone in the transdermal patch by controlling the drying temperature under the ventilation condition in the preparation process, thereby conveniently and easily controlling the production of related substances and obtaining the transdermal patch meeting the clinical stability requirement.
In another aspect, the present invention provides a transdermal patch containing lidocaine, which comprises lidocaine as an active ingredient, an acrylic pressure-sensitive adhesive and optionally other pharmaceutically acceptable auxiliary materials, wherein the weight ratio of the compound of the structure shown in formula (I) and/or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%;
more preferably, the transdermal patch is prepared by a method comprising the steps of: uniformly mixing lidocaine, acrylic acid pressure-sensitive adhesive and other pharmaceutically acceptable auxiliary materials to obtain clear glue solution, and then drying under ventilation at 50-60 ℃, preferably 55-60 ℃.
In yet another aspect, the present invention provides a method for preparing the lidocaine-containing transdermal patch of the present invention, comprising the steps of:
(1) Uniformly mixing the lidocaine, the acrylic pressure-sensitive adhesive and the transdermal enhancer in the prescription amount to obtain clear glue solution;
(2) Coating the glue solution obtained in the step (1) on a protective layer, and drying;
(3) Compounding the product obtained in the step (2) with a backing layer, and cutting to obtain the transdermal patch;
Preferably, wherein the mixing of step (1) is performed by:
(a) Mixing acrylic pressure sensitive adhesive and penetration enhancer, adding lidocaine, and mixing, or
(B) Uniformly mixing a permeation enhancer and lidocaine, and then adding an acrylic pressure-sensitive adhesive for mixing;
Preferably, the step (1) further comprises mixing a prescribed amount of other pharmaceutically acceptable excipients with the lidocaine, acrylic pressure sensitive adhesive and permeation enhancer;
Preferably, in the step (2), the drying is performed at 50 to 60 ℃, more preferably at 55 to 60 ℃, under ventilation.
Controlling the temperature during the drying process is critical to obtaining a patch with good stability. Drying at 80 ℃ can lead to rapid increase of relevant substances of the product, and the quality of the product is disqualified. In addition, the research shows that the sample can generate new unknown single impurity (impurity N) in the placing process, and the further research confirms that the impurity N is the impurity generated by the reaction of lidocaine and the residual cross-linking agent acetylacetone in the acrylic pressure-sensitive adhesive, when the temperature is 50-60 ℃ and the pressure-sensitive adhesive is dried under the ventilation condition, the residual cross-linking agent acetylacetone in the pressure-sensitive adhesive can volatilize along with the solvent, so that the generation of the impurity N is greatly reduced. The content of acetylacetone in the transdermal patch can be controlled to avoid overrun of related substances generated in the long-term placement process of the transdermal patch, thereby conveniently and easily controlling the quality of the product.
Preferably, the weight ratio of acetylacetone to lidocaine in the transdermal patch after the drying step in step (2) is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%.
In a further aspect, the present invention provides the use of a transdermal patch comprising lidocaine according to the invention in the manufacture of a medicament for the treatment of peripheral nerve-related pain, preferably selected from one or more of postherpetic neuralgia, trigeminal neuralgia, sciatica and diabetic peripheral neuralgia.
The API content of the patch of the present invention is far lower than that of the marketed productsBut achieve a permeation capacity comparable thereto, while the permeation capacity of the patch of the present invention is much higher than/>The patch has simple prescription and process, can simultaneously meet the clinical treatment requirement of drug permeation, has good colloid application performance in a long-term application period, has no crystallization, cold flow and residual gum phenomena, has high stability, can be continuously used for a long time without causing skin irritation, can reduce replacement frequency, improves the compliance of patients, and is suitable for treating peripheral nerve related pain, in particular to patients needing long-term administration such as postherpetic neuralgia and the like. In addition, the invention prevents the overrun of related substances generated in the long-term placement process of the patch by controlling the content of acetylacetone in the transdermal patch, thereby improving the stability of the product.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows 1 H-NMR spectrum of unknown single impurity 2 in example 14 of the present invention;
FIG. 2 shows patches of examples 1-2 and comparative example 1 of the present invention and a reference formulation Average cumulative permeation versus time curve at 24 hours for porcine ear skin labeled skin 1; marked 14%, 21%, 28% and in the figureThe curves of (2) represent comparative example 1, example 2 and reference formulation/>, respectivelyExperimental results of (2);
FIG. 3 shows a patch of example 2 of the present invention and a reference formulation And/>Average cumulative permeation versus time curve at 24 hours for porcine ear skin labeled skin 2; marked 28%,/>, in the figureAndThe curves of (2) represent example 2, reference formulation/>, respectivelyAnd/>Experimental results of (2);
FIG. 4 shows patches of example 3 and comparative examples 2-3 of the present invention and reference formulations Average cumulative permeation versus time curve at 4 hours for porcine ear skin labeled skin 3; marked 35% API, 30% API+10% IPP and/>Is representative of the curves for comparative example 3, comparative example 2, example 3 and reference formulation, respectivelyExperimental results of (2);
FIG. 5 shows comparative examples 8-10 and reference formulations Average cumulative permeation versus time curve at 24 hours for porcine ear skin labeled skin 4; labeled 18% API, 18% API+IPM, 18% API+IPP, andIs representative of the curves for comparative example 8, comparative example 9, comparative example 10 and reference formulation/>, respectivelyExperimental results of (2);
FIG. 6 shows the distribution of drugs in each tissue of animals in the 6h group of test example 4;
FIG. 7 shows the distribution of drugs in each tissue of animals in a group of 12h sampling time in test example 4;
FIG. 8 shows the drug distribution in each tissue of each animal of the 24-hour group in test example 4.
Detailed Description
Definition of terms:
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly used in the art to which this invention belongs. For the purposes of explaining the present specification, the following definitions will apply, and terms used in the singular will also include the plural and vice versa, as appropriate.
The term "transdermal" or "transdermal" as used herein refers to a mode of administration that delivers an active ingredient through the skin or mucosa into the local or systemic system. The invention has the same meaning and can be mutually universal.
The term "polymeric matrix layer" or "colloidal matrix layer" as used herein refers to a combination of polymeric pressure sensitive adhesive, lidocaine, and any other pharmaceutically acceptable auxiliary materials included in a transdermal drug delivery system. Typically, the polymeric matrix layer is located intermediate the release film and the backing film. The polymer matrix layer is used as the drug delivery layer of the transdermal drug delivery system to form the transdermal drug delivery system with mixed gel drugs.
The term "transdermal patch" or "transdermal delivery system" as used herein refers to a system for transdermal delivery of an active ingredient, typically comprising a backing layer and a release film, and a polymeric matrix delivery layer positioned between the two layers. The polymer matrix administration layer can be generally divided into a reservoir type and a gel drug mixed type according to the combination mode of the active ingredient and other components. Transdermal drug delivery systems may also be referred to simply as patches or transdermal patches, and these designations may be used interchangeably herein. The polymeric matrix delivery layer typically contains an active ingredient, a transdermal enhancer and/or other pharmaceutically acceptable excipients suitable for transdermal delivery patches, including but not limited to pressure sensitive adhesives, fillers, cross-linking agents, antioxidants, ultraviolet absorbers, antimicrobial agents, and the like.
The term "permeability" as used herein means the ability of a drug to permeate the skin or mucous membrane in a passive diffusion manner, with a driving force being the difference in concentration of the active ingredient on both sides of the skin. The cumulative permeation per unit time and unit area can be used as an examination index of the permeation capacity of the patch, and is generally marked as flux with the unit of mug/cm 2/h. The cumulative transmission per unit area at each time point can also be examined and is generally designated as Q t in μg/cm 2.
The term "lidocaine" as used herein refers to the free base of lidocaine.
The term "pressure sensitive adhesive" or "adhesive" as used herein refers to a class of viscoelastic polymeric materials that adhere together and maintain long-lasting adhesion with only a light amount of pressure when in contact with the surface of most other materials. Pressure-sensitive adhesives generally comprise two types, one of which is pressure-sensitive adhesive per se, and the other of which can be used to achieve the function of pressure-sensitive adhesive by adding a tackifier or plasticizer. The pressure-sensitive adhesive has satisfactory physical properties such as good skin adhesiveness at room temperature, maintains adhesiveness for a certain period of time, can be peeled off without damaging the skin, and can control cold flow, thereby satisfying application requirements. Generally, acrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives and rubber pressure-sensitive adhesives are included, and the above pressure-sensitive adhesives are formed into a new mixed pressure-sensitive adhesive by physical mixing or chemical bonding so as to regulate the properties of the pressure-sensitive adhesive to meet specific requirements.
The term "acrylic pressure sensitive adhesive" as used herein includes dimer macromolecules, trimer macromolecules and multimers, including, for example, acrylic homopolymers, copolymers and multimers. Monomers useful in preparing the acrylic pressure sensitive adhesive of the present invention include acrylates, including for example unsubstituted acrylates, methyl substituted acrylates. Specifically, monomers useful in preparing the acrylic pressure-sensitive adhesive of the present invention include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, lauryl methacrylate, myristyl methacrylate, and the like. Monomers useful in preparing the acrylic pressure sensitive adhesive of the present invention also include acrylic acid amides such as acrylic acid amides and methacrylic acid amides. Further, the acrylic pressure-sensitive adhesive of the present invention includes a dimer or polymer formed from an acrylic monomer and a non-acrylic monomer. The non-acrylic pressure sensitive adhesive refers to polymerized monomers other than acrylic compounds, such as vinyl acetate and acrylic monomers, to form a copolymer polymer. In some embodiments, the acrylic pressure sensitive adhesive of the present invention comprises only one acrylic polymer. In other embodiments, the acrylic pressure sensitive adhesive of the present invention comprises two or more acrylic polymers. For an acrylic polymer comprising two or more kinds, the ratio of each component can be adjusted to obtain physical and pharmaceutical properties such as wear properties, permeation rate of lidocaine, etc. that satisfy the requirements.
The term "transdermal enhancer" as used herein refers to a substance capable of changing the rate of diffusion of an active ingredient into the skin, and is generally miscible with the active ingredient and uniformly dispersed in the polymeric matrix layer.
The term "antioxidant" as used herein refers to a substance capable of inhibiting oxidation of an active ingredient, such as phenols, ascorbic acid, and the like.
The term "crystallization inhibitor" as used herein refers to a polymer commonly used in the art, such as polyethylene glycol 1000, succinate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poloxamer, sodium dodecyl sulfate, polysorbate, povidone, celluloses, etc., which is capable of inhibiting precipitation of an active ingredient in a colloidal matrix.
The term "… … weight content … … based on the weight of the polymeric matrix layer" as used herein refers to the dry weight ratio of the components to the polymeric matrix.
The term "backing layer" as used herein refers to a layer that is impermeable to the drug in a transdermal patch. One surface of the back lining layer is directly connected with the polymer matrix layer, and the back lining layer plays a role in protecting the polymer matrix layer from being contacted with the surrounding environment and preventing the loss of medicines when in use. The raw material for the backing layer is generally referred to as the backing film. The backing layer is made of polyester, polyethylene-polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, non-woven fabric, stretch cloth, etc. and has a thickness of 10-200 μm. For example, scotchPakTM, 9701, 9720, 9723 of U.S. 3M company, chinese xiaoshan stretch cloth 6015A, japanese plumes nonwoven EW2080, EW2083, or Shanghai winning family PE3601 may be used. The backing films with different properties have different physicochemical properties such as extensibility, air permeability, oxygen permeability, light repellency and the like. The backing layers or films of the present invention are the same meaning and may be mutually generic.
The term "release film" as used herein may also be referred to as a protective layer, which is directly attached to the other surface of the polymeric matrix layer. The transdermal patch is removed from the release film prior to use.
The term "transdermally effective dose" or "therapeutically effective amount" or "effectiveness" as used herein means that the active ingredient is delivered through the skin in an amount sufficient to achieve the desired effect, either locally or systemically, to achieve a particular pharmacological effect, such as cure, alleviation or control of a disease or condition, when the transdermal patch is in use. These terms are used interchangeably throughout this disclosure.
The term "application property" as used in the present invention is meant to include all processes including the peeling force of the patch from the release film, the peeling force of the patch from the application site after application, the initial adhesion, the holding adhesion, and the cold flow. Wherein: "peel force" refers to the force applied to remove the patch from the skin after application of a backing layer containing a polymeric matrix layer from a release film, and is not required to be excessive to cause peeling failure or to leave a gel on the skin; "tack" refers to the degree of wetting of the backing layer containing the polymeric matrix layer and the application site, reducing the risk of peeling during application; "adhesion" refers to the degree of displacement of the patch at the site of application, and is reflected in the strength of the application during application; "Cold flow" refers to the viscoelastic creep of the polymeric matrix layer, which results in a black ring during wear of the patch, and may adhere to the protective layer and packaging container during storage, affecting patient safety and effectiveness. The patch generally needs to balance the properties of peeling force, initial adhesion, holding adhesion, cold flow and the like.
In order to make the technical scheme and the beneficial effects of the invention more obvious and understandable, the following detailed description is given by way of example only with reference to the accompanying drawings. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The specific techniques or conditions are not identified in the examples and are generally performed according to conventional techniques or conditions described in the literature in this field or according to the product specifications. The reagents, materials, or apparatus used, unless otherwise specified, are those conventionally commercially available.
In the following examples, comparative examples and test examples, pressure-sensitive adhesive types and shorthand are shown in table 1.
TABLE 1 pressure sensitive adhesive model and shorthand list
For simplicity of writing, the pressure-sensitive adhesive letter parts are omitted in the examples, the comparative examples and the test examples of the invention, and only the shorthand numerals are used for substitution.
The physicochemical properties of each pressure sensitive adhesive in table 1 are listed in table 2 below:
TABLE 2 physicochemical Properties of the pressure sensitive adhesive
In the following examples, comparative examples and test examples, english abbreviations are shown in Table 3.
Table 3 english shorthand table
Reference formulations used in the following examples, comparative examples and test examplesPurchased from Imperial pharmaceutical Co., ltd (Teikoku Seiyaku Co., ltd.),/>Purchased from Nitto electric Co.
Examples 1 to 13: preparation of transdermal patches of the present invention
Examples 1 to 13 provide a lidocaine-containing transdermal patch comprising a polymer matrix layer containing lidocaine as an active ingredient, an acrylic pressure-sensitive adhesive, a permeation enhancer and optionally other pharmaceutically acceptable auxiliary materials (such as an antioxidant), wherein the weight content of lidocaine is 21% to 33%, the weight content of acrylic pressure-sensitive adhesive is 45% to 75%, the weight content of permeation enhancer is 3% to 25%, and the weight content of optional antioxidant is 0.01 to 0.1% based on the weight of the polymer matrix layer.
Transdermal patches containing different weight contents of lidocaine, acrylic acid pressure-sensitive adhesive, a transdermal enhancer and optionally other pharmaceutically acceptable auxiliary materials (such as antioxidants) are prepared according to the following preparation method, and specific components and contents are shown in the following table 4 (the contents in the table are weight percentages of each component in the total polymer matrix layer after drying).
The preparation method comprises the following steps: weighing the prescription amount of the transdermal enhancer, the acrylic pressure-sensitive adhesive and other optional pharmaceutically acceptable auxiliary materials (such as an antioxidant and the like), and stirring to uniformly mix the materials; and adding lidocaine, and continuously stirring until the lidocaine and the lidocaine are uniformly mixed to obtain clear glue solution. And coating the prepared glue solution on a selected release film, wherein the coating thickness is determined according to the use requirement. Drying the coated polymer matrix at 50-60 ℃ under the ventilation condition. And then compounding the dried product with a selected backing film, cutting into a proper size and shape according to the use requirement, and packaging. Of these, release film model 1022 (from 3M company), backing film model 1109 (from 3M company) and coating thickness 150 μm.
TABLE 4 kinds and contents of the respective components in the patches of examples 1 to 13
/>
Example 14: investigation of factors influencing stability of preparation
The influence of the drying temperature on the patch quality was examined by using the intermediate glue solution of example 2, and the examination results are shown in Table 5-1, with the relevant substances as evaluation indexes.
TABLE 5-1 influence of drying temperature on related substances
Controlling the temperature during the drying process is critical to obtaining a patch with good stability. Drying at 80 ℃ can lead to rapid increase of relevant substances of the product, and the quality of the product is disqualified.
Further high temperature stability studies of samples numbered 1-4 have found that new unknown mono-impurity 2 is also generated during high temperature 40 ℃ and 60 ℃ storage, and the impurity is detected to be approaching or exceeding the limit at high temperature 40 ℃ and 60 ℃ storage for 25 days, and the results are shown in tables 5-2 and 5-3.
Table 5-2 results of stability investigation at high temperature 40 ℃
Table 5-3 results of stability investigation at 60℃high temperature
Further researches prove that the unknown single impurity 2 is an impurity generated by the reaction of lidocaine and acetylacetone serving as a residual crosslinking agent in the acrylic pressure-sensitive adhesive, and the molecular formula of the high-resolution mass spectrum prompt sample is C 15H17NO3; the hydrogen spectrum gives a total of 17 hydrogen signals including 12 methyl hydrogens, 4 methine hydrogens and 1 active hydrogen signal (see figure 1). 13 The C-NMR spectrum gives a total of 15 carbon signals, which in combination with the DEPT 135 spectrum were determined to contain 4 methyl carbons, 4 methine carbons and 7 quaternary carbons. The 1D-NMR data combined with the 2D-NMR (HSQC, HMBC and COSY) data suggests that the structure is as shown in the following formula (I):
the molecular formula: c 15H17NO3
Molecular weight: 259.31
The specific reaction process is presumed to be as follows:
the presence of this impurity affects the patch product quality, in the present invention it is preferred that the weight ratio of the compound of the structure of formula (I) (in the context of the present invention also referred to as unknown impurity 2 or impurity N) to lidocaine of the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%.
In the process of examining the generation condition of the impurity N, the lidocaine and the acetylacetone are found to be placed at a high temperature of 60 ℃ for 15 days to generate the impurity N, but the impurity N is smaller in quantity; the addition of acrylic acid pressure-sensitive adhesive into lidocaine and acetylacetone generates impurity N after standing at 60 ℃ for 5 days, and the trend of increasing is that the addition of acrylic acid pressure-sensitive adhesive generates more impurities after continuing for 15 days, which is faster than the addition of the same condition of lidocaine and acetylacetone, thus indicating that the reaction is accelerated due to the addition of acrylic acid pressure-sensitive adhesive.
The inventors have unexpectedly found that the residual cross-linking agent acetylacetone in the pressure-sensitive adhesive can be volatilized with the solvent when dried at 50-60 ℃, preferably 55-60 ℃, and under ventilation conditions, thereby greatly reducing the generation of impurity N during the placement process. The impurity N overrun generated in the long-term placement process of the patch can be avoided by controlling the content of acetylacetone in the patch, so that the product quality can be easily controlled. The amount of acetylacetone in the patch can be further reduced by increasing the ventilation amount or prolonging the drying time. Preferably, the weight ratio of acetylacetone to lidocaine in the patch is controlled to be less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, and particularly preferably less than 0.1%. Further preferably, the sum of the weight ratio of the compound of formula (I) to lidocaine and the weight ratio of acetylacetone to lidocaine in the patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%.
Comparative examples 1 to 13: preparation of patches of different components and contents
Patches were prepared according to the preparation method of the patches described in examples 1 to 13, except that the respective components and their contents are shown in table 6 below.
TABLE 6 kinds and contents of each component in the patches of comparative examples 1 to 13
Comparative example 14:
lidocaine patch is prepared according to the prescription and the method of the embodiment 1 of the patent CN109316469B, wherein the weight contents of the lidocaine and the acrylic pressure-sensitive adhesive in the high polymer matrix layer are respectively 60 percent, 39.8 percent and the balance is 0.2 percent of antioxidant BHA, and the preparation method is as follows:
The acrylic pressure-sensitive adhesive DURO-TAK 87-4098 with the formula weight is weighed and added into ethanol and stirred uniformly. And then adding lidocaine in batches under the condition of keeping stirring, stirring until the lidocaine is completely dissolved, finally adding antioxidant BHA, and continuously stirring until a uniform transparent solution is formed. The prepared solution was coated on a release film. The coated polymer matrix is passed through an oven with air exhaust function, heated and dried for 5-15 minutes at 60-80 ℃ to form a uniform blend of lidocaine and acrylic pressure-sensitive adhesive, and the organic solvent is removed. And then compounding the dried product with a backing film, cutting into proper size and shape, and packaging.
Test example 1: in vitro transdermal experiments
In vitro transdermal experiments were determined by Franz vertical diffusion cells. Healthy pig ear skin (labeled skin1, skin2, skin3, skin4, respectively) was obtained from the horny layer of the pig ear skin according to standard thermal separation methods. An automatic percutaneous system with LOGAN SYSTEM ℃ to 12 dry heating is adopted, the pH value of the receiving solution is 6.5 phosphate buffer solution, the volume of a diffusion cell is 12ml, the permeation diameter is 15mm, the sampling volume is 5ml, the temperature is 32 ℃, the full-evacuation mode is adopted, the rotating speed is 600 revolutions per minute, the operation is performed according to law, and the sampling is carried out at a preset time point. Examples 1-3, comparative examples 1-3 and 8-10 and reference formulations were takenAnd/>Samples, 3 replicates per group, and one blank as a control. The cumulative transmittance at each time point was calculated from the results, which are shown in fig. 2 to 5.
FIG. 2 shows patches of examples 1-2 and comparative example 1 of the present invention and a reference formulationAverage cumulative permeation versus time curve at 24h of porcine ear skin labeled skin 1. The results showed that at an API content of 14%, the 24h cumulative transmission of the sample was equal to/>Substantially consistent, there was a trend towards an increase in 24h cumulative transmission with increasing API concentration, with samples having 24h cumulative transmission significantly higher than/>, at API levels of 21% and 28%Respectively isAbout 2 or 3 times the cumulative transmission.
FIG. 3 shows a patch of example 2 of the present invention and a reference formulationAnd/>Average cumulative permeation versus time curve at 24h of porcine ear skin labeled skin 2. The results show that the 24h cumulative transmission of the patch of the invention is significantly higher than that of/>And do with/>Proximity. Wherein/>Is gel plaster containing 5% lidocaine,/>Is a hot melt adhesive patch containing 60% lidocaine. The API content of the patch of the present invention is, although much lower than/>But realizes the equivalent permeability, and the permeability of the patch of the invention is far higher than that of the patchTherefore, the proper prescription is selected to achieve the transmission capacity basically equivalent to that of the prescription with the highest saturation content according to the proper API content, and the transmission capacity is far higher than that of the gel plaster, so that the invention predicts that the gel plaster has better drug effect and is used for meeting the clinical requirement of treating the peripheral neuralgia.
FIG. 4 shows patches of example 3 and comparative examples 2-3 of the present invention and reference formulationsAverage cumulative permeation versus time curve at 4h of porcine ear skin labeled skin 3. The results show that the patch of comparative example 2 containing 30% api and the patch of comparative example 3 containing 35% api were substantially comparable in permeation capacity without the addition of a permeation enhancer, and only slightly superior to the reference formulation/>And are all much lower than the permeation capacity of the patch of the present invention containing 30% api and 10% permeation enhancer. This result is unexpected because previous studies by the inventors showed that the addition of a permeation enhancer at an API content of 18% did not function to significantly increase permeation capacity (see figure 5 for specific results).
FIG. 5 shows comparative examples 8-10 and reference formulationsAverage cumulative permeation versus time curve at 24h of porcine ear skin labeled skin 4. The results show that the penetration enhancer added at lower lidocaine levels did not significantly improve penetration.
Test example 2: colloid application property and colloid character stability experiment
Lidocaine patches and reference preparations in examples 1 to 13 and comparative examples 1 to 14 were measured according to the following evaluation indexes and methodsAnd/>Colloid application property and colloid property stability (whether crystalline or not).
The evaluation index and the method are as follows:
A. Adhesion force:
The peel viscosity and the residual glue were used as evaluation indexes.
Peel viscosity: the peel viscosity at the time of peeling from the skin after d=2 cm circular lidocaine patch was applied to the skin for 24 hours was used as an evaluation index, and the intensity was described in table 7, ++, ++was acceptable.
TABLE 7 Peel viscosity and Strength description
| Peel viscosity | Description of intensity |
| – | The adhesion of the sample is weak, and the application requirement of 24 hours cannot be met |
| + | The sample is easy to peel and slightly sticky after being applied for 24 hours |
| ++ | The sample is easy to peel and has viscosity after being applied for 24 hours, and the sample is slightly dry |
| +++ | The sample is not easy to peel after being applied for 24 hours, has strong viscosity and has tearing sense |
Residual glue: the evaluation index was the residual adhesive level after peeling off the lidocaine after d=2 cm circular patch was applied to the skin for 24 hours. The intensity profile is shown in Table 8, ++, acceptable.
TABLE 8 description of degree of residual gum and strength
| Degree of residual glue | Description of intensity |
| + | Residue-free adhesive |
| ++ | Slightly residual glue |
| +++ | Residual glue is obvious |
B. Cold flow:
and (3) cutting the intermediate coiled material, placing the intermediate coiled material into a packaging bag for standing, and visually observing whether glue solution oozes out from the edge of the adhesive or whether the packaging bag is stuck or not by a microscope. Cold flow strength is described in table 9, ++, acceptable.
Table 9 cold flow strength description
| Cold flow | Description of intensity |
| + | Almost no cold flow, non-stick packing bag |
| ++ | Slightly cold flow and slightly sticky packaging bag |
| +++ | The periphery of the sample is provided with a circle of cold flow or a large block, and the packaging bag is adhered |
C. And (3) crystallization:
in the visual inspection method, lidocaine patch was exposed to room temperature, and the deposition of crystals was periodically observed.
The experimental results are shown in table 10 below.
D. skin irritation
After the lidocaine patch was applied to the skin for 24 hours by visual inspection, whether the skin became red or not was observed.
Table 10 results of comparison of the properties of lidocaine patches and reference formulations of examples 1 to 13 and comparative examples 1 to 14
/>
As can be seen from the above experimental results, the reference preparationAnd/>The adhesive has poor application performance, can not meet the application requirement of 24 hours, and/>There is also a devitrification phenomenon.
The adhesive patches of examples 1 to 13 of the present invention can significantly improve the adhesive properties of the adhesive patches by incorporating a suitable amount of lidocaine in the polymeric matrix layer, and simultaneously adding a certain amount of a permeation enhancer and optionally an antioxidant, and the resulting adhesive patches have a suitable peel-off viscosity after 24 hours of application, are free or slightly free of residual adhesive and cold flow phenomena (both within an acceptable range), are free of skin irritation, and are free of crystallization phenomenon after long-term storage. Particularly when a crosslinked acrylic pressure-sensitive adhesive, and/or a pressure-sensitive adhesive having an appropriate viscosity and Tg (e.g., pressure-sensitive adhesives 2852 and 2074) is used, a patch excellent in various aspects of peel viscosity, residual adhesive, cold flow, crystallization, and skin irritation is obtained. And, it was determined that the patch has both extremely excellent release and permeation capabilities.
Comparative examples 1to 14 are other prescriptions which the inventors have tried to solve the technical problems to be solved in the course of development, however, due to the complexity of patch development, satisfactory results in all aspects have not been obtained by conventional means such as using a pressure-sensitive adhesive such as polyisobutylene, silicone, etc. or by adding a plasticizer, filler and/or crystallization inhibitor, etc. which are conventionally used.
Test example 3: long term stability and accelerated stability experiments
Long-term stability and accelerated stability experiments were carried out at a temperature of 25 ℃ ± 2 ℃, a relative humidity of 60% rh ± 5% rh, and a temperature of 40 ℃ ± 2 ℃ and a relative humidity of 75% rh ± 5% rh, respectively, and the samples of example 4 were examined periodically for the relevant substances and API contents, and the results are shown in tables 11 to 12, respectively.
TABLE 11 results of long-term stability experiments
Table 12 results of accelerated stability experiments
From the results in tables 11-12, it can be seen that the patches of the present invention were stable with respect to substances, release rates, and API content, meeting the limit requirements, and were free of other unknown impurities during the long-term stability and acceleration stability experiments, indicating that the patches of the present invention were excellent in stability.
Test example 4: local tissue distribution study of lidocaine in Bama miniature pigs
The common-grade Bama miniature pigs are selected for 6, and the male and female pigs are respectively 3. The administration route adopts transdermal application for administration, and self-made preparation (lidocaine patch of the embodiment 2 of the invention) and reference preparation are prepared) The clinical quasi-dosage is adopted for comparison study, the self-made preparation has the application specification of 78 mg/patch, the single patch application area of 7cm multiplied by 10 cm/patch, and the reference preparationThe application specification is 700 mg/patch, and the single patch application area is 10cm multiplied by 14 cm/patch. The left and right backs of each animal were given 3 patches of each of the self-made and reference formulations, corresponding to time points of 6h (6 h applied), 12h (12 h applied) and 24h (12 h applied) after administration, respectively.
The animals were sacrificed at the endpoint and skin, muscle, subcutaneous fat samples were collected at the corresponding time points and blank samples were collected at non-dosing sites for evaluation of possible cross-interference using the reverse patch method. After tissue samples are collected, physiological saline is used for cleaning the surface, filter paper is sucked dry, and the tissue samples are placed in a refrigerator at the temperature of minus 80 ℃ for freezing and preserving to be measured.
Table 13 administration information for each group
The concentration of lidocaine in the tissue was determined by LC-MS/MS. Tissue concentration data were processed with DAS3.2 and the non-compartmental model was used to calculate the main pharmacokinetic parameters.
Results: after the lidocaine patch is applied to the miniature Bama pig for a single time, the lidocaine in each tissue reaches a peak after 12 hours of administration, the patch is removed after 12 hours of application, and the drug concentration in each tissue is obviously reduced until 24 hours after administration; single-time plaster for Bama miniature pigsAnd then, the lidocaine in each tissue reaches a peak after 12 hours of administration, the patch is removed after 12 hours of application, and the drug concentration in each tissue is obviously reduced after 24 hours of administration.
As shown in FIGS. 6-8, the Lidocaine patch or the present invention is applied to a miniature Bama pig in a single applicationAfter that, the medicine concentration at different time points is skin > subcutaneous fat > muscle, and the medicine concentration in skin tissue is obviously higher than that of subcutaneous fat and muscle. The drug concentration in the skin and fat of the lidocaine patch is higher than/>, 6 hours after administrationThe concentration of the medicine in the skin, fat and muscle of the lidocaine patch is lower than that of the lidocaine patch of the invention at 24 hours (12 hours of application)Drug exposure in fat and muscle (AUC (0-24h)) and after administration of lidocaine patch of the present inventionEquivalent, whereas the drug exposure in skin (AUC (0-24h)) is about/>1.3 Times of (2).
Conclusion: the Lidocaine patch of the invention is applied to miniature pigs in a single timeAnd then, the skin, fat and muscle of the administration part reach the peak 12h after administration, the patch is removed after 12h of application, the drug concentration in each tissue is obviously reduced to 24h after administration, and the drug concentration at different time points after administration is skin > subcutaneous fat > muscle.
Single administration of lidocaine patches of the present invention followed by single administrationIn contrast, drug exposure in fat, muscle (AUC (0-24h)) versus/>Equivalent, the drug exposure (AUC (0-24h)) in the skin is significantly higher thanAbout/>1.3 Times of (2).
Test example 5: investigation of pain sensation of human body application
Investigation of homemade formulations (lidocaine patch of example 2 of the invention) and reference formulations @) Pain sensation differences of 0.75h, 1.5h, 3h, 6h and 12h are respectively applied, and a circular patch with an application area d=2cm is applied. /(I)
The application parts of the volunteers A, B, C and D are the inner sides of the lower arms, and the volunteers A, B, C and D are taken down at the same time by adopting a reverse application method, and the pain feeling is felt by the application parts of sharp objects. Evaluation index: the pain feeling at the non-applied part is 5, and the lower the value is, the smaller the pain feeling is.
Table 14 results of investigation of pain sensation in human application
Conclusion: the pain feeling of the volunteers is obviously weakened after the self-made preparation is applied for 3 hours, the pain feeling is rated for 1-3 hours, the pain feeling of three volunteers is slightly weakened after the reference preparation is applied for 6-12 hours, and the pain feeling of one volunteer is obviously weakened about 3 hours; the pain feeling of the volunteer when the self-made preparation is applied for 3 hours in the same area and the same time is obviously lower than that of the reference preparation.
Claims (12)
1. A transdermal patch containing lidocaine comprises a polymer matrix layer, wherein the polymer matrix layer comprises active ingredients of lidocaine, acrylic acid pressure sensitive adhesive and a transdermal enhancer,
Wherein the lidocaine is present in an amount of 21% to 33%, preferably 25% to 30%, the acrylic pressure sensitive adhesive is present in an amount of 45% to 75%, preferably 55% to 68%, and the permeation enhancer is present in an amount of 3% to 25%, preferably 5% to 15% by weight based on the weight of the polymeric matrix layer.
2. The transdermal patch of claim 1, wherein the weight content of lidocaine in the polymeric matrix layer is lower than its weight content when saturated solubility in the acrylic pressure sensitive adhesive is achieved.
3. The transdermal patch of claim 1 or 2, wherein:
The acrylic pressure-sensitive adhesive is a crosslinked acrylic pressure-sensitive adhesive,
The viscosity of the acrylic pressure-sensitive adhesive at room temperature is 1500-8000 mPas, preferably 1500-6500 mPas;
the Tg value of the acrylic pressure-sensitive adhesive is-50 ℃ to-10 ℃, preferably-40 ℃ to-20 ℃; and/or
The acrylic pressure sensitive adhesive is selected from one or more of DURO-TAK 87-2852、DURO-TAK 87-900A、DURO-TAK 87-2074、DURO-TAK 387-2510/87-2510、DURO-TAK 387-2052/87-2052、DURO-TAK 87-2196、DURO-TAK 387-2051/87-2051 and DURO-TAK 87-4098.
4. The transdermal patch of any one of claims 1 to 3, wherein the transdermal enhancer is selected from one or more of fatty alcohols, monohydric alcohol esters, glycerides, and polyethylene glycol esters; preferably, the penetration enhancer is selected from one or more of isopropyl palmitate, glycerol monooleate, ethyl oleate, octyldodecanol, triethyl citrate, terpineol, azone, cocoyl caprylyl caprate, basf cross povidone PVPCL-M, glyceryl triacetate and isopropyl myristate.
5. The transdermal patch of any one of claims 1 to 4, further comprising other pharmaceutically acceptable excipients;
preferably, the other pharmaceutically acceptable auxiliary material is an antioxidant;
more preferably, the antioxidant is present in an amount of 0.01 to 0.1%, preferably 0.02 to 0.05% by weight based on the weight of the polymeric matrix layer;
Further preferably, the antioxidant is selected from one or more of dibutyl hydroxytoluene, tocopherol, sodium metabisulfite, ascorbyl palmitate.
6. The transdermal patch of any one of claims 1-5, wherein the polymeric matrix layer does not contain other crystallization inhibitors, tackifiers, plasticizers, and/or fillers therein.
7. The transdermal patch according to any one of claims 1 to 6, wherein the transdermal patch contains lidocaine in an amount of 0.20mg to 2.0mg per square centimeter; preferably, the transdermal patch has a delivery area of 5cm 2～100cm2.
8. The transdermal patch of any one of claims 1 to 7, further comprising a backing layer and a protective layer; the polymer matrix layer is positioned between the backing layer and the protective layer.
9. The transdermal patch according to any one of claims 1 to 8, wherein the transdermal patch has a weight ratio of the compound of the structure of formula (I) and/or acetylacetone to lidocaine of less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%;
More preferably, the transdermal patch is prepared by a method comprising the steps of: uniformly mixing the lidocaine, the acrylic acid pressure-sensitive adhesive and the penetration enhancer in the prescription amount to obtain clear glue solution, and then drying the glue solution under the ventilation condition at 50-60 ℃, preferably at 55-60 ℃.
10. A lidocaine-containing transdermal patch comprising the active ingredient lidocaine, an acrylic pressure-sensitive adhesive and optionally further pharmaceutically acceptable auxiliary materials, wherein the weight ratio of the compound of the structure of formula (I) and/or acetylacetone to lidocaine in the transdermal patch is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%;
more preferably, the transdermal patch is prepared by a method comprising the steps of: uniformly mixing lidocaine, acrylic acid pressure-sensitive adhesive and other pharmaceutically acceptable auxiliary materials to obtain clear glue solution, and then drying under ventilation at 50-60 ℃, preferably 55-60 ℃.
11. A method of preparing the transdermal patch of any one of claims 1 to 10, comprising the steps of:
(1) Uniformly mixing the lidocaine, the acrylic pressure-sensitive adhesive and the transdermal enhancer in the prescription amount to obtain clear glue solution;
(2) Coating the glue solution obtained in the step (1) on a protective layer, and drying;
(3) Compounding the product obtained in the step (2) with a backing layer, and cutting to obtain the transdermal patch;
Preferably, wherein the mixing of step (1) is performed by:
(a) Mixing acrylic pressure sensitive adhesive and penetration enhancer, adding lidocaine, and mixing, or
(B) Uniformly mixing a permeation enhancer and lidocaine, and then adding an acrylic pressure-sensitive adhesive for mixing;
Preferably, the step (1) further comprises mixing a prescribed amount of other pharmaceutically acceptable excipients with the lidocaine, acrylic pressure sensitive adhesive and permeation enhancer;
preferably, in said step (2), said drying is carried out at 50 ℃ to 60 ℃, more preferably at 55 ℃ to 60 ℃, under ventilation;
Preferably, the weight ratio of acetylacetone to lidocaine in the transdermal patch after the drying step in step (2) is less than 0.4%, preferably less than 0.3%, more preferably less than 0.2%, particularly preferably less than 0.1%.
12. Use of a transdermal patch according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of peripheral nerve-related pain, preferably selected from one or more of postherpetic neuralgia, trigeminal neuralgia, sciatica and diabetic peripheral neuralgia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311839093.2A CN117899056A (en) | 2023-12-28 | 2023-12-28 | Transdermal patch containing lidocaine, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311839093.2A CN117899056A (en) | 2023-12-28 | 2023-12-28 | Transdermal patch containing lidocaine, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117899056A true CN117899056A (en) | 2024-04-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311839093.2A Pending CN117899056A (en) | 2023-12-28 | 2023-12-28 | Transdermal patch containing lidocaine, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117899056A (en) |
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2023
- 2023-12-28 CN CN202311839093.2A patent/CN117899056A/en active Pending
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