TW201801717A - A fast acting orally disintegrating film for administration of local anesthesia - Google Patents

Abstract

A fast acting orally disintegrating film (ODF) for administration of local anesthetic for alleviating physical and psychological discomfort in the oral cavity during procedures such as dental procedures or for relieving pain generally such as toothaches. The ODF comprises an active pharmaceutical ingredient such as lidocaine free base or a pharmaceutically acceptable salt thereof in a therapeutically acceptable amount such as about 24 mg, at least one primary hydrophilic film forming polymer, at least one secondary hydrophilic film forming polymer, wherein the ratio of the primary hydrophilic film forming polymer to the secondary hydrophilic film forming polymer is about 1:1 to about 20:1 by weight. The ODF further comprises a plasticizer wherein the ratio of the total weight of primary and secondary hydrophilic film forming polymer to the weight of the plasticizer is about 4:1 to about 4:3.

Description

Rapidly disintegrating oral film containing local anesthetic

The present invention relates to a rapid-acting oral disintegrating film (ODF) containing lidocaine, its use, and a method of producing ODF.

A local anesthetic is a drug used to alleviate pain perception at the site of administration. An example of a local anesthetic is lidocaine, which has the chemical name 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide.

Lidocaine is commonly used in dentistry, in dental procedures, such as dental surgery, tooth extraction, root canal treatment, to reduce the physical discomfort and psychological stress of patients, and to relieve toothache, mouth ulcers, cold sore or long teeth Pain. For dental treatment, lidocaine is usually administered by injecting, for example, "Xylocaine® Cartridge for Dental Use" (Fujisawa Pharmaceutical Co., Ltd.). However, the injection itself is invasive and may cause physical and psychological discomfort to the patient. Further, for applications other than dental treatment, such as alleviating toothache, it is usually preferred to use a non-invasive administration method. Furthermore, the method of administering lidocaine is to provide a rapid therapeutic effect, which is beneficial to both the physician and the patient. Therefore, there is a need for a method of non-invasive and rapid administration of a local anesthetic.

In summary, one of the objects of the present invention is to provide for local anesthesia for administration. A fast acting oral disintegrating membrane (ODF).

The present invention provides a fast-acting ODF comprising a lidocaine free-base or a pharmaceutically acceptable salt thereof, at least a first film-forming polymer, at least a second film-forming polymer, and at least one a plasticizer, wherein the first film-forming polymer and the second film-forming polymer are present in a weight ratio of about 1:1 to 20:1, and wherein the first film-forming polymer and the second film-forming polymer are polymerized The substance is hydrophilic.

In some embodiments, the pharmaceutically acceptable lidocaine salt comprises lidocaine hydrogen chloride. In another embodiment, lidocaine is present in an amount from at least about 10% to about 20% by dry weight of the film. In another embodiment, the first film forming polymer comprises hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC). In some embodiments, the second film-forming polymer comprises HPC, HPMC, flulan and/or povidone (PVP). In another embodiment, the HPMC comprises HPMC 3cps, HPMC 6cps or HPMC 15cps. In another embodiment, the PVP comprises PVP K-30 or PVP K-90. In some embodiments, the at least one plasticizer comprises polyethylene glycol (PEG), glycerol or Tween 20. In another embodiment, the PEG comprises PEG 400, PEG 4000, and/or PEG 6000. In some embodiments, the ratio of the dry weight of the first polymer to the dry weight of the second polymer is from about 1:1 to about 7:1. In another embodiment, the ratio of the dry weight of the first and second polymers to the dry weight of the plasticizer is about 4:1. In another embodiment, the first polymer comprises HPMC 6 cps, and the plasticizer comprises a plastic having a high viscosity of greater than about 500 cps but less than about 2000 cps and a low molecular weight of less than about 1000 aurens. Chemical agent. In some embodiments, the first polymer comprises HPMC 15 cps, and the plasticizer comprises a low viscosity having less than about 200 cps but greater than about 3 cps and greater than about 5,000 ampoules but less than about 5,000,000 ears. A high plasticizer that is swallowed by a plasticizer.

In other embodiments, the first polymer comprises HPMC 15 cps, the second polymer comprises HPMC 3 cps or HPMC 6 cps, and the plasticizer comprises glycerol or PEG 6000, wherein the first film forming polymer, The second film-forming polymer And the plasticizer is present in a ratio of from about 2:1:1 to about 7:1:2 by weight. In another embodiment, the first polymer comprises HPMC 15 cps, the second polymer comprises HPMC 3 cps, HPMC 6 cps or pullan, and the plasticizer comprises PEG 6000, wherein the first film forming polymer, The second film-forming polymer and the plasticizer are present in a ratio of about 3:1:1 by weight. In some embodiments, the first polymer comprises HPMC 6 cps, the second polymer comprises HPMC 3 cps or pullan, and the plasticizer comprises glycerol, wherein the first film forming polymer, the second The film forming polymer and the plasticizer are present in a ratio of about 3:1:1 by weight. In another embodiment, the first polymer comprises HPMC 6cps, the second polymer comprises PVP K-90, and the plasticizer comprises PEG 4000, wherein the first film forming polymer, the second film forming The polymer and the plasticizer are present in a ratio of about 7:1:2 by weight.

In some embodiments, the fast-acting ODF disintegrates within about 60 seconds of administration. In other embodiments, the rate of dissolution of the fast-acting ODF is such that about 90% of lidocaine is released within about 5 minutes to about 10 minutes of administration. In another embodiment, the rate of penetration of the fast-acting ODF is such that lidocaine penetrates through the target area treated with the ODF at about 0.8 to about 1.7 mg/cm ² for about 5 minutes of administration. In some embodiments, the composition is free of traces of organic solvents.

In some embodiments, the method of producing the orally disintegrating film comprises the steps of mixing the local anesthetic, the two polymers, and the at least one plasticizer in an aqueous solution, and transferring the aqueous solution to a suitable one. One surface of the carrier material, and the aqueous solution on the surface of the carrier material is dried to form a film.

The present invention also provides a method of providing local anesthesia to a patient in need thereof, the method comprising: orally administering to the patient in need thereof an effective amount of a composition comprising a lidocaine free base (free -base) or a pharmaceutically acceptable salt thereof, at least a first film-forming polymer, at least a second film-forming polymer, and at least one plasticizer, wherein the first film-forming polymer and the second The weight ratio of the film-forming polymer It is from about 1:1 to 20:1, and wherein the first film-forming polymer and the second film-forming polymer are hydrophilic. In some embodiments, the method is for use in oral surgery or dental treatment.

Figure 1 is a graph showing the dissolution profile of lidocaine ODF of the present invention and Trachisan® Sore Throat Lozenges (Engelhard Arzenimittel GmbH & Co. KF, Germany) in 0.1 N HCL (pH 1.2).

Figure 2 is a graph showing the dissolution profile of lidocaine ODF of the present invention and Trachisan® Sore Throat Lozenges (Engelhard Arzenimittel GmbH & Co. KF, Germany) in phosphate buffer (pH 4.5).

Figure 3 is a graph showing the dissolution profile of lidocaine ODF of the present invention and Trachisan® Sore Throat Lozenges (Engelhard Arzenimittel GmbH & Co. KF, Germany) in phosphate buffer (pH 6.8).

Figure 4 is a graph showing the dissolution of lidocaine ODF of the present invention and Trachisan® Sore Throat Lozenges (Engelhard Arzenimittel GmbH & Co. KF, Germany) in water.

Figure 5 is a graph showing the in vitro permeation profile of the lidocaine ODF of the present invention and Xylocaine® Jelly 2% (Swedish Recipharm Karlskoga AB) in water.

Figure 6 is a diagram showing the method of preparing the ODF of the present invention.

In the following, the singular forms "a" and "the" are intended to include a plurality of referents. Therefore, for example, reference to "a component" includes a mixture of a plurality of components, and reference to "one active agent" includes more than one active drug, and the like.

In the present disclosure, the "active ingredient", "active ingredient" and "drug" used interchangeably refer to a chemical substance or a compound which has desired pharmaceutical and physiological effects and contains a therapeutically effective agent. These words also include those specifically mentioned in this article. Some active agents are pharmaceutically active derivatives and analogs, including but not limited to salts, esters, guanamines, sulfates, prodrugs, active metabolites, intrinsic complexes, and the like.

In the present disclosure, the term "about" as a modifier of quantity is used to mean + or -10% of the amount included.

In the present disclosure, the term "disintegration" is used to mean distracting or splitting into small pieces that are invisible to the naked eye.

In the present disclosure, the term "dissolved" is used to mean disintegration as defined above, and then further split into small fragments, thereby releasing the active pharmaceutical ingredient from the excipient or any other composition of the invention for mucosal absorption.

The term "effective amount" or "therapeutically effective amount" of a pharmaceutical or pharmaceutically active ingredient is used to mean an amount of a drug or active agent that is non-toxic but sufficient to provide the desired therapeutic effect. The amount "effective" will vary from individual to individual, depending on the age and general condition of the individual, the particular active agent, and the like. Those skilled in the art will use routine experimentation to determine the appropriate "effective" amount in any particular example.

In the present disclosure, the term "hydrophilic" means that the substance has a strong polar group and can easily interact with water.

In the present disclosure, a "local anesthetic" is a drug that provides local numbness or pain relief.

It will be understood that the term "film" includes films and sheets which are of any shape, including rectangles, squares or other shapes that are most suitable for a particular application. The film of the present disclosure can be of any desired thickness and size suitable for the intended use. The size and shape of the film of the present invention can be targeted to a particular administration site, for example, it can be easily placed in the mouth of a user to achieve effective topical administration of lidocaine. In addition, some films may have a relatively thin thickness of from about 10 to about 500 microns, while others may have a relatively thick thickness of from about 500 to about 10,000 microns. A change in ODF thickness is desirable, and thus the ODF of the present invention can deliver a higher or lower dose of lidocaine to a particular treatment area. In addition, the term "membrane" consists of a single layer. The composition as well as the multilayer composition, such as a pressure film, a film coating, and the like.

The present invention discloses a fast-acting ODF comprising lidocaine as a pharmaceutically active ingredient for administration under conditions of no or no fluid intake. Due to the characteristics of the ODF of the present invention, such as rapid disintegration, dissolution, and penetration speed, etc., it is quick-acting. In particular, the fast-acting ODF of the present invention disintegrates within about 60 seconds of saliva. The faster-acting ODF of the present invention also provides higher dissolution and permeation rates than the currently commercially available non-invasive methods of administration, such as gels and lozenges, as will be illustrated in Examples 2 and 3 below. Figures 1 to 5.

The fast-acting properties of ODF help to quickly produce the required anesthetic effect. As described in the background of the invention, a fast acting ODF is required to make dental treatment as short and efficient as possible, and to quickly relieve pain, which is beneficial to both the physician and the patient, especially for patients who are averse to dental treatment. Even when multiple doses of lidocaine are required, the quick-acting properties become more important.

Another advantage of the present invention is that the ODF form allows for customization of its size and shape to better target the location of the administration as well as the purpose of administration. Furthermore, the ODF described herein can deliver a local high dose with low systemic absorption, minimizing undesirable side effects associated with systemic absorption of local anesthesia.

In one embodiment, lidoca is in the form of a free-base of lidocaine. In other embodiments, the local anesthetic can be any pharmaceutically acceptable salt and prodrug of lidocaine, such as a hydrochloride, hydrobromide, acetate, citrate, or sulfate.

In some embodiments, the ODF of the present disclosure comprises from about 10% to about 60% of the total anesthetic of the total weight of the formulation. More specifically, the lidocaine ODF described in the present disclosure comprises about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% of the total weight of the formula. Lidocaine.

The lidocaine ODF of the present invention further comprises one or more film-forming polymers (film-forming polymer). The film-forming polymer preferably has one or more of the following properties: easy to obtain, inexpensive, hydrophilic, non-toxic, odorless, and hypoallergenic. Further, the film-forming polymer is easily dissolved in a solvent such as water and rapidly disintegrates and dissolves in a buccal cavity.

The film-forming polymer provides key properties to the ODF of the present invention, such as film formation, scalability, homogeneity, and smoothness of surface properties, as will be more specifically illustrated in Example 1. The film-forming property is based on the degree of fracture of the ODF based on the film formation process. The scalability is based on the degree of fracture of the ODF which is usually the result of stretching or bending of the ODF under normal processing conditions. Homogenization is based on the degree of stratification of the ODF formed in the film forming process. The smoothness of the surface properties is based on the extent of precipitates or bubbles in the ODF formed during the film forming process.

Exemplary film-forming polymers having one or more of the above preferred properties include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), pululolan, poly Povidone (PVP), hydroxyethyl cellulose, sodium carboxy methyl cellulose, starch, and derivatives thereof. An example of HPMC is HPMC having a viscosity of from about 3 cps to about 100,000 cps, more specifically HPMC 3 cps, HPMC 6 cps, and HPMC 15 cps. Examples of PVP include PVP K-12 to PVP K-120, more specifically PVP K-30 and PVP K-90.

The ODF of the present invention may include a first film-forming polymer (first polymer) and a second film-forming polymer (second polymer), wherein the first polymer includes the same or Greater weight. The inclusion of first and second polymers having different properties such as viscosity and molecular weight in an appropriate ratio is important for ODF having the desired properties such as film formation, homogeneity, and surface The smoothness will be described in the following Example 1 and Tables 1A and 1B.

The ratio of the first polymer to the second polymer is in the range of % by weight From about 1:1 to about 20:1. In some embodiments, the first polymer to second polymer is present in a ratio of from about 1:1 to about 10:1 by weight percent. In some embodiments, the ratio of the first polymer to the second polymer is about 1:1, 2:1, 3:1, 3:2, 4:1, 5:1, 5 in weight %: 2, 5:3, 6:1, 7:1, 8:1, 9:1 or 10:1.

In some embodiments, both the first polymer and the second polymer are hydrophilic, wherein the first polymer can comprise HPC or HPMC and the second polymer can comprise HPC, HPMC, PVP and/or pulmul. More specifically, in some embodiments, the first polymer comprises HPMC 6 cps or HPMC 15 cps, and the second polymer comprises HPMC 3 cps, HPMC 6 cps, PVK-30, PVK-90 or pullan. In other embodiments, the first polymer comprises HPMC 15 cps and the second polymer comprises HPMC 3 cps, HPMC 6 cps, povidone K-30, povidone K-90, or pullan.

The ODF of the present invention may additionally comprise at least one plasticizer. The plasticizer is an important component because the plasticizer can improve the scalability of the ODF while providing flexibility to the ODF to minimize breakage that may occur under normal processing conditions, as described in Example 1 below. Exemplary plasticizers may include polyethylene glycol (PEG), glycerol, Tween 20, phthalate derivatives (eg, dimethyl phthalate, orthophthalic acid). Diethyl phthalate, dibutyl phthalate, citrate derivatives (eg, tributyl citrate, triethyl citrate, triethyl citrate) Acetyl citrate), citric acid), glycerol monoacetate, glycerol diacetate, triacetate, triacetin, polysorbate, hexadecyl Cetyl alcohol, 1,3-butanediol, 1,4 butanediol, sorbitol, sodium sulfosuccinate (sodium) Diethylsulfosuccinate), as well as castor oil. In some embodiments, an example of PEG is from PEG 200 to PEG 35000, more specifically PEG 6000, PEG 4000, PEG 3350, PEG 2000, PEG 1000, and PEG 400. ( Molecular weight was measured according to the method described by Neira-Velazquez MG, Rodriguez-Hernandez MR, Hernandez-Hernandez E, Ruiz-Martinez ARY. Polymer Molecular Weight Measurement . Handbook of Polymer Synthesis, Characterization, and Processing , 1st ed. New York :John Wiley &Sons;2013.p 355)

Table 2 below illustrates some of the preferred formulations of the ODF of the present invention described in Example 1. As shown in Table 2, some combinations of film-forming polymers achieve better interaction with each other by some plasticizers. Some of these embodiments are as follows: In some embodiments including HPMC 6 cps as the first polymer, the ODF of the present invention further comprises a plasticizer having a temperature above about 500 cps but less than about 2000 cps. High viscosity and low molecular weight below about 1000 Daltons. Exemplary plasticizers having such high viscosity and low molecular weight include glycerol.

In other embodiments comprising HPMC 15 cps as the first polymer, the ODF of the present invention further comprises a plasticizer having a low viscosity of less than 200 cps but greater than 3 cps and a higher than about 5,000 ear amps but Low molecular weight below about 5,000,000 auricular. Exemplary plasticizers having such low viscosity and high molecular weight include PEG 6000.

In some embodiments, the first polymer is HPMC 6 cps and the second polymer is pullan or HPMC 3 cps, and the plasticizer is glycerol, the three being present in a ratio of about 3:1:1 by weight. .

In some embodiments, the first polymer is HPMC 6 cps and the second polymer is PVP k-90, and the plasticizer is PEG 4000, the three being present in a ratio of about 7:1:2 by weight.

In some preferred embodiments, the first polymer is HPMC 15 cps and the second polymer is HPMC 3 cps or HPMC 6 cps, and the plasticizer is glycerol or PEG 6000, the ratio of the three being about by weight. 2:2:1 to about 7:1:2.

In some embodiments, the first polymer is HPMC 15 cps and the second polymer is HPMC 3 cps, HPMC 6 cps or pulan, and the plasticizer is PEG 6000, the three are present in a ratio of about 3:1 by weight. :1.

The fourth formulation shown in Table 2 is used for dissolution and infiltration studies, and is currently commercially available as a Trachisan sore throat lozenge (Engelhard Arzenimittel GmbH & Co. KF, Germany) for oral administration of lidocaine tablets. The gel was compared to Xylocaine Jelly 2% (Swedish Recipharm Karlskoga AB). These studies are described in detail in Examples 2 and 3, respectively. The results of the dissolution studies are presented in Figures 1 to 4 to compare the ODF of the present invention with the Trachisan sore throat ingot (Engelhard Arzenimittel GmbH & Co. KF, Germany). The results of the permeation study are presented in Figure 5, comparing the ODF of the invention with Xylocaine Jelly 2% (Recipharm Karlskoga AB, Sweden).

As shown in Figures 1 to 4, the lidocaine ODF of the present invention can release about 90% in about 5 minutes to about 10 minutes after administration in various pH conditions to simulate various pH conditions of the human GI system. Lidocaine, while lozenges release about 90% of lidocaine takes about 30 minutes. In addition, Figure 5 illustrates that the ODF of the present invention provides an infiltration rate of from about 0.8 to about 1.7 mg/cm ² during the first 5 minutes of administration, which is about three times higher than the gel. Therefore, both studies indicate that the ODF of the present invention dissolves faster and has a faster penetration rate than the commercially available orally administered lidocaine products such as Trachisan sore throat ingots and Xylocaine Jelly.

Further, any of the foregoing embodiments may additionally include one or more fillers, which may be any pharmaceutically acceptable filler. Examples of such fillers include, but are not limited to, calcium phosphate, calcium sulfate, powdered sugar, citrate, dextrose, fructose, glucose, lactose, kaolin, starch, sucrose, maltose, mannitol, sorbus Alcohol, microcrystalline cellulose, powdered cellulose, or any combination of the foregoing. In some embodiments, the filler is maltose, mannitol, or a combination thereof. In some embodiments, the filler consists of a water soluble or water insoluble filler.

In any of the foregoing embodiments, the orally disintegrating film of the local anesthetic provided may contain one or more active ingredients such as a pharmaceutical ingredient, a functional ingredient, a skin care ingredient, and a supplement. In some embodiments, the active agent is present in an amount from about 0.001% to about 60% by weight of the total ingredients of the film. In other embodiments, the active agent is present in an amount from about 0.1% to about 45% by weight of all components of the film. In other embodiments, the active agent is present in an amount from about 1% to about 40% by weight of all components of the film.

Furthermore, other ingredients may be added to the provided film, including but not limited to sweeteners, flavoring agents, coloring agents, saliva stimulating agents, taste masking agents, surfactants, preservatives, antifoaming agents, penetration enhancers, Saliva irritants, dispersants, buffers, thickeners, enzyme inhibitors, and co-solvents.

In some embodiments, the provided film comprises a sweetener. Sweeteners can be used to improve palatability and are generally classified as natural or artificial sweeteners. Exemplary natural sweeteners include, but are not limited to, dextrose, fructose, glucose, liquid glucose, maltose, rebiana, glycyrrhizin, thaumatin, sorbitol, mannitol, sucrose Isomalt, maltitol, xylitol, and erythritol. Exemplary artificial sweeteners include, but are not limited to, saccharin, cyclamate, aspartame, acesulfame-K, sucralose ( Sucralose), alitame, and neotame. In some embodiments, the sweetener comprises from about 0% to about 30% by dry weight of all ingredients of the film. In some embodiments, the sweetener comprises from about 0.1% to about 25% by dry weight of all ingredients of the film. In some embodiments, the sweetener comprises from about 1% to about 10% by dry weight of all ingredients of the film. In some embodiments, the sweetener comprises from about 1% to about 7% by dry weight of all ingredients of the film. In some embodiments, the sweetener comprises from about 1% to about 6% by dry weight of all ingredients of the film. In some embodiments, the sweetener comprises from about 1% to about 5% by dry weight of all ingredients of the film.

In some embodiments, the provided film includes a flavoring agent. Flavoring Examples may include, but are not limited to, flavor oils such as peppermint oil, cinnamon oil, spearmint oil and nutmeg oils, as well as flavored essential oils extracted from vanilla, cocoa, coffee and chocolate, and by apples, Fruit essential oils of raspberries, cherries, pineapples and other citrus fruits such as orange, lemon and lime. Specific examples of the sweetener used in the present invention may include saccharin, sucrose, fructose, glucose, sucralose, and mannitol.

In some embodiments, the provided film comprises a colorant. In particular, when the formulation ingredients or drugs are in an insoluble or suspended form, the addition of a colorant enhances the aesthetic appearance of the oral film. Exemplary colorants may include, but are not limited to, Food Drug and Cosmetic (FD&C) colors, such as FD&C Blue 1 Aluminum Lake, FD&C Yellow No. 5 FD&C Yellow 5 Aluminum Lake), FD&C Yellow No. 6 Lake, or any other pharmaceutically acceptable color additive that imparts color when added to a pharmaceutical composition. In some embodiments, the colorant comprises from about 0% to about 1% by dry weight of all components of the film. In some embodiments, the colorant comprises from about 0.001% to about 1% by dry weight of all components of the film.

Other examples of pharmaceutically acceptable excipients or additives known to those skilled in the art may be added to the active ingredient, as desired.

In some embodiments, the ODF of the invention can include a saliva stimulating agent. Saliva stimulating agents can be added to increase the rate at which saliva is produced to accelerate disintegration of the orodidispersible film. Exemplary salivary stimulators include, but are not limited to, acidic compounds such as citric acid, malic acid, lactic acid, ascorbic acid, and tartaric acid. In other embodiments, some sweeteners may be used as saliva stimulating agents, including but not limited to glucose, fructose, xylose, maltose, and lactose. In some embodiments, the saliva stimulating agent comprises from about 0% to about 10% by dry weight of all components of the film. In some embodiments, the saliva stimulating agent comprises from about 0% to about 7% by dry weight of all components of the film. In some embodiments, the saliva stimulating agent comprises from about 0% to about 6% by dry weight of all ingredients of the film. In some embodiments The saliva stimulating agent comprises from about 2% to about 6% by dry weight of all components of the film.

In some embodiments, the provided film includes a taste masking agent. The addition of a taste masking agent improves the sensory properties of the film. In some embodiments, a taste masking agent can be used to mask the taste of some ingredients that are difficult to access. In some embodiments, exemplified taste masking agents include, but are not limited to, cyclodextrin, maltodextrin, ion exchange resin, amino acid, gelatin, gelatinized starch, fat body, lecithin , lecithin-like substances and salts. In some embodiments, the taste masking agent comprises from about 0% to about 15% by dry weight of all components of the film. In some embodiments, the taste masking agent comprises from about 0% to about 10% by dry weight of all components of the film. In some embodiments, the taste masking agent comprises from about 0% to about 7.5% by dry weight of all components of the film. In some embodiments, the taste masking agent comprises from about 0% to about 5% by dry weight of all components of the film.

In some embodiments, the invention can include a surfactant. Surfactants are surfactants that reduce surface tension and thus increase the emulsification, foaming, dispersing, spreading, and wetting properties of the product. Exemplary edible surfactants include, but are not limited to, sorbitan fatty acid esters (eg, orbitan monoisostearate, sorbitan monolaurate) , sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiolisate Sorbitan sesquistearate, sorbitan sesquioleate, sorbitan trilaurate, sorbitan trioleate, dehydrated Sorbitan tristearate, sucrose palmitate, glyceryl monooleate, vitamin E, polyethylene glycol succinate, propylene glycol Propylene glycol monolaurate, myristyl alcohol, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative (polyoxyet) Hylene castor oil derivative), sodium lauryl Sulfate), and propylene glycol dilaurate. In some embodiments, the surfactant comprises from about 0.01% to about 5% by dry weight of all components of the film. In some embodiments, the surfactant comprises from about 0.4% to about 0.7% by dry weight of all components of the film.

In some embodiments, the ODF of the present invention can include a dispersant for the film forming polymer. Film-forming polymers are typically supplied as a solution containing a dispersant to maintain the stability of the film-forming polymer dispersion. For example, a dispersing agent may be provided for polyvinyl acetate, and the dispersing agent may be sodium lauryl sulfate, povidone or the like. In another example, a methacrylate copolymer may be provided with macrogol cetostearyl ether and sodium lauryl sulfate, or ascorbic acid and sodium hydroxide as a dispersing agent. Typically, the dispersing agent will comprise from about 0.001% to about 10% by dry weight of all ingredients of the film. In some embodiments, the dispersant comprises from about 0.01% to about 8% by dry weight of all components of the film. In some embodiments, the dispersant comprises from about 0.1% to about 5% by dry weight of all components of the film. In some embodiments, the dispersing agent comprises from about 0.001% to about 1% by dry weight of all components of the film. In some embodiments, the dispersant comprises from about 0.04% to about 0.7% by dry weight of all components of the film. In some embodiments, the dispersing agent comprises from about 0.01% to about 7.5% by dry weight of all components of the film.

In some embodiments, the ODF of the invention can include a buffer. A buffer can be added to adjust the pH. The pH system is related to the dissolution and stabilization of the ingredients in the formulation and also to the absorption through the oral mucosa. Exemplary buffers include, but are not limited to, citrate buffers, phosphate buffers, acetate buffers, carbonate buffers, ammonia buffers, borate buffers, lactate buffers, ethanolamine buffers, glycine Buffer, methionine buffer, glutamate buffer, and succinate buffer. In some embodiments, the pH buffer is an acid/acid salt system. Exemplary acid/salt systems include, but are not limited to, citric acid/citrate (eg, sodium citrate, potassium citrate), citric acid/phosphate (eg, sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid) Trisodium, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), citric acid/tartrate (eg sodium tartrate, potassium tartrate), citric acid/borate (eg sodium borate, potassium borate), citric acid/apple Acid salts (such as sodium malate, potassium malate), citric acid/maleate (such as sodium maleate, potassium maleate), tartar Acid/citrate (eg sodium citrate, potassium citrate), tartaric acid/phosphate (eg sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium dihydrogen phosphate, phosphoric acid Dipotassium hydrogen), tartaric acid/tartrate (such as sodium tartrate, potassium tartrate), tartaric acid/borate (such as sodium borate, potassium borate), tartaric acid/malate (such as sodium malate, potassium malate), tartaric acid/horse Acid salts (such as sodium maleate, potassium maleate), boric acid/citrate (such as sodium citrate, potassium citrate), boric acid/phosphate (such as sodium aluminum phosphate, sodium dihydrogen phosphate, hydrogen phosphate II) Sodium, trisodium phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), boric acid/tartrate (eg sodium tartrate, potassium tartrate), boric acid/borate (eg sodium borate, potassium borate), boric acid/apple Acid salts (such as sodium malate, potassium malate), boric acid/maleate (such as sodium maleate, potassium maleate), malic acid/citrate (such as sodium citrate, potassium citrate), apple Acid/phosphate (eg sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, Tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), malic acid/tartrate (such as sodium tartrate, potassium tartrate), malic acid/borate (such as sodium borate, potassium borate), malic acid/malate ( For example, sodium malate, potassium malate), malic acid/maleate (sodium maleate, potassium maleate), maleic acid/citrate (eg sodium citrate, potassium citrate), maleic acid /phosphate (eg sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), maleic acid / tartrate (eg sodium tartrate, tartaric acid) Potassium), maleic acid/borate (eg sodium borate, potassium borate), maleic acid/malate (eg sodium malate, potassium malate), maleic acid/maleate (eg sodium maleate) , potassium maleate). In some embodiments, the buffer system comprises from about 0% to about 15% by weight of the film. In some embodiments, the buffer system comprises from about 0% to about 10% by weight of the film. In some embodiments, the buffer system comprises from about 0% to about 7.5% by weight of the film.

Preparation of oral disintegration film

The present invention also provides a method of preparing the ODF of the present invention, as shown in FIG. Preferably, the method comprises the steps of dissolving the appropriate amount and ratio of the first and second film-forming polymers and the plasticizer in water. Note that no organic solvent is required. In fact, since the film-forming polymer of the present invention is easily dissolved in water, it is not necessary to prepare the ODF of the present invention. Organic solvents. Since even small amounts of organic solvents may be toxic to humans, it is advantageous to avoid the use of organic solvents to make ODF. Compared to other known film-forming polymers, HPMC is a hydrophilic polymer that is easier to dissolve, easier to obtain, and less expensive during ODF manufacturing and is therefore particularly suitable as a film-forming polymer.

Next, lidocaine or a salt thereof, such as lidocaine hydrogen chloride, is also dissolved in the solution. In order to save production time, the solution is then subjected to an ultrasonic oscillating process to help eliminate air bubbles.

The solution is maintained in rotation until the hydrophilic film-forming polymer has completely dissolved and a homogeneous mixture has been obtained. The solution was prepared in this manner to form a pre-casting blend. The solution is then transferred to the surface of a suitable carrier material and dried to form an ODF. Suitable support materials are, for example, non-deuterated polyethylene terephthalate films, non-deuterated paper, polyethylene impregnated kraft paper or non-deuterated polyethylene films. The transfer solution can be applied to the bulk material using any conventional film coating apparatus. Preferably, the drying of the film is carried out in a high temperature air bath using a drying oven, drying tunnel, vacuum, dryer, or any other suitable drying equipment known to those skilled in the art. For example, the film can be dried in an oven at about 80 ° C for about 20 minutes to form an oral film of the desired thickness, which is then cut to the desired size.

In another embodiment, the method may further comprise the step of adding other ingredients, such as one or more flavoring agents, sweeteners, and coloring agents to pharmaceutically active ingredients, hydrophilic film forming polymers, and water soluble in the method. The plasticizer is dissolved or mixed for the preparation of the film.

Use of oral disintegration membrane

The orally disintegrating film of the present disclosure can be used in various situations including, but not limited to, local anesthesia for dental treatment, such as dental surgery, tooth extraction, root canal treatment, and for relieving toothache, mouth ulcers, cold sore or The pain caused by long teeth. The ODF described in the present disclosure can be orally administered to a painful area of oral surgery or dental treatment or Nearby to relieve, eliminate or prevent pain. In a preferred embodiment, the ODF is designed to exert its local anesthetic effect by diffusion through the oral mucosa, thereby providing an alternative local anesthesia administration route and alleviating short-term local pain due to sore throat. The ODF of the present invention can be administered one or more times a day.

In some embodiments, the provided film can be administered to the oral mucosa or other mucosa where it can rapidly disintegrate by saliva and/or other aqueous materials on the mucosal surface. In some embodiments, after disintegration, the provided film releases one or more formulations (eg, pharmaceutical ingredients, functional ingredients, supplements, or skin care ingredients) to the mucosa. The membrane provided can be administered in this manner, thereby delivering a therapeutically effective amount of the formulation.

In one embodiment, the lidocaine ODF of the present invention contains about 24 mg of lidocaine per ODF. It will be appreciated that the attending physician can determine the total daily usage of the film of the present disclosure within the scope of sound medical judgment. For any particular patient or organism, the particular therapeutically effective dose will depend on the various factors, including the condition to be treated and the severity of the disease; the activity of the particular compound employed; the particular composition employed; the age of the patient , weight, general health, gender and diet; time of administration, route of administration, and excretion rate of the particular compound used; period of treatment; drugs used in conjunction with or in combination with the particular compound used; and in the field of medicine Similar factors that have been notified (for example, see Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001 ).

The following representative examples are provided to illustrate the invention, but are not intended to limit or be construed as limiting the scope of the invention. Indeed, various modifications and many other embodiments of the invention are apparent to those skilled in the art in light of this disclosure. Patent literature. It is to be understood that the various references are incorporated herein by reference to the extent of the disclosure of the disclosure. The following embodiments contain important additional information, examples, and guidance that can be used in various embodiments. The invention and its equivalents are practiced.

These and other aspects of the invention will be more apparent from the following description of the preferred embodiments of the invention. Range definition.

Example 1: Effect of film-forming polymer and plasticizer on ODF properties

The film-forming polymer and plasticizer and their individual weight % in ODF substantially affect the properties of the ODF. The study tested and evaluated various formulations using a combination of a film forming polymer, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), in combination with a plasticizer. , pullan and/or polyvinyl alcohol (PVA), the plasticizer such as glycerol, Tween 20, PEG 400, PEG 4000 and/or PEG 6000.

The four properties of ODF were evaluated: A. Film formation, B. Film scalability, C. Membrane homogeneity, and D. Smoothness of the film surface. To quantify the film-forming properties, a score of 1 indicates no signs of cracking in the film, and a score of 0 indicates the presence of cracks in the film. To quantify the film scalability results, a score of 1 indicates no signs of cracking after stretching or bending, and a score of 0 indicates cracking after stretching or bending. To quantify the membrane homogeneity results, a score of 1 indicates no delamination and a score of 0 indicates stratification. In order to quantify the smoothness of the surface, 1 point means no precipitate or bubbles, and 0 means there is a precipitate or bubbles. Table 1A lists the tested formulations of lidocaine ODF and their results.

Studies were conducted on ODF with only one film-forming polymer. As shown in Table 1A below, the ODF including only one film-forming polymer was unsuccessful since no formulation reached 4 points, indicating that other ingredients may be required, such as another film-forming polymer to produce a successful ODF. However, these results do show that HPC and HPMC tend to have higher scores.

Additional studies were carried out using HPC and HPMC as the first polymer with a formulation comprising the first polymer and the second polymer. An overview of some of the more successful results is shown in Table 1B below. As shown in Table 1B, the inclusion of the first and second polymers produced some preferred results, but the resulting ODF still lacked the scalability properties (column B).

Table 1B

To overcome the scalability problem, a plasticizer is incorporated into the formulation, such as a higher molecular weight PEG (PEG 4000 or PEG 6000) or a low molecular weight PEG (PEG 400), glycerol, and Tween 20. In the presence of the polymer, the plasticizer is incorporated into the formulation to substantially improve the resulting ODF. Table 2 lists several more successful formulations.

Among all the polymers tested, HPMC, povidone (PVP), and pulmulon were suitable for the preparation of ODF. Preferably, HPMC 6cps and HPMC 15cps are available as the first polymer. As described in the section on the preparation of ODF, HPMC polymers provide additional advantages at lower cost, are readily available, and have the property of rapidly dissolving in water, as compared to other film-forming polymers described herein. Thus, in some embodiments, the HPMC polymer can serve as the first polymer as well as the second polymer. Suitable plasticizers include PEG 6000, PEG 4000, PEG 400, glycerol, and Tween 20.

In the following two examples, a dissolution study and an infiltration study were performed to compare the lidocaine ODF of Formula 4 in Table 1B with the lidocaine lozenge Trachisan sore throat ingot (Engelhard Arzenimittel GmbH & Co. KF, Germany) and coagulation Xylocaine Jelly 2% (Recipharm Karlskoga AB, Sweden).

Example 2: In vitro dissolution of lidocaine ODF

Membrane dissolution studies were performed on a USP device IIV (rotary basket device) at 50 revolutions per minute (rpm) simulating the in vivo environment in the stomach, duodenum and jejunum using 0.1 N HCl (pH 1.2), phosphate buffer ( pH 4.5 and 6.8) and water at 37.0 ± 0.5 ° C as a dissolution medium.

The lidocaine ODF and the tablet Trachisan sore throat ingot (Engelhard Arzenimittel GmbH & Co. KF, Germany) were placed in a dissolution medium. 5 ml aliquots of samples were collected at 3, 6, 9, 12, 15, 30, 45 and 60 minutes over 1 hour. The drug content in the aliquots was analyzed using a UV spectrophotometer at a wavelength of 230 nm. The cumulative percentage of drug release is calculated to establish the dissociation condition, as shown in Figures 1 through 4.

All experiments were performed N=3 times each. It should be noted that the dissociation condition is slightly stable due to changes in the micro-lidocaine content above or below 100%. In all cases, the stability of the dissociation condition curve should indicate that the dissociation is complete. The results of the dissociation study (Figures 1 to 4) show that lidocaine ODF can release 90% of lidocaine within about 5 to about 10 minutes, while the lozenge takes about 30 minutes to release 90% of the lidocaine. Cain.

Example 3: Infiltration of lidocaine ODF

In vitro permeation studies of membranes were performed using a Transdermal Franz Diffusion Cell in which lidocaine ODF and gel Xylocaine Jelly 2% (Swedish Recipharm Karlskoga AB) spread from artificial donor skin through artificial skin to acceptance The compartment is used to simulate drug diffusion through the oral mucosa. The conditions between the receptor compartments were 37.0 +/- 0.5 °C with deionized water to mimic the physiological environment of the oral cavity. Three samples (N=3) of 0.99 to 1 ml were collected at 5, 10, 15, 20, 30 and 60 minutes over a one hour period for HPLC analysis. Figure 5 illustrates the results of the permeation showing that the lidocaine ODF has a substantially higher permeability than the gel. For example, Figure 5 illustrates that the lidocaine ODF penetrates about twice as much as the gel at 30 minutes.

While the present invention has been described in terms of the specific embodiments and examples, it will be understood by those skilled in the art that Therefore, it is to be understood that the invention is not limited by the embodiments disclosed,

It is to be understood that the foregoing general description and the following detailed description are exemplary It is intended to be illustrative only and not to limit the invention as claimed.

The above and other changes can be made according to the detailed description. In general, the words used in the following disclosure are not to be construed as limiting the invention to the particular embodiments disclosed. Accordingly, the actual scope of the technology includes the disclosed embodiments and all equivalent ways of implementing the technology.

Claims (25)

An orally disintegrating film (ODF) comprising: lidocaine free-base or a pharmaceutically acceptable salt thereof; at least one first film-forming polymer; at least one second a film polymer; and at least one plasticizer, wherein the first film-forming polymer and the second film-forming polymer are present in a ratio of from about 1:1 to about 20:1 by weight, and wherein the first The film forming polymer and the second film forming polymer are hydrophilic. The composition of claim 1, wherein the lidocaine hydrochloride comprises lidocaine hydrogen chloride. The composition of claim 1, wherein the amount of lidocaine is at least about 10% to about 60% by dry weight of the film. The composition of claim 1, wherein the first film-forming polymer comprises hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC). The composition of claim 1, wherein the second film-forming polymer comprises HPC, HPMC, flulan and/or povidone (PVP). The composition of claim 4, wherein the HPMC comprises HPMC 3cps, HPMC 6cps or HPMC 15cps. The composition of claim 5, wherein the PVP comprises PVP K-30 or PVP K-90. The composition of claim 1, wherein the at least one plasticizer comprises polyethylene glycol (PEG), glycerol or Tween 20. The composition of claim 8 wherein the PEG comprises PEG 400, PEG 4000 and/or PEG 6000. The composition of claim 1, wherein the ratio of the dry weight of the first polymer to the dry weight of the second polymer is from about 1:1 to about 7:1. The composition of claim 1, wherein the ratio of the dry weight of the first and second polymers to the dry weight of the plasticizer is about 4:1. The composition of claim 1, wherein the first polymer comprises HPMC 6 cps, and the plasticizer comprises a high viscosity of greater than about 500 cps but less than about 2000 cps and less than about 1000 ears. A plasticizer that is swallowed with a low molecular weight. The composition of claim 1, wherein the first polymer comprises HPMC 15 cps, and the plasticizer comprises a low viscosity of less than about 200 cps but greater than about 3 cps and greater than about 5,000 ears. A plasticizer with a high molecular weight of less than about 5,000,000 ear swallows. The composition of claim 1, wherein the first polymer comprises HPMC 15 cps, the second polymer comprises HPMC 3 cps or HPMC 6 cps, and the plasticizer comprises glycerol or PEG 6000, wherein The first film-forming polymer, the second film-forming polymer, and the plasticizer are present in a ratio of from about 2:2:1 to about 7:1:2 by weight. The composition of claim 1, wherein the first polymer comprises HPMC 15 cps, the second polymer comprises HPMC 3 cps, HPMC 6 cps or pulan, and the plasticizer comprises PEG 6000, wherein The first film-forming polymer, the second film-forming polymer, and the plasticizer are present in a ratio of about 3:1:1 by weight. The composition of claim 1, wherein the first polymer comprises HPMC 6 cps, the second polymer comprises HPMC 3 cps or pulan, and the plasticizer comprises glycerol, wherein the first The film forming polymer, the second film forming polymer, and the plasticizer are present in a ratio of about 3:1:1 by weight. The composition of claim 1, wherein the first polymer comprises HPMC 6cps, the second polymer comprises PVP K-90, and the plasticizer comprises PEG 4000, wherein the first film-forming polymer, the second film-forming polymer and the plasticizer are present in a weight ratio The word is about 7:1:2. The composition of claim 1, wherein the fast-acting ODF disintegrates within about 60 seconds of administration. The composition of claim 1, wherein the rate of dissolution of the fast-acting ODF is such that about 90% of lidocaine is released within about 5 minutes to about 10 minutes of administration. The composition of claim 1, wherein the rate of penetration of the fast-acting ODF is such that lidocaine permeates through the target treated with the ODF at a rate of from about 0.8 to about 1.7 mg/cm ² within about 5 minutes of administration. region. The composition of claim 1, wherein the composition has no trace of an organic solvent. The composition of claim 1, wherein the orally disintegrating film is produced by a method comprising the steps of: mixing the local anesthetic, the two polymers, and the at least one plasticizing agent In an aqueous solution; transferring the aqueous solution to the surface of one of the suitable support materials; and drying the aqueous solution on the surface of the support material to form a film. The composition of claim 19, wherein any organic solvent is not required to produce the orally disintegrating film. A method of providing local anesthesia to a patient in need thereof, the method comprising: orally administering to the patient in need thereof an effective amount of the composition of claim 1 of the patent application. The method of claim 24, wherein the method is used during oral surgery or dental treatment.