FILMOGENIC COMPOSITIONS FOR TOPICAL ANAESTHETIC BIOADHESIVES - TABS, FOR CONTROLLED RELEASE OF ACTIVE PRINCIPLES AND TOPICAL ANAESTHETIC BIOADHESIVES

Abstract

Filmogenic compositions are described for topical anaesthetic bioadhesives (TABs) comprising a) a xanthan biopolymer matrix selected from Xanthomonas species and pathovars, including Xanthomonas campestris pathovars campestris and maninhotis, and Xanthomonas arboricola pathovar pruni, a producer of pruni xanthan, wherein the matrix is made of pure or combined xanthan varieties in any proportion, said matrix comprising between 1% and 95% by weight of the total weight of the composition, and additives or excipients; b) at least one anaesthetic, in a proportion of 0.1% to 50% by weight of the total weight of the composition. The topical anaesthetic bioadhesives (TABs) are also described, and they may be applied to the gingival mucosa and/or alveolar mucosa on the buccal (1) or lingual/buccal (2) surfaces with extensions and anatomical contours for crowns of the upper and lower dental arches.

Claims

1. Filmogenic compositions for topical anaesthetic bioadhesives (TAB) for controlled release of active principles and topical anaesthetic bioadhesives, characterized by comprising: a) a biopolymer matrix of xanthan selected from xanthan produced by Xanthomonas arboricola pathovar pruni with viscosity of 1% of aqueous solutions with 1% potassium chloride (KCl) at 25° C. (degrees Celsius) from 1500 to 1700 mPas1 (MiliPascal per second), alternatively from 1200 to 1600 mPas1, and low acetylation, such as between 0.2 and 4% including 0.2 to 1.0% and pyruvate between 0.4 and 1.3%, alternatively from 1.5 to 3.0% or 4.0 to 4.8% for a higher viscosity, chemically modified or not, with the matrix comprising from 1% to 95% by weight relative to the total weight of the composition, and additives or excipients; and b) at least one active ingredient, pure or in combination, selected among topic anaesthetics, in the proportion of 0.1% to 50% by weight of the total weight of the composition.

2. Filmogenic compositions according to claim 1, characterized in that alternatively the biopolymer matrix of xanthans of pathovar pruni comprises xanthans of the strains of Xanthomonas campestris pathovar. campestris with mannose and acetyl in any ratio.

3. Filmogenic composition according to claim 1, characterized by comprise between 2.0 and 45.0%, including 3.0 to 40.0% of weight from combined or pure active ingredients in any proportion.

4. Filmogenic composition according to claim 2, characterized by comprise between 2.0 and 45.0%, including 3.0 to 40.0% of weight from combined or pure active ingredients in any proportion.

5. Filmogenic composition according to claim 1, characterized by, alternatively, do not have any active ingredient.

6. Filmogenic composition according to claim 1, characterized by comprise an anesthetic agent as the active principle, such as benzocaine, tetracaine, procaine, lidocaine, ropivacaine, bupivacaine, prilocaine and articaine, alone or combined in any proportion.

7. Filmogenic composition according to claim 2, characterized by comprise an anesthetic agent as the active principle, such as benzocaine, tetracaine, procaine, lidocaine, ropivacaine, bupivacaine, prilocaine and articaine, alone or combined in any proportion.

8. Filmogenic composition according to claim 3, characterized by comprise a) an antimicrobial agent as the active ingredient, such as quaternary ammoniums, pyrazole derivatives, functionalized methacrylates (such as silver, zinc, copper, tin methacrylate), chlorhexidine digluconate, antibacterial monomers; and b) alternatively an anti-inflammatory agent as the active principle, such as ibuprofen, acetylsalicylic acid, diclofenac, paracetamol or c) a hemostatic agent as the active principle, such as ferric sulfate, heparin, warfarin, citrates, oxalates.

9. Filmogenic composition according to claim 3, characterized by comprise the active principle as chemotherapeutic agents, such as cisplatin, azathioprine, bleomycin, carboplatin, cyclophosphamide, doxorubicin, etoposide, hydroxyurea, fosfamide, methotrexate, mitomycin, cetuximab.

10. Filmogenic composition according to claim 3, characterized by comprise the active ingredient natural extracts, such as essential oils of copaiba, butiá, vitis, cardol, cardenol, oregano, aroeira, garlic, propolis.

11. Filmogenic composition according to claim 3, characterized by comprise the active principle as cytokines molecules, such as transforming growth factors (TGFs), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF).

12. Filmogenic composition according to claim 3, characterized by comprise reducing agents, such as sodium ascorbate, glutathione, catalases, dismutase, peroxidases.

13. Filmogenic composition according to claim 3, characterized by comprise inhibitors of matrix metalloproteinases (MMPs), such as digluconate of chlorhexidine, tetracycline, am inocycline, galardin, ethylenediamine tetraacetic acid (EDTA), zinc oxide, zinc methacrylate.

14. Filmogenic composition according to claim 1, characterized by comprise the additives or excipients of a) comprise 0-60% fillers, 0-6% nanocomposites, 0-60% fibers, 0 to 6% of nanofibers, 0 to 90% starches, 0 to 70% natural polymers, 0.1 to 85% dispersants, 0 to 5% defoamers, 0 to 5% emulsifiers, and 0 to 10% antioxidants, and dyes, pigments, soluble salts, preservatives, antioxidants, sweeteners, flavorings, anti-fouling agents.

15. Filmogenic composition according to claim 3, characterized by comprise the additives or excipients of a) comprise 0-60% fillers, 0-6% nanocomposites, 0-60% fibers, 0 to 6% of nanofibers, 0 to 90% starches, 0 to 70% natural polymers, 0.1 to 85% dispersants, 0 to 5% defoamers, 0 to 5% emulsifiers, and 0 to 10% antioxidants, and dyes, pigments, soluble salts, preservatives, antioxidants, sweeteners, flavorings, anti-fouling agents.

16. Filmogenic composition according to claim 1, characterized by comprise casting or extrusion process to produce topical anaesthetic bioadhesive in films, strips ou tape form.

17. Filmogenic composition according to claim 3, characterized by comprise casting or extrusion process to produce topical anaesthetic bioadhesive in films, strips or tape form.

18. A bioadhesive according to claim 1, characterized by comprise botulinum toxin between 50 and 500,000 units.

19. A topical anesthetic bioadhesive (TAB) for controlled release of active principles for topical application in the inner or outer part of the mouth or through a mucous membrane, characterized by comprise bioadhesive in the form of films, strips or tapes considering the filmogenic composition according to claim 1.

20. A bioadhesive according to claim 19, characterized by comprise, in addition to the bioadhesive layer containing anesthetic and drugs, at least one drug-free outer layer to reduce undesired dissolution thereof to adjacent areas, the outer layer being selected from among compositions of pruni xanthanes in specific or chemically modified associations, low or medium crystallinity PHAs, including PHB, hydroxymethylpropylcellulose phthalate or methacrylic acid/methyl methacrylate copolymer, and non-biodegradable non-edible films, including food grade PVC.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0097] FIG. 1 attached depicts topical anesthetics adhesive films applied to the gingival mucosa and/or alveolar mucosa in the buccal (1) or lingual/buccal (2).

[0098] The FIGS. 2A and 2B show adhesive films with various extensions, thicknesses, and shapes.

[0099] FIG. 3 represents anesthetic adhesive films with a full outline of topics or anatomical cervical part with 360° contour on a tooth that will receive a clamp for absolute isolation.

[0100] FIG. 4 attached illustrates anesthetic adhesive films with variants of anatomical conformation for insertion and positioning in interproximal areas.

[0101] FIG. 5 illustrates attached adhesive films with topical anesthetic effect in various shapes and colors, and with centralized chromatic markings.

[0102] FIGS. 6A and B attached exemplifies the use of topical anesthetics films in ulcerated and/or traumatic injuries.

[0103] FIG. 7 attached shows anesthetic adhesive films threads for insertion and positioning on the lips.

[0104] FIG. 8 attached shows adhesive film according to the invention inserted and positioned in a region adjacent to the dental implant.

[0105] FIG. 9 attached exemplifies several shapes of the anesthetic adhesive films of the invention, with a playful appeal for children's use.

[0106] FIG. 10 attached is a bar graph for graphical illustration of the statistical analysis between groups of anesthetics in the NIH/3T3 fibroblast cell line cytotoxicity test (Absorbance at 540 mm), where different letters indicate a statistically significant difference between groups (p<0.05).

[0107] FIG. 11 is a graphical illustration attached via the adhesive Box plot analysis between groups of anesthetics when compared to denture fixatives. Different letters indicate a statistically significant difference between groups (p<0.05).

DETAILED DESCRIPTION OF THE INVENTION

[0108] One aspect of the invention is the filmogenic composition for the controlled release of active ingredients, based on xanthan, was useful for the preparation of topical anesthetics adhesive.

[0109] Another aspect of the invention is the mono, bi or multilayer topical anesthetic adhesives obtained after processing the compositions of the invention.

[0110] Yet another aspect of the invention involves the use of the adhesives obtained according to the invention.

[0111] Advantageously, the adhesives of the invention exhibit effective adhesion, the area of application control and numbed region due to the use of a film, dosage control, water solubility control as well as the encapsulation of the unpleasant flavors of certain anesthetics or other drugs added together.

[0112] The filmogenic compositions for the controlled release of active ingredients according to the invention have a biomatrix or biopolymer matrix and structural polymer xanthan, biodegradable biomolecule and is biocompatible with the skin of the lips and oral mucous membranes and upper digestive tract. Potential fields of application of the anesthetic adhesives are proposed herein.

[0113] Xanthan, preferably used to make a pure or majorly form the support or biopolymer matrix with a structural and drug release function, must be produced by Xanthomonas arboricola pv. pruni called xanthan pruni, with purity suitable for use in pharmaceuticals and foods, high viscosifying power as measured by viscosity values of 1500 to 1700 mPas.sup.1 or from 1200 to 1600 mPas.sup.1 and low acetylation (preferably from 0.2 to 4% and more preferably 0.2 to 10%) while pyruvatation can be about 0.4 to 1.3%, from 2.5 to 3.0% or even from 4.0 to 4.8% (higher levels promote higher viscosity), chemically modified or not.

[0114] Still useful for the invention, pure or in combination, are other varieties of pharmaceutical and food grade xanthan having equivalent properties such as high heat resistance and rheological stability of the solutions against a wide range of temperature, pH, and ionic strength.

[0115] The matrix may also comprise other biopolymers with structural function, such as modified starches and starches, or to help control the release of anesthetic drugs and other drugs in the composition, preferably galactomannans, of microbial or non-microbial origin, such as guar gum, or other soluble biopolymers such as those from chemical modification of cellulose, namely methyl cellulose and the like, or water soluble, under specific conditions, such as chitosan, and various additives.

[0116] The polymer matrix may also be produced in combination with other hydrophilic and/or lipophilic components, such as food grade additives or pharmaceutical additives, in accordance with good pharmaceutical practice, including the Brazilian Pharmacopoeia and/or internationally acceptable manuscripts, such as USP.

[0117] Advantageously, xanthan is compatible with various existing anesthetics, both the amino group and the ester group or the amide group, which enables a multitude of anesthetics or associations of the same product.

[0118] Xanthan may be associated with many drugs, additives, and substances, which allows the obtaining of a variety of topical anesthetic adhesives, with different degrees of adhesion, dissolvability, flexibility, among others.

[0119] The filmogenic compositions of the invention for controlled release of active ingredients comprise dry components and wet components that are combined and processed in adhesive films of various types for the desired applications.

[0120] The dry components comprise the polymeric matrix selected from xanthan, combined or not, pure or compounding the polymeric matrix or carrier at concentrations of 1.0 to 95%, preferably 5.0% to 70.0% and most preferably 15 to 60%, the said matrix being combined with:

[0121] Nanofiller type silicates or sheet silicates, natural or modified by organic ions or non-organic ions, and silicas (including hydrophobic fumed silica), mixed or not, from 0.0% to 8.0%, preferably 0.01% to 6.0%, more preferably 0.1% to 5.0%.

[0122] Nanofibers, combined or not, from 0.0% to 6.0%, preferably from 0.1% to 5% more preferably from 0.01% to 5.0% selected from celluloses obtained from natural sources such as rice husks, wheat straw, soybean hulls and other permitted food.

[0123] Other natural polymers, chemically modified or unmodified or derived from semi-synthesis, selected from galactomannans, pectins, saccharide polymers of microbial origin such as gellan and dextran, combined cyclodextrins or not, or chitin and chitosan, and natural celluloses or modified in a proportion of 0.0% to 70.0%, preferably 0.0 to 60.0% and more preferably 0.0 to 50.0%.

[0124] Additives in a solid form selected from preservatives, colorants, sweeteners, flavorings, anti-caking agents, in amounts sufficient to achieve the desired effect (qsp).

[0125] The components of the wet portion comprise:

[0126] Wetting and dispersing agents of the biopolymer matrix, combined or not, selected from among: i) Lipophilic, comprising oils from natural sources, including vegetable oils of rice, soybean, sunflower, canola, peanuts and corn, coconut, nuts, almonds and edible nuts, copaiba, of grape seed and phospholipids such as lecithins; and ii) Hydrophilic, comprising the synthetic dispersants and humectants including propylene glycol and polyethylene glycol, and those of natural sources, glycerin, glycerol, sorbitol and similar effect polyols, alone or combined, from 0.1% to 85.0%, preferably from 0.5% to 65.0%, more preferably from 2.0% to 60.0%;

[0127] Defoamers, combined or not, selected from among those allowed for food or allowed for drugs, selected from sorbitan trioleate (Span 85) and sorbitan tristearate (Span 65), 0.0% to 5.0%, preferably 0.5% to 3.0%, more preferably from 0.5% to 2.0%;

[0128] Emulgents, selected from among mono- and esterified glycerides, sorbitan esters, such as Spans 60 and 80, polyoxyethylene esters, selected from WYRJ 45, Atlas 2142 and Atlas 2127 esters of polyoxyethylene sorbitan, selected from Tweens 60 and 80 and lecithin, 0.0% to 5.0%, preferably 0.0% to 3.0%, more preferably from 0.0% to 2.0%;

[0129] Antioxidants, combined or not, selected among primary and chelators, synergists such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), and ascorbic acid and erythorbic and their salts, respectively, suitably diluted, 0.0% to 10% of the lipid fraction, preferably from 0.2% to 5%, more preferably from 0.5 to 1.5%;

[0130] Natural flavors, combined or not, selected from essential oils, or synthetic, preferably identical to natural, in amounts according to good manufacturing practices (qsp);

[0131] Dyes and pigments for drugs and food, selected from dyes and natural organic pigments, chlorophylls, carotenoids, betalains, and anthocyanins, or inorganic such as titanium dioxide, calcium carbonate, iron oxides in amounts sufficient to obtain the desired effect (qsp);

[0132] Acidity regulators or alkalizing agents selected from inorganic bases and/or low molecular weight pharmaceutically acceptable amines, selected from sodium hydroxide and/or triethanolamine for the composition of the pH adjustment in the range 4.5 to 9 and more preferably from 6.0 to 7.5; and:

[0133] At least one local anesthetic selected from benzocaine, tetracaine, procaine, lidocaine, ropivacaine, bupivacaine, articaine, prilocaine and in concentrations by weight from 0.1% to 50%, preferably 2.0 to 45.0%, more preferably 3.0 to 40.0% by weight.

[0134] Compounds with antimicrobial, anti-inflammatory, wound healing, cytotoxic or anti-tumor characteristics of topical use in pharmacologically active concentrations (qsp); and where the percentage of the constituents of the dry portion (ps/pt) and wet portion (pu/pt) is calculated based on the total weight of the components of the composition except for water or other solvents or solvent mixtures capable of solubilizing xanthan or other solid drugs.

[0135] For illustrative purposes, Table 1 below summarizes the percentages by weight of components of the inventive compositions.

TABLE-US-00001 TABLE 1 Range   in % Wide Medium Short Components range range range Xanthan  1-95  5-70 15-60 Water soluble polymer 0.0-70   0-60  0-50 Nanofillers 0-6 0.1-0.5 0.15-5   Nanofibers 0-6 0.1-0.5 0.15-5   Plasticizers 0.1-85  0.5-65  5.0-60  Dispersants 0.1-85  0.5-65  2.0-60  Defoamers 0-5 0.5-3   0.5-2.0 Emulsifiers 0-5 0-3 0-2 Antioxidants  0-10 0.2-5   0.5-1.5 Preservatives 0.1-2.0 0.2-1.8 0.3-1.5 Anesthetics 0.1-60   3-45  5-40 Acidity Regulators for pH between qsp qsp qsp 4.5 and 9.0 Antimicrobial, anti-inflammatory, qsp qsp qsp healing Sweeteners, colors qsp qsp qsp

[0136] Table 2 below lists some bioadhesive formulations of the invention prepared for cell toxicity tests.

TABLE-US-00002 TABLE 2 EXAMPLES COMPONENTS 1 2 3 4 Xanthan (g) 3 3 3 3 Cloisite 30B (g) 0.15 0.15 — 0.15 Ca triphosphate (g) 0.03 — 0.05 — Glycerin (g) 2.9 3.0 3.0 3.0 Tween (g) 0.5 0.3 0.3 0.3 Copaiba (g) 0.1 0.3 0.3 0.3 Benzocaine (g) 1.0 1.7 0.85 — Methylparaben (g) 0.07 — 0.06 — Ethylparaben (g) 0.01 — 0.02 — Water + alcohol (ml) 260 300 300 250 Characteristics Very dry, Medium Medium Dry. low adhesive adhesive Medium adhesive properties. properties. adhesive properties More properties. flexible Flexible than and example 2. translucent

[0137] The cytotoxicity of the products of the invention is evaluated with the cell line of mouse fibroblasts (NIH/3T3).

[0138] The test is performed according to ISO 10993 (2009). The cell suspension is plated at a concentration of 2×10.sup.4 cells per well and delivered into a cell culture dish of 96 wells. Each well receives 200 μl DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% Fetal Bovine Serum. The plate is then incubated at 37° C. in an atmosphere containing 5% CO.sub.2 for 24 hours. The groups used are shown in Table 1. In control wells, 200 μl DMEM (Dulbecco's Modified Eagle Medium) is supplemented with fetal bovine serum 10%. After removal of the test extracts, 200 μl PBS (phosphate buffered saline) and 20 μl of MTT (tetrazolium salt [3-(4,5-dimetltiazol-2-yl)-2,5-diphenyltetrazolium bromide] are added to each well. The plate is incubated in a room without light for 24 hours at 37° C. After that, MTT is aspirated and 200 μl dimethylsulfoxide (DMSO) is added to each well. Thereafter, absorbance at 540 nm is measured using a spectrophotometer and the results were analyzed statistically.

[0139] The data are tabulated and submitted to Kruskal-Wallis nonparametric statistical analysis and Tukey's complementary test (p<0.05). In the analysis, the product of the invention M20, prepared according to Example 2 of Table 2 above, with 20% benzocaine, demonstrated statistically similar results to the commercial control (Benzotop, DFL, Brazil).

[0140] The results of cytotoxicity testing are illustrated in FIG. 10. In FIG. 10, the legend is used as shown in Table 3 below.

[0141] As an illustration, the same results are given in Table 3 as the numerical results of the cytotoxicity tests.

TABLE-US-00003 TABLE 3 ABSORBANCE GROUP DESCRIPTION (540 nm)* M Negative control of bioadhesive 0.686 (±0.186).sup.A M20 Product of the invention with 20% 0.015 (±0.027).sup.B benzocaine C20 Commercial topical anesthetic 20% 0.000 (±0.000).sup.B (Benzotop 20%, DFL, Brazil) P20 20% benzocaine powder 0.511 (±0.032).sup.A C Cell control (Positive controle) 1.284 (±0.039).sup.A The negative control means membrane without the anesthetic; Positive control means only the cells that were cultured in the wells, without contact with any material. *Different letters indicate statistically different groups (p < 0.05).

[0142] After defining the composition of the formulation, the method of production is chosen.

[0143] Solvents and/or diluents are required to allow the formation of the matrix and the incorporation of the primary active ingredient, namely the topical anesthetic, or other solid drugs in the matrix.

[0144] The solvents or diluents used are preferably water for xanthan and other water soluble polymers and amine type drugs, and alcohol and weak acid solutions as required.

[0145] For some water soluble drugs such as local anesthetics of the ester type, edible vegetable oils may be used such as canola and rice; or of pharmaceutical use, such as grape seed and almonds, or essential oils with properties that are sapid, odorants and even pharmacological, such as clove oil, cinnamon, ginger, mint and other such diluents; one or several of these but not limited thereto.

[0146] Anesthetics in liquid form can be inserted into the hydrophilic and/or lipophilic portion of the matrix for adhesive construction.

[0147] All mixtures and additions must be made respecting and avoiding possible incompatibilities between the components, making use of emulsifiers as needed. These different formulations or bioadhesive compositions allow obtaining a multitude of different characteristics as to their physical, chemical and physicochemical properties, which allows for the different uses.

[0148] The casting method (solvent evaporation method) is the preferred method for the preparation of the bioadhesive invention.

[0149] Other methods include extrusion or even other methods of producing tapes, wires, strips and adhesive films, known or that may be used for this type of production, provided that they do not adversely modify the properties of the anesthetics and other added drugs or with the same properties of the composition.

[0150] The obtainment of the finished bioadhesive threads by casting method provides ways of bioplastic or adhesive biofilm forms that can be modeled in different formats at the end of the process, enabling several applications of the topical bioadhesive.

[0151] The preparation of the biopolymer compositions and the preparation of adhesives may be performed in a single step or in two or more steps, depending on the method used to obtain the product.

[0152] Production by the casting method, for example, is performed in two stages, the preparation stage of the composition followed by the preparation of the product based on solvent evaporation.

[0153] In the preparation by solubilization, xanthan, and other water-soluble or solubilizable polymers which will form the polymeric matrix, should be completely solubilized in water and/or alcohol solution of suitable pH.

[0154] To this solution, other constituents are added, if any, such as humectants, anti-caking agents, antifoams, preservatives, dyes and colorings, antioxidants, sweeteners, salts, and water-soluble drugs, fillers and/or nanofillers, or some of these, depending the end product desired, respecting and avoiding possible incompatibilities and making use of emulsifiers as needed.

[0155] The direct incorporation of these materials, or previously dispersed or solubilized or emulsified or mixed, as to its characteristics, without loss of homogeneity of the composition, namely, uniform distribution of the components is possible because the xanthan solution has high stabilizing capability of suspensions and emulsions.

[0156] After mixing the constituents of the biopolymer matrix composition for the processing and obtaining the adhesive threads by the casting method, it is still necessary to add specific conditions for solvent evaporation, with the use of heat being preferred.

[0157] Other forms for partial removal of the solvent may be used until complete removal of the solvent, and other volatilizable components is complete so that the formation of the topical film, tape or strip occurs.

[0158] This method enables the shaping or embossing of adhesives that can easily be made at the end of the formation step of the adhesive.

[0159] Furthermore, the casting method makes it possible to obtain special multilayer films by the addition of liquid compositions of a different formulation, for example, without anesthetic, on previously formed anesthetic film; the second added layer should also have the solvent evaporated for final formation of the bilayer adhesive.

[0160] The extrusion method may be used provided that the extrusion conditions do not alter the properties of topical anesthetics and other drugs in the composition.

[0161] When using this method to obtain compositions by solubilization, this will be followed by pre-concentration.

[0162] If the preparation is by liquid phase dispersion, the compositions should subsequently be subjected to temperatures below the melting point of the xanthan or combinations thereof.

[0163] In this process, obtaining combinations of the materials initially follows the same procedure, but the addition of the constituents is reset and/or solvent content used is not sufficient to completely solubilize the xanthan.

[0164] In the extrusion process, the final product is not in the form of biofilms adhesive; it is necessary to subject it to a further step for stamping the adhesive. To obtain the adhesives, it is necessary for the extrusion of the material to pass by a new melting, now outside the extruder, wherein the molding step can be done by thermoform ing.

[0165] Topical anesthetics adhesives of the invention are tested for their retention and adhesion using standard tests.

[0166] The adhesives are prepared by casting or by extrusion.

[0167] In principle, topical anesthetics do not have adhesive properties, since the usual presentation is a gel/paste and liquid (spray), so there is no study reporting adhesiveness thereof. Thus, the adhesion test was based on articles for denture fasteners, which has the most similar presentation with the adhesive product of the invention. As there is no ISO standard for such fasteners, the evaluation was adapted from articles for this type of material.

[0168] The analysis of retention and stickiness or adhesion is carried out through the acrylic resin specimens mounted on mechanical testing machines to perform a tensile test. Marketed denture fixatives are used as reference materials for this test.

[0169] The groups (n=12) are shown in Table 4 below.

[0170] Acrylic resin cylinders are 21.9 mm in diameter and 55 mm in height with a flat surface where the materials are applied. Initially, 0.3 g of each tested material is applied on the polished surface of the lower cylinder attached to the machine base, and the resin cylinder previously immersed in artificial saliva. Then, the upper cylinder with the flat side facing downwards is positioned on the lower cylinder to leave the interposed material. A pressure of about 2 kg is applied to the upper cylinder acrylic resin (mobile) for 15 seconds to simulate the applied pressure of fasteners on an upper denture. The upper mobile cylinder is connected to the load cell, the tensile test is carried out with a speed of 1 mm/min until the separation of the rolls. The maximum adhesion strength (MPa) was recorded at the time of separation from the set.

[0171] The data were tabulated and submitted to Kruskal-Wallis nonparametric statistical analysis and Tukey's complementary (p<0.05). The product of the invention called M20, prepared in Example 2 of Table 2, demonstrates bond strength values similar to the Corega Adhesive Paste and Corega Powder being, however, lower than the Corega tape group.

[0172] From the test used, it can be inferred that the bioadhesive of the invention as tested possesses adhesive characteristics in a simulated oral environment.

[0173] FIG. 11 attached illustrates the retention and adhesiveness test results. In this Figure, the following groups have the same interpretation as in Table 4 below. The bond strength data obtained for the various groups are expressed in MPa.

TABLE-US-00004 TABLE 4 BOND STRENGTH GROUPS DESCRIPTION (MPa)* Corega Corega ® Powder 1.708 (±0.994).sup.C Powder Corega Paste Corega ® Paste 4.442 (±0.865).sup.AB Corega Strip Corega ® Strip 6.958 (±3.222).sup.A M20 Product of the invention with 2.816 (±1.077).sup.BC 20% benzocaine Membrane Negative controlo of bioadhesive 2.425 (±0.823).sup.C All Corega ® products are owned by Glaxo Smith Kline, UK. *Different letters indicate statistically different groups (p < 0.05).

[0174] As shown in Table 4 above, the item “negative control membrane” means a membrane free from the anesthetic.

[0175] The lack of adhesiveness of topical anesthetics of prior art is extremely problematic, especially in wet areas, which is solved by the characteristics of the adhesives currently proposed.

[0176] According to the invention, the material can be constructed although they do not have any prior adhesiveness, when the material comes into contact with a damp area, it is fixed and remains in place, releasing the anesthetic and other drugs from the composition, which facilitates the use in the oral cavity and upper digestive tract, including the esophagus.

[0177] In the oral cavity, this feature facilitates dental procedures and provides a more effective analgesia than traditional anesthetics, mainly presented in the form of mouthwashes, solutions, gels or ointments used for this purpose.

[0178] The adhesiveness of the material may be inherent or arise at the time of contact with moist areas, such as the oral mucosa. For areas that are not normally damp such as the lips, the adhesive can exhibit prior adhesiveness to facilitate attachment on the site. This adhesiveness guarantees the permanence of the material for the time required to start the dental procedure completely painless or with a significant minimization of this.

[0179] Regarding some topical adhesives and the invention's adherence, the results also showed high stickiness (tack) which, in addition to being advantageous for use in less humid places, is interesting for obtaining films, foil and bi- or multilayer strips.

[0180] For the various adhesives developed for this application, different adhesion tests were performed on the oral mucosa, and outside, between the anesthetic adhesives, and between the adhesive and different materials in a qualitative manner, as can be seen in FIGS. 2A and 2B attached.

[0181] Thus, all the films, tapes and adhesive strips of topical anesthetics obtained by using different combinations of preliminary tests remained adhered to the oral mucosa for a period of 30 minutes to 3 hours.

[0182] The topical anesthetic adhesives of the invention, besides its effective adhesiveness, still have the advantage of limiting its anesthetic action to the applied area. This provides the safety of anesthetizing only the region in which the procedure will be performed, which does not occur with anesthetics presented in the form of mouthwashes, solutions, gels or ointments that do not allow this control action area, inducing gustatory anesthesia.

[0183] The anesthetics adhesives of the invention can even be designed so as to perfectly match areas with specific shapes, such as around the teeth, or even have markings that guide the exact place for punctures, as can be seen in the drawings in FIGS. 1 to 5. These adhesives with indicative markings are also applied in the medical field, in surgeries and procedures in the upper digestive tract.

[0184] The method of production and the composition of adhesives allow for pre-determining the concentration of anesthetics and other drugs added, depending on the area of adhesion and the onset of drug release so that perfect dose control is possible. Thus, they allow a more efficient control of the desired action, and provide a more effective analgesia in the oral mucosa with no toxic or allergenic effects caused by overdoses. The controlled release is made possible through the use of xanthan gum and of the auxiliary polymers which can be associated with it.

[0185] The topical anesthetic adhesive materials proposed herein may be soluble in water and have controlled solubility. This may vary from completely dissolvable and soluble, at higher or lower speed, to fully not soluble, suffering only waterlogging, which reduces the release rate of the drug and prolongs the anesthetic action.

[0186] Xanthans may have varying translucency and opacity and these characteristics are transferred to the adhesive threads. However, the concentration and type of substances having a pharmacological action, such as anesthetics and the like, or only technological, such as fillers and nanofillers that may be added, may alter the translucency of the adhesive; thus, the adhesives can range from translucent to opaque.

[0187] Furthermore, the biopolymer matrix used in the topical adhesives of the invention permits the addition of various dyes, making it possible to create adhesives with different colors.

[0188] The encapsulating action of the aromas and flavors of xanthan is well known. Thus, the particular composition of the biomatrix has the ability to encapsulate the unpleasant taste of some anesthetics and this provides a differentiating factor because it contributes to the masking of the undesirable taste of the anesthetic, which provides a lower rejection by the patient; thus, facilitating its use.

[0189] In addition, some studies have shown the capacity to potentiate the action of antioxidants. Thus, the bioadhesive matrix of anesthetics proposed here can preserve the drugs contained therein.

[0190] An additional means of controlling the release of drugs to adjacent areas that are part of the composition of anesthetics bioadhesive of the invention comprises, in addition to the bioadhesive layer containing the anesthetic and pharmaceuticals, the addition of at least one thin film or film/layer which does not contain anesthetic drugs or others to form the bi- or multilayers of the anesthetic bioadhesives, so that this additional layer(s) or film(s) acts as an aid to reduce the patient's discomfort caused by the unwanted dissolution to adjacent areas.

[0191] The outside(s) layer(s) is (are) consist(s) of insoluble or low dissolving plastic materials formed from the xanthan polymeric matrix, preferably xanthan pruni compositions in specific association, more preferably chemically modified, and/or by addition of other biocompatible and biodegradable materials such as thin films or post-formed films, PHAs low or medium crystallinity, including PHB of hydroxymethylpropylcellulose phthalate or copolymer of methacrylic acid/methacrylate methyl; or non-biodegradable and non-toxic non-edible films, such as food grade PVC.

[0192] The strategy of forming bi- or multilayer films as a means of reducing an undesired drug release to adjacent areas covered by the local anesthetic adhesives can be used for all of the adhesives object of the present application.

[0193] Advantageously, the present bioadhesives have the following characteristics: [0194] anesthetize only the desired area with a reduction in the area of anesthetic activity, freeing the patient from receiving unnecessary doses of drugs contained in the adhesives, which makes them even safer; [0195] greater penetration of anesthetic due to adhesiveness and stable viscosity that keeps the drug longer and in greater concentration at the site of action; [0196] being wholly or partly water-soluble but always biocompatible with the tissues of areas of use, namely the mouth and upper digestive tract; [0197] the dissolution time at the time of use may vary or even not dissolve while maintaining the release of the active principle of the anesthetic if necessary; [0198] the matrix of the adhesives is edible and because they are biodegradable they do not require special disposal; [0199] the matrix allows obtaining the AAT adhesives by different methods; [0200] are of small volume, light and easy to be packaged, stored, transported and used; and [0201] in addition to anesthetizing, they can play other roles, such as protecting injured or ulcerated surfaces.

[0202] The description of the invention as well as the description of the accompanying figures, which are given as non-limiting examples will explain the invention well.

[0203] Initially, FIG. 1 represents anesthetic topical adhesive films applied to the gingival mucosa and/or alveolar mucosa on the buccal (1) or lingual/buccal (2) with anatomical extensions and contours for crowns of the upper and lower dental arches.

[0204] FIGS. 2A and 2B show adhesive films with various extensions, thicknesses, and shapes applied as a local anesthetic film in anatomical regions of the palatine mucosa prior to the infiltration of the anesthetic for local or regional blockade (3 and 4).

[0205] FIG. 3 shows the topical anesthetic adhesives, total or partial outline or full anatomical lap films with a 360° contour on a tooth that will receive a clamp for absolute isolation, protruding from the palatal/lingual regions (5a) to vestibular regions of the gums (5b); wire, tape or fibers intertwined for gingival protection (6a and 6b).

[0206] FIG. 4 shows topical anesthetics adhesive films with variants of anatomical design for insertion and placement in interproximal regions and can be invaginated into the gingival sulcus (7a and 7b).

[0207] FIG. 5 represents adhesive films with topical anesthetic effect in various shapes and colors, and with centralized chromatic markings indicating the needle puncture site (8a and 8b) for anesthetic infiltration.

[0208] FIGS. 6A and B illustrate the use of topical anesthetics films in ulcerated and/or traumatic lesions in various regions of the oral mucosa (9, 10 and 11).

[0209] FIG. 7 depicts topical anesthetics adhesive films with shaping variants (12, 13) for insertion and placement in the mouth.

[0210] FIG. 8 depicts adhesive film inserted and positioned in the region adjacent to the dental implant (14) showing the designed variant in detail (14a).

[0211] FIG. 9 illustrates various formats that can present the anesthetic adhesive films with playful appeal to be preferentially used by a child.

[0212] FIGS. 10 and 11 are detailed above in this report and relate respectively the results of cytotoxicity and retention and adhesion tests.