TWI789000B - Topical anesthetic agent-clay composite compositions - Google Patents

Abstract

The present invention relates to a topical anesthetic containing anesthetic agent-clay composite as the anesthetic agent in a delivery vehicle suitable for administration to the skin for increasing anesthetic agent permeation into the skin in order to decreasing onset time. In addition, the compositions of the invention have been shown to exhibit good storage stability with low ester type of anesthetic agent decomposition even at relatively high storage temperatures.

Description

Local anesthetic-clay composite composition

This invention relates to a biomedical or biopharmaceutical technology focused on compositions and methods for topical administration of pharmaceutically active agents to mammals. The present invention relates to local anesthetics, including the use of complexes of clay anesthetics as suitable delivery vehicles.

With the advancement of surgical technology, the demand for better efficacy of local anesthesia has become higher, and related technologies have also continued to develop. Patients often experience pain as a venipuncture or catheter is inserted into a vein while anesthesia is administered. Therefore, fast-acting and long-lasting local anesthetics can help reduce the pain caused by clinically invasive treatments.

Anesthetics with local anesthetic properties can be used for infiltration anesthesia and block nerve conduction, such as lidocaine, prilocaine, mepivacaine, and bupivacaine. However, these local anesthetics must be applied in high concentrations to be effective, so their use is limited, and they also increase the risk of irritation and skin damage toxicity.

Esters of local anesthetics are also strong vasodilators, such as tetracaine. Clinically, vasodilation will play an important role in promoting blood absorption of local anesthetics, thereby shortening the duration and quality of pain control. At the same time, vasodilation will also increase the concentration of anesthetics in the blood and the possibility of overdose. Therefore, how to increase the anesthetic dose accumulated in local tissues is the focus of designing local anesthetic preparations. In addition, ester components of local anesthetics or ester local anesthetics Narcotics are susceptible to chemical degradation, resulting in decreased drug concentrations and/or production of impurities. Tetracaine is a local anesthetic component that is not easy to store stably for a long time, especially in water-soluble preparations. Tetracaine is slightly soluble in water, the pH value in water is usually between 8 and 11, and there is a high hydrolysis rate under the pH value condition. In addition, almost all human tissues have esterase, so tetracaine is quite unstable in the human body.

Many patent documents disclose the composition of local anesthetic, for example US8968710B1 discloses a kind of carrier of transporting tetracaine, and it contains water-soluble mucoadhesive (mucoadhesive) composition, like macromolecule poly(ethylene oxide) (poly(ethylene oxide) oxide)) homopolymers and cellulosic polymers. The carrier contains propylene glycol, which acts as a penetration enhancer and is essential in two situations: (1) to deliver a stable form of tetracaine free base, and (2) to facilitate transmucosal drug penetration Transport at the pH of the flux. Tetracaine is ground into a powder and then dissolved in a plasticized hydrocarbon gel to make the carrier.

US6562326B1 discloses a method of treating skin by applying a topical composition to the affected area due to burns, irritations, blisters, rashes and the like. The topical composition contains as active ingredients an anesthetic and a surfactant: the anesthetic tends to be tetracaine at a concentration of about 1% to 2% by weight, and the surfactant tends to be used at a concentration of about 0.5% by weight to 5.0% sodium lauryl sulfate.

US20070232695A1 discloses a composition containing a high concentration of tetracaine, which can be absorbed by a high surface area material and dispersed in a liquid carrier, such as an ion exchange polymer. The composition can release medicine in the oral cavity through cation exchange, thereby prolonging the time of anesthetizing the gums.

US8513304B2 describes a topical composition comprising: (1) at least one active agent selected from lidocaine and tetracaine; (2) a first compound and (3) a second compound, both Different and selected from N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, isopropyl myristate , oleic acid, glyceryl oleate, and sodium lauryl sulfoacetate. The topical composition can improve the osmotic flux of therapeutically active agents.

US20140163105A1 discloses a composition for relieving pain, which can be multiplied with an effective amount of amino benzoate (amino benzoate) local anesthetics, such as 2% tetracaine, methylsulfonylmethane and ethoxylated Diethylene glycol (ethoxydiglycol). Pain relief is achieved by applying the composition to the skin to block nerve signals.

The study of Liu et al. (Liu et al ., International Journal of Pharmaceuticals 305(1-2): p31-36, 2005) disclosed polyacrylic acid (carbomer) anesthesia gel containing 4% tetracaine, and divided into two Species: with and without menthol. Menthol facilitates the diffusion and absorption of tetracaine on the skin, and tetracaine with menthol diffuses significantly better than without menthol in full-thickness mouse skin.

US20140205589A1 discloses a composition that can reduce or counteract skin reactions and improve the stability of its components. The composition comprises an emulsion of an oily phase and an aqueous phase, wherein the oily phase is a co-melt consisting of at least one anesthetic compound (such as tetracaine) and at least one adrenergic receptor agonist (such as brimonidine) mixture.

US5227165A discloses a local anesthetic lipid sphere, which is a water-insoluble solid particle with a layer of phospholipid embedded on its surface. The core of the lipid globule is the solid anesthetic tetracaine, the anesthetic lipid Plasmids can control the delivery of local anesthetics by slowly releasing anesthetics from the solid hydrophobic core, thereby achieving long-lasting analgesia.

US4937078A discloses tetracaine lipid capsule analgesic, when applied to skin or mucous membrane, the local anesthesia and analgesic effect of this analgesic are better than tetracaine using conventional carrier.

EP0522122B1 pointed out that salts are the key factors to reduce the decomposition rate of tetracaine.

US3272700 shows that tyloxapol can inhibit the decomposition rate of tetracaine.

US8907153B2 relates to drug delivery systems for skin application. More specifically, the adhesive peeling preparation invented by this document has a viscosity suitable for the skin surface and can form a solidified peelable layer on the skin.

US9358219B2 relates to a multi-molecular topical formulation that promotes penetration. In a preferred embodiment, one or more active ingredients extracted from lidocaine and tetracaine can permeate the preparation and be applied to the skin transdermally or topically.

US6325990 discloses a spray composition for application to the skin, which is a lipophilic active compound containing an analgesic ingredient such as lidocaine, and the composition ratio is as follows: 0.5 to 25% by weight of a silicone (silicones) adhesive polymer composition; 0 to 25% by weight absorption enhancer; 25 to 95% by weight volatile silicone solvent; 0.5 to 50% by weight pressurized propellant gas. Among them, volatile silicone accounts for 50 to 85% by weight of the total, and the composition contains up to 25% of volatile solvent, such as ethanol.

US20060147383 discloses a pharmaceutical active agent, which is lidocaine hydrochloride dissolved in an alcohol carrier. The alcohol component contains at least one volatile silicone and a non-volatile oil phase, which is applied in the form of a spray. The volatile silicone content accounts for 25% to 95% by weight of the composition; The concentration of the solvent should be at least 15%, preferably at least 25% ethanol.

US9308181 discloses topical formulations, transdermal systems and related methods. In one embodiment, reference to a local anesthetic includes the first compound and the second compound. The first compound and the second compound are different and are obtained from N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, iso-myristate, respectively. isopropyl myristate, oleic acid, glyceryl oleate, and sodium lauryl sulfoacetate.

US6528086B2 relates to an apparatus and method for administering medicine on human skin. The preparation is composed of a drug, a transforming agent and a carrier medium, and the transforming agent can transform the preparation from a nearly solid state to a softer solid state. The drug formulation is initially nearly solid, allowing it to be applied to the surface of human skin, and transforms into a soft-solid phase as the drug penetrates the skin. After the administration is completed, the softening preparation solidified on the surface of the body can be removed or peeled off.

US9693976 discloses a solid local anesthetic formulation for pain control, the ingredients comprising lidocaine base, tetracaine base, polyvinyl alcohol, water and an emulsifier. The preparation is semi-solid before application to the skin, and forms a solidified soft layer after application, which adheres to the surface and relieves pain on the affected area and adjacent areas.

US20140205589A1 describes a composition that can reduce the degradation rate of a drug and/or improve the stability of its components, which can reduce or counteract skin reactions. The composition is an emulsified liquid with both oil phase and water phase, and the oil phase material can be a eutectic mixture containing at least one anesthetic compound and one adrenergic receptor stimulator. Methods of using such compositions are described in this patent document.

While many local anesthetic compositions have been approved, it has now been found that one or more anesthetics are dissolved in a solvent and incorporated into a pharmaceutically acceptable carrier. This way you can Utilizing aqueous formulations provides more rapid delivery of anesthetics to human tissues, however, may result in lower local anesthetic concentrations and/or increased impurities in the drug.

The skin is a structurally complex, relatively thick membrane. For molecules from the environment to enter unwounded skin, they must first pass through the stratum corneum, the substance on the surface of the skin. These molecules must penetrate the viable epidermis, papillary dermis, and capillary walls before entering the bloodstream or lymphatic channels in order to be absorbed. Therefore, the molecule must overcome the osmotic resistance of each tissue. The skin is a multi-layered structure that protects the body from the hazards of the external environment. The main barrier is located in the upper layer of the skin, the stratum corneum, which is the main difficulty point for transdermal drug delivery. This impermeable barrier is attributable to the skin's normal development and physiological changes resulting in a thin film. After the cells form the basal layer, they begin to move toward the surface of the skin until they eventually fall off. During the movement, the cells will gradually dehydrate and start to keratinize. When they reach the surface, they form a thin layer of dense, metabolically inactive cells, about ten microns thick, before shedding them. A strong barrier is created due to the hyperkeratinization of the cells that make up the stratum corneum. Conversely, absorption through the mucosal surface is usually effective because the stratum corneum is absent from the mucosa. Therefore, any effective percutaneous local anesthetic must find a way to overcome the above problems and find a way to allow the drug to be easily absorbed by the skin.

"Coating" is the method by which ointments and medications can be effectively absorbed by the skin because coating promotes skin hydration. If the skin is covered with a dressing or plastic wrap, the moisture in the body has nowhere to go, allowing the skin to bond with excess moisture. This excess hydration helps active ingredients or medications penetrate the skin more easily; Ametop gel, for example, must be covered with plastic wrap for 30-45 minutes to work. Another way to allow active ingredients or drugs to penetrate the skin is to use a hydrophobic carrier such as petroleum jelly to occlude the skin pores; however, applying ointments containing petroleum jelly often leaves a sticky or greasy feeling for a long time. has been developed to contain active Film-like polymeric compositions of sexual ingredients as an alternative to conventional formulations such as ointments. Film-like polymeric compositions mainly help active ingredients to be delivered through the skin, such as transdermal patches, or recently, film-like solutions containing film-like polymers, plasticizers, and low-molecular-weight volatile solvents. When the solution is applied to the skin, a thin polymer film forms as the solvent evaporates. For example, US8907153B2 discloses an adhesive desquamation agent for skin, the ingredients of which include a drug, a volatile solvent, a non-volatile solvent and a desquamation agent. Peeling ingredients derived from polyvinyl alcohol, polyvinyl pyrrolidone, carrageenan, gelatin, dextrin, guar gum, xanthan gum (xanthan gum), polyethylene oxide, starch and cellulose derivatives having a weight average molecular weight greater than about 5,000 Mw. However, the film-form preparation needs to wait for the volatilization of the solvent, so it takes a longer time to achieve the drug effect than the preparation using a plastic film dressing.

The eutectic mixed local anesthetic currently used clinically is EMLA cream (a cream containing 2.5% lidocaine and 2.5% prilocaine), but this ointment at least requires anesthesia onset time and duration of action. Tetracaine free base, a topical anesthetic, is more lipophilic and it penetrates the stratum corneum more easily than EMLA cream (Romsing et al., 1999). Tetracaine free base is an ester local anesthetic consisting of 40 mg of active ingredient (4% by weight), aqueous gel and pharmaceutically acceptable salts. AMETOP, while an improved local anesthetic, lacks a stable dosage form capable of delivering tetracaine free base in a delivery system. The local anesthetic used in recent TFDA and US FDA certifications is a eutectic mixture containing 7% lidocaine and 7% tetracaine (Pliaglis-Galderma S.A.), which is the active anesthetic ointment with the highest concentration. Pliaglis anesthetic ointment can form a coating film by itself after exposure to air, and does not need to be covered with plastic film. Apply Pliaglis ointment with a thickness of about 1mm on the skin (approximately 1.3g of ointment per 10cm2 area), and use it according to different skin The medicine process stays for 30 or 60 minutes. However, Pliaglis ointment has the same storage problems as AMETOP gel, and Pliaglis must be stored at 2-8°C.

Clay in soil is so tiny that it consists of only a few atoms. Clay is very small, so a large amount of clay aggregates between its particles and creates many small spaces; while larger soil particles are usually firmer (such as sand), the total volume of the voids formed between them is smaller than that formed between the same amount of clay particles. void volume. The increase in the gap between clay particles will increase the contact surface area, and water molecules can adhere to it; fine, high surface area clay can absorb a large amount of water and has better water retention capacity. Therefore, clay may reduce the degree of tetracaine degradation due to its good water absorption capacity, and thereby promote hydration by forming a skin occlusive effect and water retention capacity, thereby increasing the permeability of active ingredients to the skin.

In summary, there is currently a need in the art for new and improved anesthetic compositions. Therefore, effective penetration of the drug into the skin to shorten the onset time and good storage stability are very important considerations in designing an ideal local anesthetic.

The present invention aims to provide a compound composition of clay anesthetics, tetracaine (tetracaine) in the composition will not degrade significantly and still maintain its chemical stability during the storage period. Another object of the present invention is to develop a clay anesthetic composite composition with the effect of self-forming skin occlusion, which can allow the anesthetic to quickly penetrate into the skin, so that the onset time of the composite composition is shorter than that of a film-like one. combination.

In a first aspect, the present invention is an anesthetic composition for topical application, comprising: (a) at least one pharmaceutically active agent in a therapeutically effective amount; (b) at least one pharmaceutically acceptable solvent carrier; (c) at least one clay; the pharmaceutically active agent is an ester or amide anesthetic.

In preferred embodiments, the pharmaceutically active agent should be soluble in the solvent so that when the agent is mixed with the clay or carrier, it will be dispersed in the composition in the form of fine particles.

In preferred embodiments, the composition is semi-solid and stored at room temperature.

In a preferred embodiment, the ester anesthetic comprises about 1 to 10% by weight of the entire composition.

In a preferred embodiment, the amide anesthetic comprises about 1 to 10% by weight of the entire composition.

In some preferred embodiments, the ester anesthetic comprises about 5% or 7% by weight of the entire composition.

In some preferred embodiments, the amide-based anesthetic accounts for about 5% or 7% by weight of the entire composition.

In a preferred embodiment, the clay comprises about 5% to 60% by weight of the entire composition.

In some preferred embodiments, the clay comprises about 13% to 56% by weight of the entire composition.

In some preferred embodiments, the anesthetic composition is selected from benzocaine (benzocaine), chloroprocaine (chloroprocaine), cyclomethacine (cyclomethcaine), dimethylcaine (dimethocaine), piparuca Piperocaine, Propoxycaine, Procaine, Proparacaine, Tetracaine (tetracaine), lidocaine, mepivacaine, prilocaine, bupivacaine, ropivacaine, and articaine.

In other preferred embodiments, the clay is selected from nanosilicate platelets, montmorillonite, bentonite, mica, laponite , kaolin, talc, hydrotalcite, attapulgite clay, vermiculite, hectorite, saponite, stevensite, beidellite or layered double hydroxide.

In a preferred embodiment, the aforementioned anesthetic composition contains at least one excipient.

In a preferred embodiment, the aforementioned anesthetic composition contains at least one pharmaceutically acceptable carrier.

In a preferred embodiment, the anesthetic composition comprises: (a) 1-10% anesthetic; and (b) 5-60% talc; and (c) 20-90% pharmaceutically acceptable carrier; and/or ( d) 1-5% hydroxypropyl cellulose.

In some preferred embodiments, the aforementioned anesthetic composition contains 5% tetracaine and 56% talc by weight.

In some preferred embodiments, the aforementioned anesthetic composition contains 7% tetracaine, 7% lidocaine and 24% talc by weight.

In some preferred embodiments, the above-mentioned anesthetic composition contains 5% tetracaine, 56% talc, 35% dimethyl sulfoxide (DMSO), 1% HPC (hydroxypropyl cellulose).

In some preferred embodiments, the above-mentioned anesthetic composition contains 7% tetracaine by weight, 7% lidocaine, 24% talc, 32% dicalcium phosphate (dicalcium phosphate), 20% dicalcium phosphate Formazan, 3% Transcutol P and 1% Hypromellose (HPC).

In some preferred embodiments, the above-mentioned anesthetic composition contains 7% tetracaine by weight, 7% lidocaine, 24% talc, 32% dicalcium phosphate (dicalcium phosphate), 23% dicalcium phosphate Formazan, 6% Transcutol P and 1% Hypromellose (HPC).

In the second part, the present invention provides a method of administering one or more pharmaceutically active agents, the main steps are as follows: (a) using the above-mentioned anesthetic composition; and (b) the anesthetic composition must be in contact with the skin.

Figure 1 shows the results of efficacy studies of tetracaine-clay composite formulations and tetracaine-PEG formulations. The skin penetration effect of the tetracaine-clay composite formulation was faster than that of the tetracaine-PEG formulation.

Figure 2 is the action time of anesthesia effect. The duration of drug effect of tetracaine-clay composite preparation is longer than that of tetracaine-PEG preparation.

Figure 3 shows the results of efficacy studies of tetracaine-clay composite formulation M and a commercial product (AMETOP). Tetracaine-clay compound preparation M has higher skin penetration than AMETOP.

Figure 4 shows the results of efficacy studies of tetracaine-clay composite formulation M and a commercial product (AMETOP). The penetration rate of the tetracaine-clay compound preparation M to the skin is faster than that of AMETOP.

Figure 5 is the action time of the anesthesia effect. The duration of anesthesia effect of the tetracaine-clay composite preparation M was longer than that of the commercial product (AMETOP).

Figure 6 shows the results of the efficacy study of tetracaine/lidocaine-clay composite formulation N and a commercial product (Pliaglis). Tetracaine/lidocaine-clay complex formulation N penetrated the skin faster than Pliaglis.

Figure 7 shows the results of efficacy studies of tetracaine/lidocaine-clay composite formulation O and a commercial product (Pliaglis). Tetracaine/lidocaine-clay complex formulation O penetrated the skin faster than Pliaglis.

Fig. 8 is the result of efficacy study of tetracaine-clay composite formulation P and commercial product (EMLA). Tetracaine-clay compound formulation P has higher skin penetration than EMLA.

Fig. 9 is the result of efficacy study of tetracaine-clay compound formulation Q and commercial product (EMLA). Tetracaine-clay composite formulation Q has higher skin penetration than EMLA.

Through extensive screening and in-depth research, the inventor unexpectedly obtained a local anesthetic composition that can shorten the onset time of anesthesia. A local anesthetic composition can be used to numb the skin prior to performing the procedure. Compared with common local anesthetics, the anesthetic composition of the present invention can increase the permeation amount of anesthetics through the skin, and can also optimize the shelf life of anesthetics.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In other cases, certain terms used herein have their meanings clarified in the specification.

It must be noted that unless the context clearly indicates otherwise, the patent application for this article and the invention When used in the singular, "a", "an" and "the" include the plural.

Unless otherwise indicated, any numerical value such as a concentration or concentration range recited herein is to be understood in all cases as being modified by the term "about". Accordingly, numerical values generally include ±10% of the stated value. For example, a concentration of 1 mg/mL includes 0.9 mg/mL to 1.1 mg/mL. Similarly, a concentration range of 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v). A numerical range herein expressly includes all possible subranges, all individual values within that range, and integers and fractions within that range.

Unless otherwise indicated, the term "at least" in a list of elements should be read to include each and every element in the list. Those skilled in the art can ascertain that the specific embodiments of the invention described herein are not beyond the scope of routine experimentation or many equivalents. The present invention covers such equivalents.

As used herein, the terms "comprising", "comprising", "having" or any other similar words will be understood to include the stated integer or combination of integers, but not exclude any other integer or combination of integers, and are non-exclusive. For example, compositions, mixtures, preparations, methods, articles, or apparatus, these words need not be limited to the elements on the words, but may include other elements not expressly listed or inherent in these words. Furthermore, unless expressly stated to the contrary, "or" means an inclusive "or" rather than an exclusive "or". For example, any of the following conditions satisfies condition A or B: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), A and B are both true (or exist).

The combination term "and/or" used herein between multiple enumerated elements should be understood to cover both individual elements and combined elements. For example, where two elements are connected by "and/or", the first applicable option means the presence of the first element without the second element; the second applicable option term is when there is a second element but not the first; the third applicable option is when both the first and second elements are present. Any of these options or the application of more than one option should be considered within the above meaning and meet the criteria of the term "and/or" used herein.

The term "consisting of" or other similar words used in this specification and the patent claims of the invention means that any integer or group of integers including any stated element, but no additional element or combination of integers may be added to The specified method, structure or composition.

The use of "consisting essentially of" or other similar words in this specification and the patent claims of the invention means that any integer or group of integers mentioned is included, and this inclusion does not substantially change the specific method, Basic or novel properties of structure or composition.

A "subject" herein refers to any animal, preferably a mammal, most suitably a human. As used herein, the term "mammal" generally refers to any mammal, examples include but are not limited to cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., but most The best choice for humans.

When referring to the dimensions or characteristics of the elements of the invention, the terms "about", "approximately", "substantially", "substantially" and similar terms are used herein in accordance with what is generally understood by those skilled in the art, These words do not strictly limit the described size/property ranges or parameters, but do not exclude their functionally identical or similar minor changes. Such references to numerical parameters using at least art-recognized mathematical and industrial principles (eg, rounding, errors of measurement or other systems, manufacturing tolerances, etc.) contain variables that do not alter the least significant figure.

The term "particle dispersion" means that the pharmaceutically active agent will be dispersed in the solvent and carrier in the form of molecules or ions, so that the crystals of the pharmaceutically active agent cannot be observed under a microscope with a magnification of 25 times.

The term "therapeutically effective amount" refers to an amount of drug sufficient to produce an anesthetic effect when administered topically. The dosage of the drug is information known in the art, or the dosage can be determined by techniques known in the art, depending on the type of anesthetic drug selected and the site of administration (such as skin or mucous membrane). Usually, the dosage for each adult is about It is 1 to 20,000 mg, the appropriate amount is about 10 to 10,000 mg, and the most appropriate dosage is about 20 to 5,000 mg. The only limitations on the amount of anesthetic in the composition are that the formulation is substantially free of crystals of the anesthetic and that the amount of solvent used does not affect the adhesive properties of the limited composition. Accordingly, therapeutically effective amounts referred to within the above ranges apply to single component anesthetics.

In order to obtain the desired effect, the drug concentration and the anesthetic dose per unit area, that is, the anesthetic dose per square centimeter or cubic centimeter, were adjusted in the experiment. Thin application of high-concentration anesthetic can achieve rapid onset and short duration of action; thick application of high-concentration anesthetic (containing more mg of anesthetic per square centimeter or cubic centimeter) will result in rapid onset and long duration of anesthesia. Thin application of low-concentration anesthetic has mild anesthetic effect, long onset time and short action time; thick application of low-concentration anesthetic has mild anesthetic effect, requires longer onset time and longer action time. In summary, the present invention combines the effect of anesthesia concentration from a very low dose (about 1%) to a high dose (40% or higher) of the total composition with the characteristics of thick application, and then the anesthetic dose can be adjusted according to specific physiological parts .

Generally speaking, the appropriate anesthetic drug is selected according to the tissue site to be administered, and drug concentration, smear thickness and action time need to be considered; depending on the ability of the anesthetic to penetrate the tissue, usually the anesthetic effect is within about 2 minutes to 60 minutes reachable peak. The action time of the anesthetic effect on the tissue (such as the oral mucosa) should fall between about 2 to 240 minutes, which is related to the selected anesthetic, the concentration of the anesthetic, and the thickness of the application. Agents of longer or shorter duration of action can be selected by those skilled in the art based on various considerations.

The term "onset of anesthesia" refers to the time to peak effect on a single nerve. Anesthetic onset depends primarily on lipid solubility, molecular size, availability of local anesthetic, and nonionic form. Therefore, anesthetics with high lipid solubility, low pKa, or both will have anesthetic effects more quickly.

The term "duration of anesthesia" as used herein refers to the length of time that a local anesthetic blocks nerve conduction. The duration of anesthesia depends on all the factors listed under "Onset of anesthesia" above, as well as the degree to which the anesthetic is bound to the protein.

The composite composition of the clay anesthetic of the present invention comprises more than one anesthetic, more than one clay and more than one solvent carrier. The solvent carrier can contain one or more solvents, and different solvent formulations can control the solubility of the anesthetic drug in the carrier. Clay has a high water absorption capacity, which can reduce the degree of degradation of anesthetics and form an occlusive effect on the skin to increase skin hydration.

The addition of clay was found to improve the chemical stability of the anesthetic without reducing the rate of drug delivery. Suitable clays include talc, hectorite, attapulgite clay, nanosilicate platelets, laponite, mica , vermiculite, saponite, stevensite, beidellite, kaolin, montmorillonite, bentonite, bordellite, green Montronite, illite, glauconite, chlorites and polygorshites (such as attapulgite, halloysite, metabolloysite, allophane and aluminum silicate clays). Of particular utility are smectite clays. Most formulations contain clay in the range of about 5% to 60% by weight.

The anesthetic drugs of the present invention are known in the art. The local anesthetics of the present invention are amides and esters. Amides are lidocaine, prilocaine, mepivacaine, bupivacaine, dibucaine and etidocaine . Esters are procaine, tetracaine, propoxycaine, chloroprocaine, benzocaine, butyrate benzoate ( butamben picrate, cocaine, hexylcaine, piperocaine, oxyprocaine, and proparacaine. Other suitable local anesthetics for the present invention include cyclomethycaine, dimethisoquin, ketocaine, diperodon, dyclonine and pramoxine ( pramoxine), all of which are administered as hydrochloride or sulfate.

The dosage of anesthetic in the preparation will be adjusted according to the desired therapeutic effect and duration of anesthesia. The concentration of anesthetic in the present invention is 1% to 10% by weight of the total composition to deliver an effective dose.

Local anesthesia can be applied locally or injected. The clay anesthetic compound composition may contain one or more pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, diluents, dispersants, solubilizers, surfactants, stabilizers, pH adjusters, colorants, preservatives and wetting agents.

In addition to the above-mentioned ingredients, various other pharmaceutically acceptable additives including binders, preservatives, flavoring agents and coloring agents may be incorporated.

In some embodiments, the resulting mixture is a semi-solid, such as a cream, gel, lotion, lotion, salve, plaster, paste, ointment, spray, or other "non-limiting" composition. Book The final form of the inventive composition depends on the physiological site to be administered and the affinity of the drug to that tissue.

The solvent carrier can be selected from pharmaceutically or cosmetically acceptable solvents, such as methanol (methanol), ethanol (ethanol), propylene glycol (propyl glycol), ethyl acetate (ethyl acetate), isopropanol (ethyl acetate), transcutol P, PEG300 , PEG400, glycerin, acetone, lauryl alcohol, oleyl alcohol, cyclomethicone, methylene chloride, benzyl alcohol, acetone (acetone), acetic acid, propylene carbonate, chloroform, 1,4-dioxane (1,4-dioxane), dimethylformamide, dimethylformamide Dimethyl sulphoxide, toluene, tetrahydrofuran, dodecanol, etc. In addition, the composition may contain one or more solvents, the solvent being chosen to be compatible with the remaining solvents. For most formulations, the content of solvent can fall in the range of about 5% to 50% by weight.

The compositions of the present invention can be prepared by a number of methods known in the art which result in microparticle-dispersed anesthetics, including extrusion, molding, solvent casting, embedding and all other methods which use solvents to disperse the drug. Compound compositions of clay anesthetics may be in virtually any form such as lotions, ointments, creams, gels, drops, suppositories, sprays, liquids, solutions and powders.

In some embodiments, the term "pharmaceutically acceptable carrier" means any suitable limited or non-limited carrier, including liquid, semi-liquid or solid carriers, such as bioadhesives. Thus, the active agent can be mixed with: non-adhesive tapes, other limited vehicles, other "non-limited" vehicles for drug delivery. Among them, the base of non-limiting carrier can be fatty oil, sheep Hair fat, petrolatum, paraffin, glycols, higher fatty acids and higher alcohols.

The main beneficial effects of the present invention include: (a) the degradation rate of the ester anesthetic in the composition is low, even if it is stored in a higher temperature environment, it also shows good storage stability; (b) increases the permeability of the anesthetic to the skin , to shorten the onset time of anesthesia; (c) prolong the time of anesthesia effect.

The following examples further illustrate the invention. It should be understood that this embodiment is only used to describe the present invention, not to limit the scope of the present invention. The experimental methods of the examples, if no specific conditions are specified, are usually carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and other values mentioned in the examples refer to percentages and weights by weight.

The chemical stability of embodiment 1 tetracaine-talc composite composition

Table 1 shows the inhibitory effect of different talc concentrations on tetracaine impurities. All formulations were prepared as follows: first prepare a liquid mixture, and dissolve tetracaine, dimethyl sulfoxide (DMSO), and cyclomethicone in water at room temperature. Subsequently, talc was added at the same temperature to form a tetracaine-talc composite composition, followed by testing the chemical properties of the final product and testing the chemical stability of the product under appropriate storage conditions. Table 1 lists the detailed information and stability test results of the preparation.

Example 1 is the chemical stability of tetracaine for each formulation after storage at 40°C. Chemical stability is measured in terms of production of tetracaine impurities: tetracaine is known to degrade, so over a period of several weeks, lower concentrations of impurities in the formulation indicate greater stability of tetracaine over time sex. Each formulation was tested under accelerated conditions for a period of one month.

The chemical stability of the formulation was evaluated by measuring the concentration of tetracaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 1 shows the stability results under accelerated temperature conditions. These results further demonstrate that formulation A containing 48% talc exhibited only 0.06% degradation of tetracaine at 40°C, while formulation B containing 28% talc and formulation C containing 13% talc both degraded tetracaine The rates are about 1.86% and 5.54% respectively. This data on the degradation rate at 40°C showed that tetracaine produced fewer degradants or impurities as the concentration of talc was increased.

The chemical stability of embodiment 2 tetracaine-bentonite composite composition

Table 2 shows the inhibitory effect of different concentrations of bentonite on tetracaine (TTC) impurities. All formulations were prepared as follows: a liquid mixture was first prepared, and tetracaine, dimethyloxide, and cyclomethicone were miscibly dissolved in water at room temperature. Subsequently, bentonite was added at the same temperature to form a tetracaine-bentonite composite composition, followed by testing the chemical properties of the final product and testing the chemical stability of the product under appropriate storage conditions. Table 2 lists the detailed information of the formulations and the results of the stability experiments.

Example 2 is the chemical stability of tetracaine for each formulation after storage at 40°C. Chemical stability is measured in terms of production of tetracaine impurities: tetracaine is known to degrade, so over a period of several weeks, lower concentrations of impurities in the formulation indicate greater stability of tetracaine over time sex. Each formulation was tested under accelerated conditions for a period of one month.

The chemical stability of the formulation was evaluated by measuring the concentration of tetracaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 2 shows the stability results under accelerated temperature conditions. These results further demonstrate that at 40 °C, Formulation D containing 13% bentonite exhibited 9.97% degradation of tetracaine, while Formulation E containing 8% bentonite exhibited approximately 11.48% degradation of tetracaine. This data on the degradation rate at 40°C showed that tetracaine produced fewer degradation products or impurities when the concentration of bentonite was increased.

The chemical stability of embodiment 3 tetracaine-kaolin composite composition

Table 3 shows the inhibitory effect of different kaolin concentrations on tetracaine impurities. All formulations were prepared as follows: first prepare a liquid mixture, and dissolve tetracaine, dimethyl sulfoxide (DMSO), and cyclomethicone in water at room temperature. Subsequently, kaolin was added at the same temperature to form a tetracaine-kaolin composite composition, followed by testing the chemical properties of the final product and testing the chemical stability of the product under appropriate storage conditions. Table 3 lists the detailed information and stability test results of the preparation.

Example 3 is the chemical stability of tetracaine for each formulation after storage at 40°C. Chemical stability is measured in terms of production of tetracaine impurities. Tetracaine is known to degrade, so over a period of several weeks, the formulation had lower concentrations of impurities, indicating greater stability of tetracaine over time. Each formulation was tested under accelerated conditions for a period of one month.

The chemical stability of the formulation was evaluated by measuring the concentration of tetracaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 3 shows the stability results under accelerated temperature conditions. These results further demonstrate that at 40°C, Formulation F containing 28% kaolin exhibits only 3.19% degradation of tetracaine, while Formulation G containing 13% kaolin and Formulation H containing 8% kaolin both have tetracaine degradation. The degradation rates were about 6.10% and 7.77%, respectively. This data on the degradation rate at 40 °C showed that tetracaine produced fewer degradants or impurities when the concentration of kaolin was increased.

The chemical stability of embodiment 4 tetracaine-clay composite composition

Table 4 shows the inhibitory effect of different clays on tetracaine impurities. All formulations were prepared as follows: first prepare a liquid mixture, mix tetracaine, dimethyl sulfoxide (DMSO), cyclomethicone (cyclomethicone) in water at room temperature. Subsequently, bentonite, talc, or kaolin was added at the same temperature to form a tetracaine-clay composite composition. The chemical properties of the final product are then tested and the chemical stability of the product is tested under appropriate storage conditions. Table 4 lists the detailed information and stability test results of the preparation.

Example 4 is the chemical stability of tetracaine for each formulation after storage at 40°C. Chemical stability is measured in terms of production of tetracaine impurities: tetracaine is known to degrade, so over a period of several weeks, lower concentrations of impurities in the formulation indicate greater stability of tetracaine over time sex. Each formulation was tested under accelerated conditions for a period of one month.

The chemical stability of the formulation was evaluated by measuring the concentration of tetracaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 4 shows the stability results under accelerated temperature conditions. These results demonstrate that at 40°C, Formulation D containing 13% bentonite exhibited a degradation rate of 9.97% for tetracaine, while both Formulation C containing 13% talc and Formulation G containing 13% kaolin had a tetracaine degradation rate of 9.97%. The degradation rates were 5.54% and 6.10%, respectively. The data on the degradation rate at 40° C. shows that the composite composition of tetracaine-talc produces less degradation products or impurities compared to the composite composition of tetracaine-kaolin or tetracaine-bentonite.

[Table 4]

Example 5 Chemical stability of tetracaine-clay composite composition and tetracaine-PEG composite composition.

This experiment was to evaluate the effect of talc and polymers on the stability of tetracaine. Table 5 shows the inhibitory effect of different clays on tetracaine impurities. All formulations were prepared as follows: Formulation I: first prepare a liquid mixture, and dissolve tetracaine, isostearyl alcohol (ISAL), ethanol, talc and dimethyl sulfoxide (DMSO) in water. Subsequently, talc was added at the same temperature to form a tetracaine-talc composite composition.

Formulation J: Mix tetracaine, isostearyl alcohol (ISAL), ethanol, polyethylene glycol 6000 (PEG6000) and dimethylsulfoxide in water at 50°C, and leave the mixture at room temperature to form an ointment .

The chemical properties of the two final products are then tested and the chemical stability of the product is tested under appropriate storage conditions. Table 5 has listed the detailed information and stability test result of preparation

Example 5 is the chemical stability of tetracaine for each formulation after storage at room temperature. Chemical stability is measured in terms of production of tetracaine impurities: tetracaine is known to degrade, so over a period of several weeks, lower concentrations of impurities in the formulation indicate greater stability of tetracaine over time sex.

The formulations were assessed for chemical activity by measuring the concentration of tetracaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). learning stability. The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 5 shows the stability results at room temperature. These results further prove that talc has a stabilizing effect on tetracaine: at room temperature, the degradation rate of tetracaine in formulation I containing 28% talc was 2.12%, while the degradation rate of tetracaine in formulation J containing 28% PEG6000 The rate is about 6.93%. This degradation rate data at room temperature shows that the tetracaine-talc composite composition produces less degradants or impurities than the tetracaine-PEG composite composition.

Example 6 Chemical stability of benzocaine-clay composite composition and benzocaine-PEG composite composition

This experiment was to evaluate the effect of talc and polymers on the stability of benzocaine (BZC). Table 6 shows the inhibitory effect of different clays on benzocaine impurities. All formulations were prepared as follows: Formulation R: Benzocaine, polyethylene glycol 4000 (PEG4000), and dimethyl sulfoxide (DMSO), sodium hydroxide were miscibly dissolved in water at 50°C.

Formulation S: Benzocaine, talc, dimethyloxide and sodium hydroxide were miscible in water at room temperature. The steps are as follows: firstly make a liquid mixture of benzocaine, dimethyl oxide and sodium hydroxide, and then add talc at the same temperature to form a benzocaine-clay composite composition.

Finally, test the chemical properties of the two formulations and test the chemical stability of the product under appropriate storage conditions. Table 6 lists the detailed information and stability test results of the preparation.

Example 6 is the chemical stability of benzocaine for each formulation after storage at 60°C. Chemical stability is measured in terms of the production of benzocaine impurities: benzocaine is known to degrade, so over a period of several weeks, lower concentrations of impurities in the formulation indicate that benzocaine has more high stability.

The chemical stability of the formulation was evaluated by measuring the concentration of benzocaine and the formation of impurities using High Performance Liquid Chromatographic (HPLC). The HPLC method uses a flow gradient and a C18 analytical column for chromatographic separation and quantification of each component using an ultraviolet (UV) detector. Table 6 shows the stability results at room temperature. These results further prove that talc has a stabilizing effect on benzocaine: at 60°C, formulation R containing 30% polyethylene glycol 4000 had a degradation rate of 6.6% for benzocaine, while formulation R containing 30% talc S its benzocaine degradation rate is about 1.6%. This degradation rate data at room temperature shows that the benzocaine-talc composite composition produces less degradation products or impurities than the benzocaine-PEG composite composition.

Example 7 Efficacy Research of Tetracaine-Clay Composite Composition and Tetracaine-PEG Composite Composition

This experiment was to confirm the effect of talc and polymer on the efficacy of tetracaine (TTC). First, the formulation K and the formulation L were applied to Sprague-Dawley rats (mother rats, Lesco Biotechnology Co., Ltd.), and the application time was calculated from the time of application of the drugs. After 30 minutes, the medicated area was wiped with gauze for subsequent von Frey test.

In this experiment, the von Frey assay was used to detect the mechanical sensitivity of rat hind paws to evaluate the effect of anesthesia.

The von Frey hair used in the experiment is a set of nylon needles of different thicknesses. The test process is to use nylon needles for physical stimulation. There are 7 nylon needles in total. Each fiber filament will exert different strengths when punctured. 60 grams of strength. First place each rat individually on a stainless steel mesh (6.3×6.3 mm) in a transparent breeding cage, let them adapt to the mesh for 10 minutes, and then start the von Frey fiber filament test. The hind paws of the rats were erected, and then the hind paws were pierced through the gaps of the stainless steel mesh with Von Frey fiber filaments, and the rats were stimulated by keeping the fiber filaments in a bent state for 5 seconds with this force. Each intensity required 5 stimulations at any position on the hind paw; after completing the intensity test, the intensity was alternated from weak to strong until the threshold was measured and the data was recorded.

Table 7, Figure 1 and Figure 2 provide the detailed information of the formulation and the results of the efficacy study. From Fig. 1, it can be drawn that preparation K has more anesthetic effect than preparation L, and the pain threshold value of the rats using preparation K is higher than that of preparation L group. At 40 minutes, the pain threshold of the rats treated with formulation K was 3.4 times that of the formulation L group. The results show that Formulation K penetrates the skin faster than Formulation L. The results in Figure 2 show that at the 90th minute, the rats using the preparation K still had the anesthetic effect, and the response ratio was 100%; while at the same time point, only 44.4% of the preparation L group had the anesthetic effect, so the preparation K has a longer duration of anesthetic effect than formulation L.

[Table 7]

Example 8 Penetration of Tetracaine-Clay Composite Compositions and Commercial Products to Skin

In this experiment, to test the penetration of Formulation M and the commercially available topical tetracaine AMETOP in pig skin, Franz diffusion cells with a receptor pore volume of 6 mL were used. Pig skin is shaved first, then washed with phosphate-buffered saline (PBS) to remove subcutaneous fat. The area of the donor well was 0.785 cm2, while the acceptor well was filled with isotonic PBS solution. Use spring clips to clamp the flanges of the percutaneous absorption diffusion tank together with uniform force, and the temperature of the receptor well is maintained at 32°C in the stirring zone. The pigskin samples were fixed in a modified diffusion cell with the dermal side facing the fluid flow from the recipient, while the stratum corneum remained in contact with the donor compartment. Formulation M in an amount corresponding to 21 mg of tetracaine, and AMETOP in an amount corresponding to 26 mg of tetracaine were weighed and applied on the stratum corneum of the donor compartment. Aliquots of 400 microliters were withdrawn from the diffusion chamber at intervals of 0.5, 1, 2, 4, 6, 8 hours and 24 hours. After each sampling, an equal amount of PBS solution was replaced into the recipient compartment. Samples were then analyzed and quantified using HPLC.

Table 8 and Figure 3 show the detailed information of each formulation and the experimental results of the percutaneous absorption diffusion tank. The results in Table 8 show that compared to AMETOP, the penetration flux of formulation M to the skin is better. Surprisingly, compared with the commercially available product AMETOP, formulation M has about 3.8 times the tetracaine permeation flux to the skin than AMETOP. Furthermore, in Figure 3, Formulation M permeates consistently higher than AMETOP.

Example 9 Efficacy Research of Tetracaine-clay Composite Composition and Commercial Products

In this experiment, preparation M and AMETOP were applied to Sprague-Dawley rats (female rats, Lesco Biotechnology Co., Ltd.), and the application time was calculated from the time of application of the drugs. After 30 minutes, the medicated area was wiped with gauze for subsequent von Frey test.

In this experiment, the von Frey assay was used to detect the mechanical sensitivity of rat hind paws to evaluate the effect of anesthesia.

The von Frey hair used in the experiment is a set of nylon needles of different thicknesses. During the test, nylon needles are used for physical stimulation. There are 7 nylon needles in total. Each fiber filament will exert different strengths when piercing, from weak to strong in order of 4, 6, 8, 10, 15, 26 , 60 grams of strength. First place each rat individually on a stainless steel mesh (6.3×6.3 mm) in a transparent breeding cage, let them adapt to the mesh for 10 minutes, and then start the von Frey fiber filament test. The hind paws of the rats were erected, and then the hind paws were pierced through the gaps of the stainless steel mesh with Von Frey fiber filaments, and the rats were stimulated by keeping the fiber filaments in a bent state for 5 seconds with this force. Each intensity required 5 stimulations at any position on the hind paw; after completing the intensity test, the intensity was alternated from weak to strong until the threshold was measured and the data was recorded.

Figure 4 and Figure 5 present the detailed information of the formulation and the results of the efficacy study. It can be concluded from Fig. 4 that preparation M has more anesthetic effect than AMETOP, and the pain thresholds of rats using preparation M are higher than those of AMETOP group. At 40 minutes, the pain threshold that rats using formulation M can tolerate is 3.6 times of AMETOP group. The results showed that Formulation M penetrated the skin faster than AMETOP. The results in Fig. 5 show that at the 90th minute, the rats using the preparation M still had the anesthetic effect, and the response ratio was 88.9%; while at the same time point, only 50.0% of the AMETOP group had the anesthetic effect, so the preparation M The anesthetic effect lasts longer than AMETOP.

Example 10 Efficacy Study of Tetracaine/Lidocaine-Clay Composite Composition and Commercial Products

In this experiment, preparation N, preparation O and the commercially available topical lidocaine/tetracaine drug Pliaglis were applied to Sprague-Dawley rats (female rats, Lesco Biotechnology Co., Ltd.), and the drug was applied from the time Calculate application time. After 30 minutes, the medicated area was wiped with gauze for subsequent von Frey test.

In this experiment, the von Frey assay was used to detect the mechanical sensitivity of rat hind paws to evaluate the effect of anesthesia.

The von Frey hair used in the experiment is a set of nylon needles of different thicknesses. During the test, nylon needles are used for physical stimulation. There are 7 nylon needles in total. Each fiber filament will exert different strengths when piercing, from weak to strong in order of 4, 6, 8, 10, 15, 26 , 60 grams of strength. First place each rat individually on a stainless steel mesh (6.3×6.3 mm) in a transparent breeding cage, let them adapt to the mesh for 10 minutes, and then start the von Frey fiber filament test. The hind paws of the rats were erected, and then the hind paws were pierced through the gaps of the stainless steel mesh with Von Frey fiber filaments, and the rats were stimulated by keeping the fiber filaments in a bent state for 5 seconds with this force. Each intensity required 5 stimulations at any position on the hind paw; after completing the intensity test, the intensity was alternated from weak to strong until the threshold was measured and the data was recorded.

Table 9, Figure 6 and Figure 7 are the detailed information of the formulation and the results of the efficacy study. From Figure 6 can be To draw preparation N more anesthetic effect than Pliaglis. At 40 minutes, the pain threshold of the rats treated with formulation N was 4.5 times higher than that of the Pliaglis group. The results showed that Formulation N penetrated the skin faster than Pliaglis. The results in Figure 7 show that the rats using formulation O are more anesthetized than Pliaglis at 40 minutes, and the threshold of pain that can be tolerated is 2.3 times that of the Pliaglis group, and the results show that the drug of formulation O penetrates into the skin faster than Pliaglis .

Example 11 Skin Permeation of Lidocaine-Clay Composite Compositions and Commercial Products

In this experiment, to test the permeability of Formulation P and commercially available topical lidocaine/prilocaine EMLA in pig skin, Franz diffusion cells with a receptor pore volume of 6 mL were used. Pig skin is shaved first, then washed with phosphate-buffered saline (PBS) to remove subcutaneous fat. The area of the donor well was 0.785 cm2, while the acceptor well was filled with isotonic PBS solution. Use spring clips to clamp the flanges of the percutaneous absorption diffusion tank together with uniform force, and the temperature of the receptor well is maintained at 32°C in the stirring zone. The pigskin samples were fixed in a modified diffusion cell with the dermal side facing the fluid flow from the recipient, while the stratum corneum remained in contact with the donor compartment. Formulation P in an amount corresponding to 2.925 mg of lidocaine was finely weighed, and EMLA in an amount corresponding to 2.925 mg of lidocaine was weighed and applied on the stratum corneum of the donor compartment. Aliquots of 400 microliters were withdrawn from the diffusion chamber at intervals of 1, 2, 3, 4, 5, 6, 7 hours. After each sampling, an equal amount of PBS solution was replaced into the recipient compartment. Samples were then analyzed and quantified using HPLC.

Table 10 and Figure 8 are the detailed information of each formulation and the experiment of percutaneous absorption diffusion tank result. The results in Table 10 show that compared to EMLA, the permeation flux of formulation P in the skin is better; and surprisingly, compared with the commercially available product EMLA, the permeation flux of lidocaine of formulation P to the skin is about 1.9 times. Furthermore, in Figure 8, the permeation of Formulation P was consistently higher than that of EMLA.

Example 12 Permeability of Prilocaine-Clay Composite Compositions and Commercial Products to Skin

In this experiment, to test the permeability of Formulation Q and commercially available topical lidocaine/prilocaine EMLA in pig skin, Franz diffusion cells with a receptor pore volume of 6 mL were used. Pig skin is shaved first, then washed with phosphate-buffered saline (PBS) to remove subcutaneous fat. The area of the donor well was 0.785 cm2, while the acceptor well was filled with isotonic PBS solution. Use spring clips to clamp the flanges of the percutaneous absorption diffusion tank together with uniform force, and the temperature of the receptor well is maintained at 32°C in the stirring zone. The pigskin samples were fixed in a modified diffusion cell with the dermal side facing the fluid flow from the recipient, while the stratum corneum remained in contact with the donor compartment. Formulation Q in an amount equivalent to 2.925 mg prilocaine, and EMLA in an amount equivalent to 2.925 mg prilocaine were carefully weighed and applied to the stratum corneum of the donor compartment. Aliquots of 400 microliters were withdrawn from the diffusion chamber at intervals of 1, 2, 3, 4, 5, 6, 7 hours and 24 hours. After each sampling, an equal amount of PBS solution was replaced into the recipient compartment. Samples were then analyzed and quantified using HPLC.

Table 10- and Figure 9 are the detailed information of each formulation and the experimental results of the percutaneous absorption diffusion tank. Table 10 - The results show that the penetration flux of Formulation Q in the skin is better than that of EMLA. Surprisingly, compared with the commercially available product EMLA, the prilocaine permeation flux of Formulation Q to the skin was about 2.1 times that of EMLA. Furthermore, in Figure 9, the penetration of Formulation Q was consistently higher than that of EMLA.

All the documents mentioned in the present invention are cited in this application document with equivalent content. In addition, it should be understood that those skilled in the art may make various modifications and adjustments to the present invention after reading the content of the present invention, and these equivalent methods will also be included in the scope defined in the claims.

Claims (15)

A topical anesthetic composition comprising: (a) at least one pharmaceutically active agent in a therapeutically effective amount; (b) at least one pharmaceutically acceptable solvent; (c) at least one clay; wherein the pharmaceutically active agent is 1 to 10 % esters or 1-10% amide anesthetics; the clay accounts for 5-60% by weight of the composition and is selected from talc or bentonite. According to the anesthetic composition described in claim 1, the composition is in a semi-solid form. The anesthetic composition according to claim 1, wherein the ester anesthetic accounts for 5% or 7% by weight of the composition. The anesthetic composition according to claim 1, wherein the amide anesthetic accounts for 5% or 7% by weight of the composition. The anesthetic composition according to claim 1, wherein the clay accounts for 13 to 56% by weight of the composition. According to the anesthetic composition described in claim 1, wherein, the ester anesthetic is selected from benzocaine, chloroprocaine, cyclobucaine, dimethylcaine, piparucaine, propoxycaine procaine, procaine, or tetracaine. The anesthetic composition according to claim 1, wherein the amide anesthetic is selected from lidocaine, mepivacaine, prilocaine, bupivacaine, ropivacaine or articaine. According to the anesthetic composition described in Claim 1, said composition further comprises an excipient. According to the anesthetic composition described in claim 1, further comprising 1-5% hydroxypropyl cellulose vitamins. According to the anesthetic composition described in claim 1, the composition comprises 5% tetracaine and 56% talc. A topically applied anesthetic composition comprising 7% tetracaine, 7% lidocaine and 24% talc. According to the anesthetic composition described in claim 1, the composition comprises 5% tetracaine, 56% talc, 35% dimethylene and 1% hyprolose. According to the anesthetic composition described in claim 11, said composition comprises 7% tetracaine, 7% lidocaine, 24% talc, 32% dicalcium phosphate, 20% dimethyl sulfide, 3% transcutol P and 1% hydroxypropyl cellulose. According to the anesthetic composition described in claim 11, said composition comprises 7% tetracaine, 7% lidocaine, 24% talc, 32% dicalcium phosphate, 23% dimethyl sulfoxide, 6% petrolatum and 1 % hydroxypropyl cellulose. A use of the anesthetic composition according to any one of claims 1 to 14 for preparing a local anesthetic.

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