TWI704932B - 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

Fast disintegrating oral film containing local anesthetic

The present invention relates to a fast-acting orally disintegrating film (ODF) containing lidocaine (lidocaine), its use, and a method for producing ODF.

Local anesthetics are drugs used to reduce the perception of pain at the site of administration. An example of a local anesthetic is lidocaine, whose chemical name is 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide.

Lidocaine is often used in dentistry. In dental treatments, such as dental surgery, tooth extraction, root canal treatment, to relieve patients' physical discomfort and psychological stress, as well as to relieve toothache, mouth ulcers, cold sore or teething Pain. For dental treatment, lidocaine is usually administered by injection such as "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. In addition, for applications other than dental treatment, such as alleviating toothache, non-invasive administration is generally preferred. Furthermore, the method of administering lidocaine provides rapid therapeutic effect, which is beneficial to both physicians and patients. Therefore, there is a need for non-invasive and rapid administration of local anesthetics.

In summary, one object of the present invention is to provide a fast-acting orally disintegrating membrane (ODF) for administration of local anesthetics.

The present invention provides a fast-acting ODF, which includes lidocaine free-base (free-base) or a pharmaceutically acceptable salt thereof, at least one first film-forming polymer, at least one second film-forming polymer, and at least one A plasticizer, wherein the weight ratio of the first film-forming polymer to the second film-forming polymer is about 1:1 to 20:1, and wherein the first film-forming polymer and the second film-forming polymer The material is hydrophilic.

In some embodiments, the pharmaceutically acceptable salt of lidocaine includes lidocaine hydrogen chloride. In another embodiment, lidocaine is present in an amount of at least about 10% to about 20% of the dry weight of the film. In another embodiment, the first film-forming polymer includes hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC). In some embodiments, the second film-forming polymer includes HPC, HPMC, pullulan, and/or povidone (PVP). In another embodiment, the HPMC includes HPMC 3cps, HPMC 6cps, or HPMC 15cps. In another embodiment, the PVP includes PVP K-30 or PVP K-90. In some embodiments, the at least one plasticizer includes polyethylene glycol (PEG), glycerol, or Tween 20. In another embodiment, the PEG includes 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 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 includes HPMC 6cps, and the plasticizer includes a plasticizer having a high viscosity higher than about 500 cps but lower than about 2000 cps and a low molecular weight lower than about 1000 cps.化剂。 Chemical agent. In some embodiments, the first polymer includes HPMC 15 cps, and the plasticizer includes a low viscosity of less than about 200 cps but greater than about 3 cps and greater than about 5000 ears but less than about 5,000,000 ears Swallow a high molecular weight plasticizer.

In other embodiments, the first polymer includes HPMC 15cps, the second polymer includes HPMC 3cps or HPMC 6cps, and the plasticizer includes glycerol or PEG 6000, wherein the first film-forming polymer, The presence ratio of the second film-forming polymer and the plasticizer is about 2:1:1 to about 7:1:2 by weight. In another embodiment, the first polymer includes HPMC 15cps, the second polymer includes HPMC 3cps, HPMC 6cps or Pullulan, and the plasticizer includes PEG 6000, wherein the first film-forming polymer, The ratio of the second film-forming polymer and the plasticizer is about 3:1:1 by weight. In some embodiments, the first polymer includes HPMC 6cps, the second polymer includes HPMC 3cps or Pullulan, and the plasticizer includes glycerol, wherein the first film-forming polymer, the second polymer The ratio of the film-forming polymer and the plasticizer is about 3:1:1 by weight. In another embodiment, the first polymer includes HPMC 6cps, the second polymer includes PVP K-90, and the plasticizer includes PEG 4000, wherein the first film-forming polymer and the second film-forming polymer The presence ratio of the polymer and the plasticizer is about 7:1:2 by weight.

In some embodiments, the fast-acting ODF disintegrates within about 60 seconds of administration. In other embodiments, the dissolution rate 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 penetration rate of the fast-acting ODF allows lidocaine to penetrate through the target area treated with the ODF at about 0.8 to about 1.7 mg/cm ² within about 5 minutes of administration. In some embodiments, there is no trace of organic solvent in the composition.

In some embodiments, the method for producing the orally disintegrating film includes 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 A 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 for providing local anesthesia to a patient in need, the method comprising: orally administering an effective amount of a composition to the patient in need, the composition including lidocaine free base (free -base) or its pharmaceutically acceptable salt, at least one first The film-forming polymer, at least one second film-forming polymer, and at least one plasticizer, wherein the weight ratio of the first film-forming polymer to the second film-forming polymer is 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 used in oral surgery or dental treatment.

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

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

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

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

Figure 5 illustrates the in vitro permeation profile of lidocaine ODF and Xylocaine® Jelly 2% (Recipharm Karlskoga AB, Sweden) of the present invention in water.

Figure 6 illustrates the method of preparing the ODF of the present invention.

The following content used in the specification and the scope of the patent application, unless the content Special note, otherwise the singular forms "one" and "the" include plural references. Thus, for example, the reference "a component" includes a mixture of multiple components, the reference "an active agent" includes more than one active agent, and the like.

In this disclosure, the "active ingredients", "active ingredients of medicines" and "drugs" used interchangeably refer to chemical substances or compounds that have desired medicinal and physiological effects and contain therapeutically effective agents. These terms also include those pharmaceutically active derivatives and analogs of the active agents specifically mentioned herein, including but not limited to salts, esters, amides, sulfates, prodrugs, active metabolites, complexes, and Something similar.

In this disclosure, the word "about" is used as a modifier of a quantity to indicate that it includes + or -10% of the modified quantity.

In this disclosure, the term "disintegration" is used to mean scattered or split into small fragments that are not detectable by the naked eye.

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

The term "effective amount" or "therapeutically effective amount" of a drug or pharmaceutical active ingredient is used to indicate the 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 specific active agent, and the like. Those skilled in the art can use routine experiments to determine the appropriate "effective" amount in any individual case.

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

In this disclosure, "local anesthetics" are drugs that provide local numbness or pain relief.

It can be understood that the term "film" includes films and sheets, which are of any shape, including Rectangle, square, or other shape that is most suitable for a specific application. The film described in this disclosure can be any desired thickness and size suitable for the intended use. The size and shape of the film of the present invention can be targeted at a specific injection location, for example, it can be easily placed in the mouth of a user to achieve effective local injection of lidocaine. In addition, some films may have a relatively thin thickness of about 10 to about 500 microns, while others may have a thicker thickness of about 500 to about 10,000 microns. Variations in ODF thickness are desirable, so the ODF of the present invention can deliver higher or lower doses of lidocaine to specific treatment areas. In addition, the term "film" includes single-layer compositions and multi-layer compositions, such as laminated films, coatings on films, and the like.

The present invention discloses a quick-acting ODF, which includes lidocaine as a pharmaceutical active ingredient, so that it can be administered without water or fluid intake. Due to the characteristics of the ODF of the present invention, such as rapid disintegration, dissolution, and penetration rate, it is quick-acting. Specifically, the fast-acting ODF of the present invention disintegrates in saliva within about 60 seconds. Compared with the currently commercially available non-invasive administration methods, such as gels and tablets, the fast-acting ODF of the present invention also provides a higher dissolution and penetration rate, which will be described in Examples 2 and 3 and Schemes 1 to 5.

The fast-acting properties of ODF help to quickly develop the desired anesthetic effect. As mentioned in the background of the invention, a fast-acting ODF is required to make dental treatment as short and efficient as possible, and quickly relieve pain, which is beneficial to both physicians and patients, especially for patients who hate dental treatment. Even when lidocaine needs to be administered multiple times, the quick-acting properties become more important.

Another advantage of the present invention is that the ODF format allows customization of its size and shape, so as to better target the injection location and the injection purpose. Furthermore, the ODF described in the present disclosure can deliver high local doses with low systemic absorption, minimizing adverse side effects related to systemic absorption of local anesthesia.

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

In some embodiments, the ODF described in the present disclosure contains local anesthetics in an amount of about 10% to about 60% of the total weight of the formula. More specifically, the lidocaine ODF described in the present disclosure contains 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 includes one or more film-forming polymers. The film-forming polymer preferably has one or more of the following properties: easy to obtain, inexpensive, hydrophilic, non-toxic, tasteless, and hypoallergenic. In addition, the film-forming polymer is easily dissolved in a solvent, such as water, and quickly disintegrates and dissolves in the buccal cavity.

The film-forming polymer provides key properties for the ODF of the present invention, such as film formation, extensibility, homogeneity, and smoothness of surface properties, which will be more specifically described in Example 1. The film-forming property is based on the degree of ODF fracture as a result of the film-forming process. Scalability is based on the degree of ODF fracture that usually occurs as a result of ODF stretching or bending under normal processing conditions. The homogeneity is based on the degree of delamination of the ODF formed during the film forming process. The smoothness of the surface properties is based on the degree of sediment or bubbles in the ODF formed during the film-forming process.

Exemplary film-forming polymers having one or more of the above-mentioned preferred properties include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), pullulan, poly Povidone (PVP), hydroxyethyl cellulose (hydroxyethyl cellulose), sodium carboxy methyl cellulose (sodium carboxy methyl cellulose), starch and its derivatives. Examples of HPMC are HPMC having a viscosity of 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 compared with the second polymer, the first polymer includes Same or greater weight. The inclusion of the first and second polymers with different properties such as viscosity and molecular weight in an appropriate ratio is important for ODF with desired properties, such as film-forming properties, homogeneity, and surface properties. The smoothness will be described in Example 1 and Tables 1A and 1B below.

The ratio of the first polymer to the second polymer can range from about 1:1 to about 20:1 in terms of weight %. In some embodiments, the ratio of the first polymer to the second polymer is about 1:1 to about 10:1 in terms of weight %. 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 terms of 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 may include HPC or HPMC, and the second polymer may include HPC, HPMC, PVP and/or Pullulan. More specifically, in some embodiments, the first polymer includes HPMC 6cps or HPMC 15cps, and the second polymer includes HPMC 3cps, HPMC 6cps, PVK-30, PVK-90 or Pullulan. In other embodiments, the first polymer includes HPMC 15cps, and the second polymer includes HPMC 3cps, HPMC 6cps, povidone K-30, povidone K-90, or pullulan.

The ODF of the present invention may additionally include at least one plasticizer. The plasticizer is an important component, because the plasticizer can improve the expandability of the ODF and provide flexibility to the ODF to minimize the fracture 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 (such as dimethyl phthalate, phthalate) Diethyl phthalate (diethyl phthalate), dibutyl phthalate (dibutyl phthalate)), citrate derivatives (e.g. tributyl citrate, triethyl citrate, triethyl acetyl citrate ( acetyl citrate, citric acid), glycerol monoacetate, glycerol diacetate, triacetate, triacetin, polysorbate, hexadecyl Alcohol (cetyl alcohol), 1,3-butanediol (1,3butanediol), 1,4-butanediol (1,4butanediol), sorbitol, sodium diethylsulfosuccinate (sodium diethylsulfosuccinate) , And castor oil. In some embodiments, examples of PEG are in the range from PEG 200 to PEG 35000, more specifically PEG 6000, PEG 4000, PEG 3350, PEG 2000, PEG 1000, and PEG 400. (Measure the molecular weight 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 preferred formulations of the ODF of the present invention described in Example 1. As shown in Table 2, some combinations of film-forming polymers have better interactions with each other through some plasticizers. Some of these examples are as follows:

In some embodiments including HPMC 6cps as the first polymer, the ODF of the present invention further includes a plasticizer, which has a high viscosity of about more than 500 cps but less than about 2000 cps and less than about 1000 Dal The low molecular weight of Dalton. Exemplary plasticizers with such high viscosity and low molecular weight include glycerol.

In other embodiments including HPMC 15cps as the first polymer, the ODF of the present invention further includes a plasticizer, which has a low viscosity of less than 200 cps but higher than 3 cps and a high viscosity of more than about 5000 cps. High molecular weight less than about 5,000,000 ear swallows. Exemplary plasticizers with this low viscosity and high molecular weight include PEG 6000.

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

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

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

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

The fourth formula shown in Table 2 was used for dissolution and penetration studies, and the currently commercially available Trachisan sore throat lozenges (Engelhard Arzenimittel GmbH & Co.KF, Germany) for oral administration of lidocaine tablets and Compared with Xylocaine Jelly 2% gel (Recipharm Karlskoga AB, Sweden). These studies are detailed in Examples 2 and 3, respectively. The results of the dissolution study are presented in Figures 1 to 4, comparing the ODF of the present invention with Trachisan Sore Throat Tablets (Engelhard Arzenimittel GmbH & Co. KF, Germany). The results of the permeation study are presented in Figure 5, comparing the ODF of the present invention with Xylocaine Jelly 2% (Recipharm Karlskoga AB, Sweden).

As shown in Figures 1 to 4, in a solution with different pH to simulate various pH conditions of the human GI system, the lidocaine ODF of the present invention can release about 90% within about 5 minutes to about 10 minutes after administration. It takes about 30 minutes to release about 90% of lidocaine. In addition, FIG. 5 illustrates that within the first 5 minutes of administration, the ODF of the present invention provides a penetration rate of about 0.8 to about 1.7 mg/cm ² , which is about 3 times higher than the gel. Therefore, both studies show that compared to the currently commercially available lidocaine products for oral administration such as Trachisan Sore Throat Lozenges and Xylocaine Jelly, the ODF of the present invention dissolves faster and penetrates faster.

Furthermore, any of the foregoing embodiments may further include one or more fillers, which may be any pharmaceutically acceptable fillers. Examples of such fillers include but are not limited to calcium phosphate, Calcium sulfate, powdered sugar, silicate, dextrose, fructose, glucose, lactose, kaolin, starch, sucrose, maltose, mannitol, sorbitol, microcrystalline cellulose, powdered cellulose, or Any combination of the foregoing. In some embodiments, the bulking agent is maltose, mannitol, or a combination thereof. In some embodiments, the filler is composed of water-soluble or non-water-soluble fillers.

In any of the foregoing embodiments, the oral disintegrating film of the local anesthetic provided may contain one or more active ingredients, such as pharmaceutical ingredients, functional ingredients, skin care ingredients, and supplements. In some embodiments, the active agent content is about 0.001% to about 60% by weight of all ingredients of the film. In other embodiments, the content of the active agent is about 0.1% to 45% by weight of all ingredients of the film. In other embodiments, the active agent content is about 1% to 40% by weight of all components of the film.

Furthermore, other ingredients can be added to the provided film, including but not limited to sweeteners, flavoring agents, coloring agents, saliva stimulants, taste masking agents, surfactants, preservatives, antifoaming agents, penetration enhancers, Saliva stimulants, dispersants, buffers, thickeners, enzyme inhibitors, and cosolvents.

In some embodiments, the provided film includes 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, barose Alcohol (isomalt), maltitol (maltitol), xylitol (xylitol), and erythritol (erythritol). Exemplary artificial sweeteners include, but are not limited to, saccharin (saccharin), cyclamate (cyclamate), aspartame (aspartame), acesulfame-K, sucralose ( sucralose, alitame, and neotame. In some embodiments, the sweetener accounts for about 0% to about 30% of the dry weight of all ingredients of the film. In some embodiments, the sweetener accounts for about 0.1% to about 25% of the dry weight of all ingredients of the film. In some embodiments, sweeteners account for the The dry weight of all ingredients of the film is about 1% to about 10%. In some embodiments, the sweetener accounts for about 1% to about 7% of the dry weight of all ingredients of the film. In some embodiments, the sweetener accounts for about 1% to about 6% of the dry weight of all ingredients of the film. In some embodiments, the sweetener accounts for about 1% to about 5% of the dry weight of all ingredients of the film.

In some embodiments, the provided films include flavoring agents. Examples of flavoring agents may include, but are not limited to, flavor oils such as peppermint oil, cinnamon oil, spearmint oil, and nutmeg oils, and flavored essential oils extracted from vanilla, cocoa, coffee, and chocolate, and Essential oils of apple, raspberry, cherry, pineapple and other citrus fruits such as orange, lemon and lime. Specific examples of sweeteners used in the present invention may include saccharin, sucrose, fructose, glucose, sucralose, and mannitol.

In some embodiments, the provided film includes a colorant. Especially when the formulation ingredients or drugs are in an insoluble or suspended form, adding colorants can improve the aesthetic appearance of the oral film. Exemplary coloring agents 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 5 Aluminum Lake (FD&C Yellow 5 Aluminum Lake), FD&C Yellow No. 6 Lake, or any other pharmaceutically acceptable color additives that will impart color when added to a pharmaceutical composition. In some embodiments, the colorant accounts for about 0% to about 1% by dry weight of all ingredients of the film. In some embodiments, the colorant accounts for about 0.001% to about 1% by dry weight of all ingredients of the film.

If necessary, other examples of pharmaceutically acceptable excipients or additives known to those skilled in the art can also be added to the active ingredient.

In some embodiments, the ODF of the present invention may include a saliva stimulant. A saliva stimulant can be added to increase the rate of saliva production to accelerate the disintegration of the orodispersible film. Exemplary saliva stimulants 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 can be used as saliva stimulants, including but not limited to glucose, fructose, xylose, Maltose, and lactose. In some embodiments, the saliva stimulant accounts for about 0% to about 10% of the dry weight of all ingredients of the film. In some embodiments, the saliva stimulant accounts for about 0% to about 7% of the dry weight of all ingredients of the film. In some embodiments, the saliva stimulant accounts for about 0% to about 6% of the dry weight of all ingredients of the film. In some embodiments, the saliva stimulant accounts for about 2% to about 6% of the dry weight of all ingredients of the film.

In some embodiments, the provided film includes a taste masking agent. Adding taste masking agents can improve the sensory properties of the film. In some embodiments, the taste masking agent can be used to mask the undigestible taste of some ingredients. In some embodiments, exemplified taste masking agents include, but are not limited to, cyclodextrin, maltodextrin, ion exchange resins, amino acids, gelatin, gelatinized starch, fat bodies, lecithin , Lecithin-like substances and salts. In some embodiments, the taste masking agent accounts for about 0% to about 15% of the dry weight of all ingredients of the film. In some embodiments, the taste masking agent accounts for about 0% to about 10% of the dry weight of all ingredients of the film. In some embodiments, the taste masking agent accounts for about 0% to about 7.5% by dry weight of all ingredients of the film. In some embodiments, the taste masking agent accounts for about 0% to about 5% of the dry weight of all ingredients of the film.

In some embodiments, the present invention may include a surfactant. Surfactant is a surfactant, which reduces the surface tension and thus increases the emulsification, foaming, dispersion, uniformity and wetting properties of the product. Exemplary edible surfactants include, but are not limited to, sorbitan fatty acid esters (e.g., orbitan monoisostearate, sorbitan monolaurate) , Sorbitan monooleate (sorbitan monooleate), sorbitan monopalmitate (sorbitan monopalmitate), sorbitan monostearate (sorbitan monostearate), sorbitan sesquiisostearate Sorbitol (sorbitan sesquistearate), sorbitan sesquioleate, sorbitan trilaurate, sorbitan trioleate, water Sorbitol tristearate (sorbitan tristearate), sucrose palmitate (sucrose palmitate), glyceryl monooleate (glyceryl monooleate), vitamin E, polyethylene glycol succinate (polyethylene glycol succinate), propylene glycol mono Propylene glycol monolaurate, myristyl alcohol, polyoxyethylene Polyoxyethylene alkyl ether (polyoxyethylene alkyl ether), polyoxyethylene castor oil derivative (polyoxyethylene castor oil derivative), sodium lauryl sulfate (sodium lauryl sulfate), and propylene glycol dilaurate (propylene glycol dilaurate). In some embodiments, the surfactant accounts for about 0.01% to about 5% of the dry weight of all ingredients of the film. In some embodiments, the surfactant accounts for about 0.4% to about 0.7% of the dry weight of all ingredients of the film.

In some embodiments, the ODF of the present invention may include a dispersant for the film-forming polymer. The film-forming polymer is usually supplied as a solution containing a dispersant to maintain the stability of the film-forming polymer dispersion. For example, a dispersant may be provided for polyvinyl acetate, and the dispersant may be sodium lauryl sulfate, povidone and the like. In another example, macrogol cetostearyl ether and sodium lauryl sulfate, or ascorbic acid and sodium hydroxide can be provided for the methacrylate copolymer as dispersants. Generally, the dispersant accounts for about 0.001% to about 10% of the dry weight of all ingredients of the film. In some embodiments, the dispersant accounts for about 0.01% to about 8% of the dry weight of all ingredients of the film. In some embodiments, the dispersant accounts for about 0.1% to about 5% of the dry weight of all ingredients of the film. In some embodiments, the dispersant accounts for about 0.001% to about 1% of the dry weight of all ingredients of the film. In some embodiments, the dispersant accounts for about 0.04% to about 0.7% of the dry weight of all ingredients of the film. In some embodiments, the dispersant accounts for about 0.01% to about 7.5% by dry weight of all ingredients of the film.

In some embodiments, the ODF of the present invention may include a buffer. A buffer can be added to adjust the pH. The pH is related to the dissolution and stabilization of the ingredients in the formula, as well as its absorption through the oral mucosa. Exemplary buffers include, but are not limited to, citrate buffer, phosphate buffer, acetate buffer, carbonate buffer, ammonia buffer, borate buffer, lactate buffer, ethanolamine buffer, glycine Buffer, methionine buffer, glutamine buffer, and succinate buffer. In some embodiments, the pH buffer is an acid/salt system. Exemplary acid/acid salt systems include, but are not limited to, citric acid/citrate (e.g. sodium citrate, potassium citrate), citric acid/phosphate (e.g. sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid Trisodium, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), citric acid/tartrate (e.g. sodium tartrate, Potassium tartrate), citric acid/borate (e.g. sodium borate, potassium borate), citric acid/malate (e.g. sodium malate, potassium malate), citric acid/maleate (e.g. sodium maleate, horse Potassium phosphate), tartaric acid/citrate (e.g. sodium citrate, potassium citrate), tartaric acid/phosphate (e.g. sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, phosphoric acid Potassium dihydrogen, dipotassium hydrogen phosphate), tartaric acid/tartrate (e.g. sodium tartrate, potassium tartrate), tartaric acid/borate (e.g. sodium borate, potassium borate), tartaric acid/malate (e.g. sodium malate, potassium malate) ), tartaric acid/maleate (e.g. sodium maleate, potassium maleate), boric acid/citrate (e.g. sodium citrate, potassium citrate), boric acid/phosphate (e.g. sodium aluminum phosphate, dihydrogen phosphate) Sodium, disodium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), boric acid/tartrate (e.g. sodium tartrate, potassium tartrate), boric acid/borate (e.g. sodium borate, potassium borate) ), boric acid/malate (e.g. sodium malate, potassium malate), boric acid/maleate (e.g. sodium maleate, potassium maleate), malic acid/citrate (e.g. sodium citrate, lemon Potassium acid), malic acid/phosphate (e.g. 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 (e.g. sodium borate, potassium borate), malic acid/malate (e.g. sodium malate, potassium malate), malic acid/maleate (maleic acid) Sodium, potassium maleate), maleic acid/citrate (e.g. sodium citrate, potassium citrate), maleic acid/phosphate (e.g. sodium aluminum phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, triphosphate Sodium, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate), maleic acid/tartrate (e.g. sodium tartrate, potassium tartrate), maleic acid/borate (e.g. sodium borate, potassium borate), maleic acid /Malate (e.g. sodium malate, potassium malate), maleic acid/maleate (e.g. sodium maleate, potassium maleate). In some embodiments, the buffer system accounts for about 0% to about 15% by weight of the film. In some embodiments, the buffer system accounts for about 0% to about 10% by weight of the film. In some embodiments, the buffer system accounts for about 0% to about 7.5% by weight of the film.

Preparation of oral disintegrating membrane

The present invention also provides a method for preparing the ODF of the present invention, as shown in FIG. 6. The method preferably includes the steps of dissolving the first and second film-forming polymers and the plasticizer in water in appropriate amounts and ratios. Note that no organic solvent is required. In fact, due to the film-forming polymer capacity of the present invention It is easy to dissolve in water, so the ODF of the present invention does not need any organic solvent. Since even a small amount of organic solvents may be toxic to humans, it is advantageous to avoid the use of organic solvents to make ODF. Compared with other known film-forming polymers, HPMC is a hydrophilic polymer, which is easier to dissolve, easier to obtain and less expensive in the ODF manufacturing process, so it is particularly suitable as a film-forming polymer.

Then, lidocaine or its salt, 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 vibration 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 is prepared in this way to form a pre-casting blend. Next, the solution is transferred to the surface of a suitable carrier material and dried to form an ODF. Suitable carrier materials are for example non-siliconized polyethylene terephthalate films, non-siliconized paper, polyethylene impregnated kraft paper or non-siliconized polyethylene films. Any conventional film coating equipment can be used to transfer the solution to the bulk material. Preferably, a drying oven, a drying tunnel, a vacuum, a dryer, or any other suitable drying equipment known to those skilled in the art is used to dry the film in a high-temperature air bath. For example, the film can be dried in an oven at about 80° C. for about 20 minutes, thereby forming an oral film having a desired thickness, and then cutting it into a desired size.

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

Use of oral disintegrating membrane

The oral disintegrating membrane described in the present disclosure can be used in various situations, including but not limited to local anesthesia for dental treatments, such as dental surgery, tooth extraction, root canal treatment, and for relieving toothache, oral ulcers, cold sore or Pain caused by teething. The ODF described in the present disclosure can be orally administered to or near the painful area of oral surgery or dental treatment to relieve, eliminate or Prevent pain. In a preferred embodiment, the ODF is designed to diffuse through the oral mucosa to exert its local anesthetic effect, thereby providing an alternative route of local anesthesia administration and alleviating short-term local pain caused by 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 be quickly disintegrated by saliva and/or other aqueous materials on the mucosal surface. In some embodiments, after disintegration, the provided film releases one or more formulations (such as pharmaceutical ingredients, functional ingredients, supplements, or skin care ingredients) to the mucosa. In this way, the provided film can be administered, thus delivering a therapeutically effective amount of the formulation.

In one embodiment, the lidocaine ODF of the present invention contains about 24 mg lidocaine per ODF. It can be understood that the attending physician can determine the total daily use of the film described in this disclosure within the scope of reasonable medical judgment. For any specific patient or organism, the specific therapeutically effective dose depends on various factors, including the disease to be treated and the severity of the disease; the activity of the specific compound used; the specific composition used; the age of the patient , Weight, general health, gender and diet; time of administration, route of administration, and excretion rate of specific compounds used; during treatment; drugs used in combination or coincidentally with specific compounds 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 help illustrate the present invention, but are not intended to limit or be interpreted as limiting the scope of the present invention. Indeed, in addition to the content described in this disclosure, various modifications and many other embodiments of the present invention are obvious to those skilled in the art after referring to all the content of this document, which contains the following examples and references to the science and technology described herein Patent documentation. It should also be understood that unless specifically stated otherwise, each reference mentioned in this disclosure is incorporated into this disclosure as a reference to help illustrate the state of the art. The following examples contain important additional information, examples, and guidance, which can be used to implement the present invention and its equivalents in various embodiments.

Refer to the following examples to better understand these and other aspects of the present invention, to The following embodiments are used to illustrate some specific embodiments of the present invention, but the scope of the present invention is not limited to the following embodiments, but is defined by the scope of patent application.

Example 1: The influence of film-forming polymer and plasticizer on the properties of ODF

The film-forming polymer and plasticizer and their individual weight% in ODF substantially affect the properties of ODF. Research, test and evaluate various formulations using a combination of film-forming polymers and plasticizers, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and povidone (PVP) , Pullulan and/or polyvinyl alcohol (PVA), such as glycerol, Tween 20, PEG400, PEG4000 and/or PEG6000.

The four properties of ODF were evaluated: A. Film formation, B. Film expandability, C. Film homogeneity, and D. Film surface smoothness. In order to quantify the results of film formation properties, a score of 1 means that there is no sign of cracks in the film, and a score of 0 means that there are cracks in the film. To quantify the film expandability results, a score of 1 indicates that there is no sign of cracking after stretching or bending, and a score of 0 indicates that there is cracking after stretching or bending. To quantify the results of membrane homogeneity, a score of 1 means no delamination, and a score of 0 means there is delamination. In order to quantify the surface smoothness results, a score of 1 means that there is no sediment or bubbles, and a score of 0 means that there are sediments or bubbles. Table 1A lists the tested formulations of lidocaine ODF and their results.

The study was conducted on ODF with only one film-forming polymer. As shown in Table 1A below, since there is no formula to achieve a score of 4, an ODF including only one film-forming polymer is unsuccessful, which means that other ingredients, such as another film-forming polymer, may be required to produce a successful ODF. However, these results do show that HPC and HPMC tend to have higher scores.

Using HPC and HPMC as the first polymer, additional research was conducted with a formulation containing the first polymer and the second polymer. Some of the more successful results are summarized in Table 1B below. As shown in Table 1B, the inclusion of the first and second polymers produced some better results, but the resulting ODF still lacked scalability properties (column B).

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

Among all the tested polymers, HPMC, povidone (PVP) and pullulan are suitable for preparing ODF. Preferably, HPMC 6cps and HPMC 15cps can be used as the first polymer. As described in the ODF preparation section, compared to other film-forming polymers described in this disclosure, HPMC polymers particularly provide the additional advantages of lower cost, easy availability, and rapid dissolution in water. Therefore, in some embodiments, HPMC polymer can be used 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 a penetration study were conducted to compare the lidocaine ODF of formula 4 in Table 1B with the lidocaine lozenge Trachisan sore throat lozenge (Engelhard Arzenimittel GmbH & Co. KF, Germany) and the gel Xylocaine Jelly 2% (Recipharm Karlskoga AB, Sweden).

Example 2: In vitro dissolution study of lidocaine ODF

The USP equipment IIV (rotating basket device) simulates the in vivo environment in the stomach, duodenum and jejunum at 50 revolutions per minute (rpm) for membrane dissolution studies. The USP equipment IIV uses 0.1N HCl (pH 1.2), phosphate buffer ( pH 4.5 and 6.8) and water at 37.0±0.5℃ as the dissolution medium.

Lidocaine ODF and Trachisan Sore Throat Lozenges (Engelhard Arzenimittel GmbH & Co. KF, Germany) were placed in the dissolution medium. Within 1 hour, collect 5ml aliquots of samples at 3, 6, 9, 12, 15, 30, 45 and 60 minutes. Using a UV spectrophotometer, at a wavelength of 230nm, analyze the drug content in the aliquot of the sample. Calculate the cumulative percentage drug release to establish the dissociation status, as shown in Figures 1 to 4.

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

Example 3: Permeation study of lidocaine ODF

Transdermal Franz Diffusion Cell was used to conduct membrane in vitro permeation studies, in which lidocaine ODF and gel Xylocaine Jelly 2% (Recipharm Karlskoga AB, Sweden) diffused from the supplier’s compartment through the artificial skin to the recipient The compartment is used to simulate the diffusion of drugs through the oral mucosa. The conditions between the receptor compartments are 37.0 +/- 0.5°C and have deionized water to simulate the physiological environment of the oral cavity. Within one hour, at 5, 10, 15, 20, 30, and 60 minutes, three samples (N=3) of 0.99 to 1 ml were collected for HPLC analysis. Figure 5 illustrates the permeation results, showing that lidocaine ODF has substantially higher permeability than gel. For example, Figure 5 illustrates that at 30 minutes, the ODF penetration of lidocaine is approximately twice that of the gel.

Although the present invention has been described in specific exemplary embodiments and examples, those skilled in the art can understand that changes can be made to the above-mentioned embodiments without departing from the concept of the present invention. Therefore, it can be understood that the present invention is not limited to the disclosed embodiments, but encompasses modifications within the spirit and scope of the present invention defined by the scope of the patent application.

It can be understood that the foregoing general description and the following detailed description are all examples and are for illustration only, and are not intended to limit the claimed invention in the scope of the patent application.

According to the detailed description, the above and other changes can be made. Generally, unless the above detailed description clearly defines the term, the terms used in the following disclosure should not be interpreted as limiting the technology to the specific embodiments disclosed in the specification. Accordingly, the actual scope of the technology includes the disclosed embodiments and all equivalent ways of implementing the technology.

Claims (22)

A quick-acting orally disintegrating film (ODF) composition comprising: lidocaine free-base (free-base) or a pharmaceutically acceptable salt thereof; at least one first film-forming polymer; at least one A second film-forming polymer; and at least one plasticizer, wherein the ratio of the first film-forming polymer to the second film-forming polymer is about 1:1 to about 20:1 by weight; wherein the The first film-forming polymer and the second film-forming polymer are hydrophilic; wherein the first film-forming polymer includes hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC); wherein the first The second film-forming polymer includes HPC, HPMC, pullulan and/or povidone (PVP); and wherein the at least one plasticizer includes polyethylene glycol (PEG), glycerol or Tween 20; wherein the HPMC The viscosity is about 3cps to about 15cps. The composition according to item 1 of the scope of patent application, wherein the pharmaceutically acceptable salt of lidocaine includes lidocaine hydrogen chloride. The composition according to claim 1, wherein the amount of lidocaine is at least about 10% to about 60% of the dry weight of the film. The composition described in item 1 of the scope of patent application, wherein the HPMC includes HPMC 3cps, HPMC 6cps or HPMC 15cps. The composition described in item 1 of the scope of patent application, wherein the PVP includes PVP K-30 or PVP K-90. The composition described in item 1 of the scope of patent application, wherein the PEG includes PEG 400, PEG 4000 and/or PEG 6000. The composition according to item 1 of the scope of the patent application, wherein the ratio of the dry weight of the first film-forming polymer to the dry weight of the second film-forming polymer is about 1:1 to about 7:1. The composition according to item 1 of the scope of patent application, wherein the ratio of the dry weight of the first film-forming polymer and the second film-forming polymer to the dry weight of the plasticizer is about 4:1. The composition according to claim 1, wherein the first film-forming polymer includes HPMC 6cps, and the plasticizer includes a high viscosity of more than about 500cps but less than about 2000cps and less than about 1000 A low-molecular-weight plasticizer. The composition according to claim 1, wherein the first film-forming polymer includes HPMC 15cps, and the plasticizer includes a low viscosity of less than about 200cps but greater than about 3cps and greater than about 5000 A plasticizer with a high molecular weight that can be swallowed but less than about 5,000,000 canals. The composition according to item 1 of the patent application, wherein the first film-forming polymer includes HPMC 15cps, the second film-forming polymer includes HPMC 3cps or HPMC 6cps, and the plasticizer includes glycerol or PEG 6000, wherein the ratio of the first film-forming polymer, the second film-forming polymer and the plasticizer is about 2:2:1 to about 7:1:2 by weight. The composition according to item 1 of the scope of patent application, wherein the first film-forming polymer includes HPMC 15cps, the second film-forming polymer includes HPMC 3cps, HPMC 6cps or Pullulan, and the plasticizer includes PEG 6000, wherein the ratio of the first film-forming polymer, the second film-forming polymer and the plasticizer is about 3:1:1 by weight. The composition according to item 1 of the scope of patent application, wherein the first film-forming polymer includes HPMC 6cps, the second film-forming polymer includes HPMC 3cps or Pullulan, and the plasticizer includes glycerol, The ratio of the first film-forming polymer, the second film-forming polymer and the plasticizer is about 3:1:1 by weight. The composition described in item 1 of the scope of the patent application, wherein the first film-forming polymer includes HPMC 6cps, the second film-forming polymer includes PVP K-90, and the plasticizer includes PEG 4000, wherein the The ratio of a film-forming polymer, the second film-forming polymer and the plasticizer is about 7:1:2 by weight. The composition described in item 1 of the scope of the patent application, wherein the fast-acting ODF disintegrates within about 60 seconds after being administered. The composition described in item 1 of the scope of the patent application, wherein the dissolution rate 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 described in item 1 of the scope of patent application, wherein the penetration rate of the fast-acting ODF enables lidocaine to penetrate through the target treated with the ODF at about 0.8 to about 1.7 mg/cm ² within about 5 minutes of administration area. The composition described in item 1 of the scope of patent application, wherein there is no trace of organic solvent in the composition. The composition according to claim 1, wherein the orally disintegrating film is produced by a method, the method includes the following steps: mixing the local anesthetic, the two polymers, and the at least one plasticizer in In an aqueous solution; transferring the aqueous solution to a surface of a suitable carrier material; and drying the aqueous solution on the surface of the carrier material to form a film. The composition described in item 16 of the scope of patent application does not require any organic solvent to produce the orally disintegrating film. A use of the quick-acting orally disintegrating membrane as claimed in the first item of the scope of patent application, which is used to prepare a drug for providing local anesthesia to patients in need, wherein an effective amount of the film is orally administered to the patients in need Quick-acting oral disintegrating film. The use as described in item 21 of the scope of patent application, which is used in oral surgery or dental treatment.

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