MX2007002844A - Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components - Google Patents

Abstract

A method of selecting components for use in water-absorbing pressure-sensitive adhesive compositions is provided. The method involves selecting a film-forming polymer, a ladder-like non-covalent crosslinker that is capable of forming a ladder-like interpolymer complex with the film-forming polymer selected, and selecting a carcass-like non-covalent crosslinker that is capable of forming a carcass-like complex with at least one of the film-forming polymer selected or the ladder-like non-covalent crosslinker selected. The adhesive hydrogels provide high adhesion in a swollen state and bridge the gap between conventional pressure sensitive adhesives and bioadhesives. Methods for preparing and using the resulting compositions are also disclosed.

Description

METHOD FOR PREPARING POLYMERIC ADHESIVE COMPOSITIONS USING THE INTERACTION MECHANISM BETWEEN POLYMERIC COMPONENTS FIELD OF THE INVENTION The present invention relates to polymer compositions. More particularly, the present invention relates to hydrogel and bioadhesive compositions, methods for selecting materials for the manufacture of the compositions, and method for using these compositions in therapeutic applications, such as drug delivery systems (eg, topical, transdermal). , transmucosal, iontophoretic), medical skin coatings, wound dressings and wound care products, and biomedical electrodes, as well as in cosmetic applications, such as teeth whitening products.

BACKGROUND OF THE INVENTION The various types of bandages and wound dressings are known and used to protect wounds and burns. Normally, wound dressings are made with an absorbent material, so that the exudate from the wound is removed and the wound dries, facilitating healing. Wound dressings can also contain one or more pharmacologically active agents such as antibiotics, local anesthetics or the like, commonly used wound dressings include fibrous materials such as gauze or cotton pads, which are advantageous in the sense that they are absorbent, although they are problematic in the sense that the fibers may adhere to the wound or tissue in recent formation, causing injury to the wound during removal. Other wound dressings have been prepared with foams and sponges, although the absorbency of these materials is often limited. Additionally, said wound dressings require the use of adhesive tape, as they are not self-adhesive. Hydrophilic pressure sensitive adhesives ("PSAs") are used in a variety of pharmaceutical and cosmetic products, such as topical and transdermal drug delivery systems, wound dressings, face masks, bioadhesive films designed for buccal or mucosal administration , teeth whitening bands and so on. A general distinguishing feature of hydrophilic PSAs is that they usually adhere to wet biological substrates, while hydrophobic PSAs (rubber based) typically lose their adhesive properties when wetted. The adhesive properties of PSAs will vary depending on how and when the products are to be used. For transdermal drug administration and topical applications, an adhesive patch, for example, should provide high adhesion immediately after use, and said adherence must be maintained during the entire application period (from a day to a week). For patches and dental bands, it is often desirable to use elastic polymeric films, which do not exhibit adhesion to dry surfaces, although they are highly adhesive when applied to moisturized soft mucosal surfaces and / or wetted solid tissue surfaces such as teeth. . For wound dressings and other miscellaneous purposes, in order to avoid damage to the skin by removing the patch, either water-soluble adhesives or insoluble hydrogel adhesives are preferred, which lose their adhesion under dilation in a lot of water. Facial masks and some teeth whitening products better utilize the hydrophilic polymeric compositions in the form of aqueous or ethanol-water solutions, which are dried after placement on a surface, thereby forming an insoluble polymer film that is adheres to the underlying tissue surface, although it does not adhere to other surfaces. In order to effectively achieve the adhesive properties of the polymeric materials useful in pharmaceutical and cosmetic products, a method based on deep molecular knowledge on the mechanisms underlying the adhesive properties has been developed. As has been recently established, at a molecular level, pressure-sensitive adhesion is due to the coupling of two types of apparently incompatible molecular structures. This reveals that there is a fine balance between strong cohesive interaction energy and improved free volume. See, for example, the publications of Feldstein et al. (1999) Polym. Mater. Sci. Eng., 81: 465-466; Feldstein et al., General approach to the molecular design of hydrophilic pressure-sensitive adhesives, Proceed. 25th Annual Meeting Adhesion Soc. And 2nd World Congress on Accession and Relative Phenomena, February 2002, Orlando, FL, vol.1 (Oral Presentations), p. 292-294; and Chalykh et al. (2002) J. Adhesion 78 (8): 667-694. The "free volume" property of the molecular structure of the PSA polymers results in a high adhesion at a macroscopic level and a liquid-like fluidity of the PSA material, which allows rapid formation of adhesive bonding. The property of "cohesive interaction energy" or "cohesion energy" defines the cohesive strength of the PSA polymer and provides dissipation of the release energy in the course of adhesive bond failure. Based on this discovery, a method for obtaining novel hydrophilic adhesives is disclosed in the U.S. Patent. No. 6,576,712 to Feldstein et al., Which involves physically blending high molecular weight, hydrophilic, non-adhesive polymers with the appropriate short chain plasticizers. In various PSAs, different molecular structures provide the right amounts of cohesion energy and free volume, thus defining the adhesive properties of polymeric materials. For example, in acrylic PSAs, the strong cohesive interaction energy is a result of the mutual hydrophobic attraction of the alkyl radicals in side chains, while a large free volume is due either to the electrostatic repulsion of the negatively charged carboxyl groups or a large volume of isoalkyl radicals in the side chains. In synthetic rubbers, a large free volume is obtained by adding glue resin molecules of low density, high volume. In hydrophilic adhesives, when high molecular weight polyvinyl lactams (ie, poly (N-vinyl-2-pyrrolidone) ("PVP") or polyvinyl caprolactams (PVCap ")) are mixed with polyethylene glycol (PEG") ) of short chain, as described in the US Patent No. 6,576,712, the high cohesion force results from the hydrogen bond between, for example, the PVP carbonyl groups and the terminal PEG hydroxyls, while the large free volume is due to the location of reactive groups at both ends of the PEG chains, which are of appreciable length and flexibility. An adequate balance between high cohesion energy and large free volume, which is responsible for the adhesive properties of polymeric materials, is achieved by evaluating the various PSA properties. For example, the ratio between cohesion energy and free volume defines the glass transition temperature, Tg, and modulus of elasticity, E, of a polymer. The higher cohesion energy and the smaller free volume result in higher values for both Tg and E. It will be recognized that all PSAs demonstrate a Tg within the temperature range from about -55 to about -30 ° C and an E »1 -105 Pa. In the patent of E.U.A. No. 6,576,712, the hydrophilic polymers and the plasticizer have the ability to hydrogen bond or bond electrostatically themselves and are present in a proportion that optimizes the key characteristics of the adhesive composition, such as adhesive strength, cohesive strength and hydrophilicity. The plasticizer has complementary reactive functional groups at both ends and when both terminal groups interact with the complementary functional groups on the hydrophilic polymer, the plasticizer acts as a non-covalent crosslinker between the longer hydrophilic polymer chains. In doing so, the plasticizer combines the plasticizing effect with the improved cohesive strength of the PSA polymer blend. This method of molecular design to achieve new hydrophilic PSAs describes the adhesion capacity of high Tg hydrophilic polymers, long chain, as well as the proportion of hydrophilic polymer to plasticizer (cohesive improver), which provides the best adhesion. When dry, the adhesives described in the U.S. Pat. No. 6,575,712, for example, mixtures of high molecular weight PVP with oligomeric PEG vary in molecular weight from 200 to 600 g / mol, provide instead low adhesion to dry surfaces. Adhesion increases when the surface of a substrate is wetted or the adhesive absorbs water. The maximum adhesion is observed when the adhesive contains 5 to 10% of water absorbed. This is usually the case when the adhesive is exposed to an atmosphere that has a moisture relative of 50%. Additionally, under direct contact with water, the adhesive dissolves. However, these adhesives do not contain covalent crosslinks, and are therefore not suitable for applications requiring water insoluble adhesives that can still be delayed. In particular, these prior art adhesives are less useful when increased adhesion is desired from much more appreciable hydration levels (eg, 15% water absorbed and higher). Therefore, although the prior art discloses polymers and hydrogel compositions that can be achieved with respect to the cohesion force, adhesion strength, glue, elasticity and water expansion capacity, the desire to develop a molecular design method remains. to prepare novel hydrophilic PSAs that focus on balancing the cohesive interaction energy and free volume at a molecular level. In order to solve these problems, the present invention is directed to a method for obtaining water-insoluble film-forming compositions by mixing the soluble polymers. Although this has already been attempted in the past, for example, U.S. Patent Nos. Nos. 5,597,873 for Chambers et al, and 5,306,504 for Lorenz et al. (mixing carboxyl-containing polymers with polyhydric alcohols and polyamines) and U.S. Patents. Nos. 4,771, 105 for Shirai et al., And 5,726,250 for Zajaczkowski (crosslinking of polyacrylic acid "PAA" or the copolymers of acrylic acid with the di and trivalent metal salts (Ca2 +, Al3 +), all of these Procedures are directed to the production of non-adhesive water absorbers by mixing techniques.

BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention pertains to an adhesive composition comprising: a film-forming polymer selected from water-insoluble polymers and water-soluble polymers that dilate in water; a non-covalent, ladder-like cross-linker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form a complete inter-polymeric stair-like interpolymer with the film-forming polymer; and a shell-like non-covalent crosslinker containing the complementary reactive functional groups at their ends, and has the ability to form a shell-like complex with at least one of the film-forming polymers or the non-covalent, stair-like crosslinker; wherein the amount of film-forming polymer is greater than the amount of non-covalent crosslinker similar to ladder or the amount of non-covalent crosslinker similar to carcass. Another aspect of the present invention relates to a method for selecting polymeric components for use in an adhesive composition, comprising: (a) selecting a film-forming polymer; (b) select a non-covalent crosslinker similar to ladder containing complementary reactive functional groups in the repeating units of the axis, and has the ability to form an inter-polymeric stair-like complex with the selected film-forming polymer; and (c) selecting a carcass-like non-covalent crosslinker containing complementary reactive functional groups at its ends, and having the ability to form a carcass-like complex with at least one of the selected film-forming polymer or the similar non-covalent crosslinker. to selected staircase; and wherein the amount of the film-forming polymer is greater than the amount of non-covalent crosslinker similar to ladder or the amount of the non-covalent crosslinker similar to casing. Still another aspect of the present invention relates to a method for manufacturing an adhesive composition, comprising; (a) (i) selecting a film-forming polymer; (ii) selecting a non-covalent, ladder-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form an inter-polymeric stair-like complex with the selected film-forming polymer; and (iii) selecting a carcass-like non-covalent crosslinker containing complementary reactive functional groups at its ends, and having the ability to form a carcass-like complex with at least one of the selected film-forming polymer or the similar non-covalent crosslinker. to selected staircase; and wherein the amount of the film-forming polymer is greater than the amount of non-covalent crosslinker similar to ladder or the amount of non-covalent crosslinker similar to shell; (b) mixing the film-forming polymer, the non-covalent, ladder-like crosslinker and the non-covalent, shell-like crosslinker; and (c) forming an adhesive composition by melt extrusion or solution melt. Adhesive compositions produced by the methods of the present invention provide a number of significant advantages over the prior art. In particular, these compositions provide one or more of the following advantages over the technique: they provide ease of handling; they are easily modified during manufacture, such that properties such as adhesion, absorption, translucency and dilation can be controlled and optimized; they can be formulated in such a way that the glue increases or decreases in the presence of moisture, such that the composition is not tacky until it is moistened; minimizes the leakage of the active agent, when included, from the composition on a mucosal surface (eg, in the user's mouth); they can be manufactured translucently, allowing the user to see the extent of bleaching without removing the hydrogel composition of the teeth or mucosal surface; minimize the damage of gums or mucous membranes in the mouth; they can be used in a comfortable and non-obstructive way; they are easily removed from the skin, temples or mucosal surface and leave no residue; are docile for extended duration of use or action; and can provide sustained and controlled release of a variety of active agents.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic representation of a carcass-like PVP-PEG network complex. The PVP-PEG complex combines high cohesion strength (due to the H bond of PVP-PEG) with a large free volume (being the result of considerable length and flexibility of the PEG chains). In order to emphasize the improved free volume in the PVP-PEG mixture, this type of complex structure is defined as a "shell-like" structure. The shell-like structure of the complex is the result of the location of reactive functional groups at both ends of the short PEG chains. Figure 2 is a schematic representation of a ladder-like PVO complex with a complementary proton donor polymer as the non-covalent, ladder-like crosslinker. When the complementary polymer contains reactive functional groups in the repeating units of the axis, the resulting complex has a structure called "stair-like". Figure 3 demonstrates a schematic representation of an interpolymer complex that combines the shell-like and crosslinker-like types. "FFP" represents a film-forming polymer, "CCL" represents a non-covalent, shell-like crosslinker, and "LLC" represents a non-covalent, ladder-like crosslinker. Figure 4 shows the Sun fraction and the Proportion of dilation (at a pH of 4.6) for the triple PVP mixtures (50% by weight) with PEG and Eudragit L 100-55 as a function of the concentration of the H bond, the ladder-like crosslinker, Eudragit L 100-55. Figure 5 shows the dependence of the Sun fraction and the Dilation ratio (at a pH of 4.6) for the triple mixtures of PVP with PEG and Eudragit L 100-55 (PVP: Eudragit ratio of 5: 1) to the concentration of link H, shell-like crosslinker, PEG. Figure 6 demonstrates the effect of the ladder-like non-covalent reticulator, Eudragit L 100-55, on stress-strain elastic curves until the films of mixtures of PVP-PEG-Eudragit L 100-55 are broken under the uniaxial extension with the extraction rate of 20 mm / min. The concentration of the shell-like crosslinker PEG was fixed at 50% by weight. Figure 7 illustrates the effect of carcass-like non-covalent crosslinker, PEG on the stress-strain curves until the films of mixtures of PVP.-PEG-Eudragit L 100-55 under uniaxial extension with the extraction index of 20 mm / min. The ratio of PPV: Eudragit L 100-55 is 5: 1. Figure 8, illustrates the impact of the water absorbed by the adhesive properties of the PVP-PEG-Eudragit L 100-55 blends, where the composition contains 58% by weight of PVP, 30% by weight of PEG, and 12% by weight of Eudragit L 100-55. The amounts of water absorbed (in% by weight) are indicated. Figure 9 is a graph of the maximum effort and the maximum elongation under adhesive effect against the weight fraction of water absorbed by the hydrogel of PVP-PEG-Eudragit L 100-55. Figure 10 shows the work of the adhesive outcome as a function of the water absorbed by the hydrogel PVP-PEG-Eudragit L 00-55. Figure 11 illustrates the in vivo release profile of hydrogen peroxide from the teeth bleaching bands based on a carbopol bioadhesive and the PEVP-PEG-Eudragit L 100-55 hydrogel.

DETAILED DESCRIPTION OF THE INVENTION Definitions and nomenclature Before describing the present invention in detail, it should be understood that unless stated otherwise, the present invention is not limited to hydrogel materials or specific manufacturing processes, as they may vary. It should also be understood that the terminology used herein is for the purpose of describing only the particular modalities, and is not intended to be limiting. It should be noted that, as used in this specification and the appended Claims, the singular forms "a" "one" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to "a hydrophilic polymer" includes not only a single hydrophilic polymer but also a combination or mixture of two or more different hydrophilic polymers, the reference to "a "plasticizer" includes a combination or mixture of two or more different plasticizers as well as a single plasticizer, and the like During the description and claim of the present invention, the following terminology will be used according to the definitions set forth below. The definitions of "hydrophobic" and "hydrophilic" polymers are based on the amount of water vapor absorbed by the polymers at a relative humidity (rh) of 100% According to this classification, hydrophobic polymers absorb only from 1 to 10 % by weight of water at a relative humidity of 100 $, while moderately hydrophilic polymers absorb 1 to 10% by weight of water, the hydrophilic polymers have the capacity to absorb more than 10% by weight of water, and the hygroscopic polymers absorb more than 20% by weight of water.A polymer "that expands in water" is one that absorbs an amount of water greater than at least 25% by weight of its own weight, preferably at least 50% by weight, from the immersion in an aqueous medium. The term "crosslinked" herein refers to a composition that contains intramolecular and / or intermolecular crosslinks that arise from either covalent or non-covalent linkages. "Non-covalent" bonds include both hydrogen bond and electrostatic (ionic) bond. The term "polymer" includes homopolymers, linear and branched polymer structures, and also encompasses crosslinked polymers as well as well as copolymers (which may or may not be crosslinked), thus including block copolymers, alternating copolymers, random copolymers and the like. Those compounds referred to herein as "oligomers" are polymers having a molecular weight below about 1000 Da, preferably below about 800 Da. The term "water insoluble" refers to a polymer, compound or composition whose solubility in water is less than 5% by weight, preferably less than 3% by weight, more preferably less than 1% by weight (measured in water at a temperature of 20 ° C). The term "hydrogel" is used in the conventional sense to refer to polymer matrices that are dilated in water that can absorb a substantial amount of water to form elastic gels, where "matrices" are three-dimensional networks of macromolecules held together by covalent crosslinks and not covalent. During placement in an aqueous environment, wet gels dilate to the extent allowed by the degree of crosslinking. The term "hydrogel composition" refers to a composition that either contains a hydrogel or is wholly composed of a hydrogel. As such, "hydrogel compositions" encompass not only hydrogels per se, but also compositions comprising a hydrogel and one or more non-hydrogel components or compositions, for example, hydrocolloids, which contain a hydrophilic component (which may contain or be a hydrogel) distributed in a hydrophobic phase. The terms "stuck" and "sticky" are qualitative. However, the terms "substantially non-sticky", "slightly sticky" and "sticky" as used herein can be quantified using the values obtained in a PKI bond determination, a TRBT bond determination, or a glued PS / Poliken Probe (Solutia, Inc.). The term "substantially non-sticky" means a hydrogel composition having a tack value that is less than about 25 g-cm / sec, "slightly sticky" means a hydrogel composition having a bond value within the range of from about 25 g-cm / sec to about 100 g-cm / sec, and "sticking" means a hydrogel composition having a bond value of at least 100 g-cm / sec. The term "pressure sensitive adhesive" (PSA) refers to polymeric materials, which form a strong adhesive bond to any surface with the application of a very small external pressure for a short period of time (eg, 1 to 5 seconds). The term "bioadhesive" means a hydrogel that exhibits a pressure sensitive adhesion character towards highly hydrated biological surfaces such as mucosal tissue. The term "complex" or "interpolymeric complex" refers to the association of macromolecules of two or more complementary polymers that they are formed as a result of favorable interactions between their macromolecules. In general, the interpolymeric complex between the film-forming polymer, the stair-like cross-linker and the shell-like crosslinker is formed by the hydrogen bond, electrostatic bond, ionic bond or a combination thereof. The term "stair-like" defines the complex or mechanism of complex formation that leads to the association of complementary macromolecules, wherein the specific interaction occurs between the complementary functional groups in the repeating units of the polymeric axes. Due to entropic reasons, the functional groups are linked together, not separately but in a cooperative way, thus forming relatively short and resistant link sequences. The schematic structure of this complex shown in Figure 2 resembles a ladder. The term "shell-like" defines the complex or mechanism of complex formation that leads to the association of the complementary macromolecule and the oligomeric chains, wherein the specific interaction occurs between the complementary functional groups in the repeating units of the the longer polymer chain and the reactive groups at both ends of the shorter oligomeric chain. In contrast to the ladder-like complex, the term "shell-like" emphasizes that the cross-links between the longer polymer chains are of appreciable length and the density of the network formed in this way is much smaller, as shown schematically in Figure 1. Complexes that are both ladder-like and shell-like are cross-linked due to the specific interactions between the reaction groups in the complementary macromolecules and thus represent "networks". In the context of the present invention, the term "network" is used interchangeably with the term "complex", although they refer more specifically to the supermolecular structure of the interpolymer complex, as shown schematically in Figure 3. The "active agent", "pharmacologically active agent" and "drug" are used interchangeably herein to refer to a material or chemical compound that induces a desired pharmacological or physiological effect, and includes agents that are therapeutically effective, prophylactically effective or cosmetically effective.The terms also cover acceptable pharmacist, pharmacologically active derivatives and analogs of those active agents specifically mentioned in the present disclosure, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, inclusion complexes, analogs and the like. When the terms "active agent", "pharmacologically active agent" and "drug" are used, it should be understood that both active agents per se, as well as salts, esters, amides, prodrugs, active metabolites, inclusion complexes are included. , pharmaceutically acceptable, pharmacologically active analogs, etc.

The term "effective amount" or "a cosmetically effective amount" of a cosmetically active agent means a non-toxic but sufficient amount of a cosmetically active agent to provide the desired cosmetic effect. The term "effective amount" or "a therapeutically effective amount" of a pharmacologically active drug or agent is intended to mean a non-toxic but sufficient amount of the drug or agent to provide the desired therapeutic effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Therefore, it is not always possible to specify an exact "effective amount". However, an "effective" amount suitable in any individual case can be determined by a person skilled in the art who uses routine experimentation. Additionally, the exact "effective" amount of the active agent incorporated in a composition or dosage form of the present invention is not critical, as long as the concentration is within a sufficient range to allow easy application of the formulation in such a manner that administer an amount of the active agent that is within a therapeutically effective range. The term "transdermal" drug administration means the administration of an active agent to the skin or mucosa of an individual, such that the drug passes through the tissue of the skin and into the bloodstream of the individual. Unless otherwise indicated, the term "transdermal" is intended to include drug administration "intramucosal", that is, the administration of a drug to the mucosal surface (eg, sublingual, buccal, vaginal, rectal, urethral) of an individual such that the drug passes through the mucosal tissue and into the blood flow of the individual. The term "topical administration" is used in its conventional sense to mean administration of an active agent to a body surface, such as skin or mucosa, as in, for example, topical administration of the drug in the prevention or treatment of various conditions. of the skin, the application of cosmetics (including humectants, masks, sunscreens, etc.), and the like, topical administration, in contrast to transdermal administration, provides a local effect instead of a systemic effect. The term "surface" or "body surface" is used to refer to any surface located on the human body or within a body orifice. Therefore, a "body surface" includes, by way of example, teeth, skin or mucous tissue, which includes the inner surface of the body cavities that have a mucosal lining. Unless indicated otherwise, the term "skin" as used herein should be construed as including mucosal tissue and vice versa. Similarly, when the term transdermal is used herein, as in "transdermal drug administration" and "transdermal drug delivery systems," it will be understood that unless explicitly stated otherwise, both administration " transmucosal "and" topical "and systems have the same intention.

Main Compositions of Adhesive Compositions It is desirable to obtain water-swelling, hydrophilic adhesive compositions (adhesive hydrogels) which have the ability to form homogeneous films either by pouring a solution into the support layer followed by drying, or under external pressure or by means of extrusion. Preferably, said compositions are also insoluble in water. The ability to form films is optimal when the mixture is free of covalent crosslinks. The specific polymers of mixture provide a convenient way to obtain composite materials with properties achieved in a specific way, because the properties of the mixture are usually intermediate between those of the unmixed components when the components are immiscible or partially miscible. In order to make the water-insoluble compound, water-insoluble materials are usually mixed with water-soluble materials. However, when this is done, phase separation that does not favor adhesion can often occur. Additionally, the insolubility of the components of the mixture can interfere with the mixing preparation process, which often involves the dissolution of all the components in a common solvent, followed by the melting of the solution and drying. The preparation of polymeric composite materials, those Properties that are new and not typical of individual components require a high degree of skill. This challenge can be solved if the individual blend components have the capacity for strong favorable interactions with each other. Normally, this interaction is due to the hydrogen, electrostatic or ionic bond. In this case, mixing the two or more soluble polymers provides a ladder-like complex, shown schematically in Figure 2 which can be dilated, although it is insoluble or partially insoluble. In order to solve these problems, the present invention is directed to a method for obtaining water-insoluble film-forming compositions by mixing the soluble polymers, more specifically by mixing the hydrophilic polymers with the complementary macromolecules having the hydrogen, electrostatic or hydrogen bonding ability. ionic bond. At least one component of the mixture is a film-forming polymer, at least one component of the mixture is a non-covalent crosslinker similar to a ladder of the film-forming polymer, and at least one component of the mixture is a non-crosslinker. covalent similar to film-forming polymer shell. The key to the present invention is that the film-forming polymer is present in a higher concentration than any of the crosslinkers. This concentration is what determines the film forming characteristics. Therefore, although there may be materials that are suitable to be used either as the film-forming polymer or as the crosslinker Non-covalent similar to staircase, its function and role in the composition will be determined by the amount of material present in the composition. For example, polyacids, such as acrylate polymers that support carboxyl proton donor functional groups or polyols that support hydroxyl proton donor functional groups and proton accepting polymers, such as poly (N-vinyl lactam) -forming polymers or polyamines are suitable for use both as the film-forming polymer as well as the non-covalent, ladder-like crosslinker. In a composition having a higher amount of an acrylate or other proton donor polymer in relation to the amount of poly (N-vinyl lactam), the acrylate polymer serves as the film-forming polymer and the poly (N-vinyl lactam) or polyamine or another polymer that accepts protons serves as the stair-like crosslinker. Similarly, in a composition having a higher amount of poly (N-vinyl lactam) or polyamine in relation to the amount of an acrylate polymer, the poly (N-vinyl lactam) or polyamine serves as the film-forming polymer and the acrylate polymer serves as the stair-like crosslinker. Therefore, one embodiment of the present invention is a method for selecting polymeric components for use in an adhesive composition. The method involves first selecting a film-forming polymer. Then, the non-covalent crosslinker similar to ladder is selected in such a way that (1) contains complementary reactive functional groups in the repeating units of the axis, and (2) tione the ability to form an interpolymeric stair-like complex with the selected film-forming polymer. Finally, a carcass-like non-covalent crosslinker is selected such that (1) contains complementary reactive functional groups at its ends, and (2) has the ability to form a carcass-like complex with at least one of the parent-forming polymer. selected film or non-covalent crosslinker similar to selected stair. The non-covalent, shell-like crosslinker is preferably compatible or at least partially compatible with both the film-forming polymer and the non-covalent, ladder-like crosslinker. The method involves not only the material selections mentioned above, although it also involves selecting the quantities of materials used. In particular, the amount of the film-forming polymer is greater than the amount of the non-covalent, ladder-like crosslinker or the amount of the non-covalent, shell-like crosslinker. The method may also comprise the steps of selecting one or more non-covalent lattice-like crosslinkers and / or selecting one or more shell-like non-covalent crosslinkers. Said additional crosslinkers will be selected based on the same criterion or a similar criterion as the first crosslinkers, ie, complement capacity and ability to form the desired complex. Typically, the composition will contain a film-forming polymer, although it may contain more than one ladder-like crosslinker and / or more than one shell-like crosslinker.

The adhesion profile of the water-insoluble film-forming compositions of the present invention can be achieved based on the materials, the proportion of composition and the amount of water in the mixture. The ladder-like crosslinker and its ratio to the amount of film-forming polymer is selected such that it provides the desired adhesion profile with respect to hydration. Generally, compositions that are relatively lightly crosslinked through the comparative loss of hydrogen bonds and demonstrate a large free volume, provide an initial bond in the dry state. As the degree of crosslinking of cohesion strength of the network in the interpolymeric complex moves above some critical value, the cohesion energy dominates under the free volume and said compositions are regularly non-sticky in the dry state. However, as the free volume in this mixture increases, adhesion immediately appears. Because water is a good plasticizer for hydrophilic polymers, the absorption of water can lead to improved adhesion. Because the electrostatic bonds are appreciably stronger than the hydrogens, the cohesion in polymer blends that support carboxyl groups is usually higher than in materials made from polymers having hydroxyl groups. The adhesion in said mixtures appears below the highest concentration of water absorbed. Flexible polymers provide a higher cohesion than polymers with rigid chains. As an example, for mixtures of PVP such as film-forming polymer, when the ladder-like crosslinker is a rigid chain cellulose ester that supports OH or cellulose groups, the composition is generally sticky before contact with water (e.g., on a wet surface) although it gradually loses sticking as the composition absorbs moisture. When the ladder-like crosslinker is an acrylate polymer or copolymer with carboxylic groups, a composition is provided in such a way that it is generally not substantially tacky before contact with water, although it becomes sticky from contact with a wet surface.

Film-forming polymers Film-forming polymers are present in the adhesive composition at a concentration higher than the amount of the ladder-like crosslinker or the amount of the shell-like crosslinker and provide film-forming properties. Typically, the amount of the film-forming polymer will vary from about 20 to 95% by weight of the composition, while the amount of the ladder-like crosslinker will vary from about 0.5 to 40% by weight and the amount of the shell-like crosslinker. It will vary from approximately 0.5 to 60% by weight. The balance of the composition can be achieved from components such as plasticizers and tackifiers, water or other solvents, active agents, pH regulators and so on, as described below.

Typically, the film-forming polymers are polymers of relatively high molecular weight and will have a molecular weight in the range of from about 20,000 to 3,000,000, preferably in the range of 100,000 to 2,000,000, more typically in the range of 500,000 to 1,500,000. The film-forming polymer has the ability to form hydrogenous or electrostatic bonds with the functional repeat units of the ladder-like crosslinker and the terminal functional groups of the shell-like crosslinker. Suitable film-forming polymers include, by way of illustration and not limitation, hydrophilic polymers, water-insoluble polymers that dilate with water, water-soluble polymers, hydrophilic and hydrophobic monomeric copolymers, and combinations thereof.

Hydrophilic Polymers Synthetic hydrophilic polymers of examples include, by way of illustration and not limitation, poly (dialkyl aminoalkyl acrylates), poly (dialkyl aminoalkyl methacrylates), polyamines, polyvinylamines, poly (alkylene imines), substituted and unsubstituted polymeric acids and polymers of methacrylic acid such as polyacrylic acids (PAAs) or polymethacrylic acids (PMAs), polymaleic acids, polysuiphonic acids, poly (N-vinyl lactams), polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates) ), poly (N-vinyl acrylamides), poly (N-) alkyl acrylamides), homopolymers, copolymers, and combinations thereof, as well as copolymers with other types of hydrophilic monomers (e.g., vinyl acetate). Exemplary natural hydrophilic polymers include, by way of illustration and not limitation, polar cellulose derivatives containing hydroxyl and carboxyl groups, such as carboxymethylcellulose and hydroxypropylmethylcellulose phthalate, alginic acid, chitosan and gelatin. Preferred hydrophilic film-forming polymers are synthetic polymers and include poly (dialkyl aminoalkyl acrylates); poly (dialkyl aminoalkyl methacrylates); polyacrylic acids; polymethacrylic acids; polymaleic acids; polyvinylamines; poly (N-vinyl lactams) such as poly (N-vinyl pyrrolidone) (e.g., poly (N-vinyl-2-pyrrolidone)), poly (N-vinyl-2-valerolactam), and poly (N-vinyl caprolactam) ) (e.g., poly (N-vinyl-2-caprolactam)); polyalkylene oxides such as polyethylene oxide (PEO) and polypropylene oxide; polyvinyl alcohols; polyvinyl phenols; and poly (hydroxyalkyl acrylates) such as poly (hydroxyethyl methacrylate) (PolyHEMA), poly (hydroxyethyl acrylate), and copolymers thereof. Other suitable hydrophilic polymers include the repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a maleic acid monomer, a dialkyl aminoalkyl acrylate or a dialkylaminoalkyl methacrylate monomer, an ethylene oxide monomer, a monomer of vinyl ester, an ester of a carboxyvinyl monomer, a vinylamide monomer and / or a hydroxyvinyl monomer.

Such polymers include, for example, polyvinylamine, polyacrylic acids, polymethacrylic acids, polymaleic acids, film-forming polymer (N-vinyl lactams), film-forming polymer (N-vinyl acrylamides), film-forming polymer (N-alkyl acrylamides). ), polyethylene oxides, polyvinyl alcohols and polyvinyl phenol. The poly (N-vinyl lactams) useful herein are preferably non-crosslinked homopolymers and copolymers of N-vinyl lactam monomer units, with monomeric N-vinyl lactam units representing most of the total monomer units of a N-vinyl lactam copolymer. poly (N-vinyl lactams). Poly (N-vinyl lactams) for use in conjunction with the present invention are prepared by polymerization of one or more of the following N-vinyl lactam monomers: N-vinyl-2-pyrrolidone; N-vinyl-2-valerolactam; and N-vinyl-2-caprolactam. Non-limiting examples of non-N-vinyl lactam comonomers useful with monomeric N-vinyl lactam units include N, N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethylacrylate, acrylamide, 2-acrylamido-2-methyl- 1-propane sulfonic acid or its salt or vinyl acetate. Poly (N-acrylamides) include, by way of example, poly (methacrylamide) and poly (N-isopropyl acrylamide) (PNIPAM). Polymers of carboxyvinyl monomers are usually formed from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride or mixtures thereof, with preferred hydrophilic polymers within this class include polyacrylic acid and polymethacrylic acid, with polyacrylic acid being more preferred. The preferred hydrophilic polymers herein are the following: poly (N-vinyl lactams), particularly poly (N-vinyl pyrrolidone) (PVP) and poly (N-vinyl caprolactam) (PVCap); poly (N-vinyl acetamides), particularly polyacetamide per se; monomeric carboxyvinyl polymers, particularly polyacrylic acid and polymethacrylic acid, polymaleic acids; and copolymers and mixtures thereof. PVP and PVCAP are particularly preferred.

Water-Insoluble Polymers That Dilate in Water Water-insoluble polymers that dilate in example water include, by way of illustration and not limitation, cellulose derivatives, such as cellulose esters and acrylate-based polymers and copolymers, as well as as also combinations thereof. The water-insoluble polymer that expands in water has the ability to at least some degree of expansion when immersed in an aqueous liquid, although it is not soluble in water. The polymer can be comprised of a cellulose ester, for example, cellulose acetate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP), cellulose butyrate (CB), cellulose propionate butyrate (CPB), diacetate of cellulose (CDA), cellulose triacetate (CTA) and the like, these cellulose esters are described in the patents of E.U.A. Nos. 1, 698,049, 1, 683,347, 1, 880,808, 1, 880,560, 1, 984,147, 2,129,052, and 3,617,201, and can be prepared using the techniques known in the art or can be obtained commercially. Commercially available cellulose esters suitable herein include CA 320, CA 398, CAB 381, CAB 551, CAB 553, CAP 482, CAP 504, all available from Eastman Chemical Company, Kingsport, Tenn. Said cellulose esters usually have an average molecular weight number between about 10m000 and about 75,000. Generally, the cellulose ester comprises a mixture of cellulose and monomer units of cellulose ester; for example, commercially available cellulose acetate butyrate contains cellulose acetate monomer units, as well as cellulose butyrate monomer units and unesterified cellulose monomer units, while cellulose acetate propionate contains monomer units, such as cellulose propionate. Preferred cellulose esters herein are cellulose acetate propionate compositions and cellulose acetate butyrate compositions having butyryl, propionyl, acetyl and unesterified cellulose content as indicated below The preferred molecular weight, glass transition temperature (Tg) and melting temperature (Tm) are also indicated. Also, suitable cellulosic polymers typically have an inherent viscosity (IV) of about 0.2 to about 3.0 deciliters / grams, preferably about 1 to about 1.6 deciliters / gram, as measured at a temperature of 25 ° C for a sample of 0.5. grams in 100 ml of a 60/40 solution by weight of the phenyl / tetrachloroethane solution. When prepared using a solvent melt technique, the water-insoluble polymer, which expands in water, must be selected to provide greater cohesive strength and thus facilitates film formation (generally, for example, acetate propionate). of cellulose tends to improve the cohesive strength to a greater degree than cellulose acetate butyrate). Other cellulose derivatives include cellulosic polymers containing monomeric units of hydroxyalkyl cellulose or carboxy alkyl cellulose. Other preferred water-insoluble polymers that dilate in water with the acrylate-based polymers and copoylmers, formed generally from acrylic acid, methacrylic acid, methylacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and / or other vinyl monomers. Several of these were previously classified as hydrophilic polymers. Suitable acrylate polymers are those copolymers available under the tradename "Eudragit" from Rohm Pharma (Germany). The series of copolymers Eudragit® E, L, S, RL, RS and NE are available solubilized in organic solvent, in an aqueous dispersion or as a dry powder. Acrylate polymers are copolymers of methacrylic acid and methacrylate, such as the series of polymers Eudragit L and Eudragit S. the particularly preferred copolymers are, Eudragit L 30D-55 and Eudragit L 100-55 (the last copolymer is a dry form of dew of Eudragit L 30D-55 that can be reconstituted with water). The molecular weight of the copolymers of Eudragit L 30D-55 and Eudragit L 100-55 is about 135,000 Da, with a ratio of free carboxyl groups to ester groups of about 1: 1. The Eudragit L 100-55 copolymer is generally insoluble in aqueous fluids having a pH below 5.5. Another methacrylic acid-methyl methacrylate copolymer is Eudragit S 100, which differs from Eudragit L 30D-55 in that the ratio of free carboxyl groups to ester groups is about 1: 2. Eudragit S 100 is insoluble at a pH below 5.5, although unlike Eudragit L 30D-55, it is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7.0. This copolymer is soluble at a pH of 7.0 and higher. Eudragit L 100 can also be used, which has a solubility profile pH dependent between that of Eudragit L 30D-55 and Eudragit and Eudragit S 100, insofar as it is insoluble at a pH below 6.0. Those skilled in the art will appreciate that Eudragit L 30D-55, L 100-55, L 100, and S 100 can be replaced with other acceptable polymers that have similar pH-dependent solubility characteristics. Other suitable acrylate polymers are those methacrylic acid / ethyl acrylate copolymers available under the tradename "Kollicoat" from BASF AG (Germany). For example, Kollicoat MAE has the same molecular structure as Eudragit L 100-55. When the water-insoluble polymer that expands in water is an acrylic acid or acrylate polymer, a gel is provided that can be dried in reverse, ie, after the removal of water and any other solvents, the dry hydrogel can be rebuilt to its original state by adding water. Additionally, hydrophilic hydrogels prepared with an acrylic acid / polymers that swells in acrylate water, are generally substantially non-tacky prior to contact with water, although they become tacky from contact with a wet surface, such as the one that is inside the mouth, such as on the surface of the teeth. This property of being non-sticky prior to contact with water, makes it possible to place or reposition on a previously chosen surface, or as the hydrogel becomes sticky. For example, once hydrated, the hydrogel becomes sticky and may adhere to a surface such as a tooth or mucosal surface.

Additionally, acrylate-containing compositions generally can provide dilation within the range of from about 400% to 1500% from the immersion of the composition in water or other aqueous liquid at a pH of less than 5.5.-6.0, although the proportion of the acrylate polymer to the other materials can be selected in such a way that the index and extent of expansion in an aqueous environment has a predetermined pH dependence. This feature is also provided for the retroactive incorporation of bleaching agents or other active agents, such as charging the composition with peroxide, peroxy acids, chlorides, stabilizers, flavoring agents, etc. In contrast, by incorporating a cellulose ester as the water-insoluble polymer that can be dilated in water, the composition is converted to sticky prior to application to a wet, non-tacky surface from the absorption of water. It will be appreciated that such a composition may be desirable when a decrease in sticking is desired for the ultimate removal of the product from the teeth.

Water soluble polymers Exemplary water soluble polymers include, by way of illustration and not limitation, water soluble cellulose derivative polymers; homopolymer and copolymers of vinyl alcohols; homopolymers and copolymers of vinyl phenols; homopolymer and copolymers of oxides of ethylene; Homopolymers and copolymers of maleic acid; collagen; jelly; alginates; starches; and polysaccharides of natural occurrence, and combinations thereof. Polymers include Exemplary water soluble cellulose-derived polymers include, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, hydratecellulose (cellophane) and hydroxypropylmethylcellulose, and combinations thereof. Exemplary natural occurring polysaccharides include, agates of various origin, such as agar gum, alginates such as alginic acid, salts of alginic acid (eg, calcium alginate, potassium alginate, sodium alginate), and acid derivatives alginic (e.g., propylene glycol alginate, Kelcoloid®, Monsanto); carrageens including kappa-, iota- and lambda carrageens; chitin; chitosan; glucomannan; gellan gum (Kelcogel®, Monsanto); jelly; guar gum (TIC Gums); arabic gum; ghatti gum; karaya gum; tragacanth gum; carob gum; pectins such as pectin and amylopectin; pullulans; starches and starch derivatives, such as potato starch acetate, Clearam® CH10, Roquette; tamarind gum; xanthanes such as xanthan gum; and combinations thereof. Exemplary water-soluble maleic acid polymers include those available under the trade name Gantrez® from International Specialty Products. Gantrez® products are a family of synthetic copolymers of methyl vinyl ether and maleic anhydride. Gantrez. AN are copolymers of methyl vinyl ether and maleic anhydride. The Gantrez S series represents the copolymers of methyl vinyl ether and maleic acid such as Gantrez S-97. Gantrez ES is the maleic acid ester half-form and represents a range of copolymers methylvinyl ether and maleic acid with alkyls of different chain lengths and molecular weights. Therefore ES-225 and Gantrez ES-425 are monoethyl and monobutyl esters of the copolymers of methyl vinyl ether and maleic acid.

Non-covalent crosslinkers similar to ladder The non-covalent crosslinker similar to ladder of the film-forming polymer is preferably a long chain polymer containing complementary reactive functional groups in the repeating units of the axis, and has the ability to form an interpolymeric complex similar to ladder with hydrophilic high molecular weight film-forming polymer. This complex can be water soluble or insoluble in water, although it is preferably insoluble in water. One function of the stair-like reticulator is to provide insolubility and limited expansion to the mixture. In essence, the ladder-like crosslinker can serve as a gel-forming agent. Suitable complementary reactive functional groups for the ladder-like crosslinker include hydroxyl, carboxyl, phenolic, sulfa and amino groups, all of which have the ability to crosslink in non-covalent form the hydrophilic polymer mixture. Normally, these polymers will have a length in the range of from about 10,000 to 1,000,000 g / mol, optimally from 100,000 to 300,000 g / mol. It may be desirable to select a ladder-like crosslinker having a lower molecular weight than that of the film-forming polymer. Exemplary long chain polymers suitable for use as the ladder-like crosslinker include, by way of illustration and not limitation, hydrophilic polymers, water-insoluble polymers that can be dilated in water, and water-soluble polymers, such as those they were previously described for use as a film-forming polymer. As noted above, the same materials can be used either as the film-forming polymer or as the non-covalent stair-like crosslinker, because both the film-forming polymer and the non-covalent, ladder-like cross-linker represent the same class of polymers, which support reactive groups, with the capacity of hydrogen bonding, electrostatic or ionic, in the repetition units of the polymeric axis. Their function and role in the composition will be determined by the amount of material present in the composition, in which the material present in the larger amount functions as the film-forming polymer, i.e., the difference between the film-forming polymer and the crosslinker Similar to ladder is a matter of your concentration. The predominant component is usually referred to as the film-forming polymer, while the minor component is referred to as the non-covalent crosslinker similar to ladder. Therefore, for the purposes of the present invention, it is not critical which polymer serves as the main film-forming polymer and which serves as the non-covalent, ladder-like crosslinker. However, the complement of the film-forming polymer and non-covalent, ladder-like crosslinker is an important aspect of the present invention. A list of exemplary functional groups and the types of bonds for the film-forming polymer and the non-covalent, ladder-like crosslinker are presented below. A distinctive feature of hydrogen bonding between complementary groups that donate protons and accept protons is that both reactive groups and the product of their interaction do not support electrical charge. The electrostatic bond is the interaction of groups that donate protons and accept protons, which initially are not charged, with the formation of the ionic bond. And ultimately, the ionic bond is the interaction of groups of opposite charge with the formation of the ionic bond.

-R and -Ph represent alkyl or phenyl radicals, respectively. The composition may also contain a second non-covalent, ladder-like crosslinker. As the first similar crosslinker of non-covalent crosslinker similar to ladder, the second ladder-like crosslinker also contains complementary reactive functional groups in the repeating units of the axis. However, the second stair-like cross-linker has the ability to form an interpolymeric stair-like complex with the film-forming polymer or the first stair-like cross-linker.

Non-covalent, shell-like crosslinkers The non-covalent, shell-like crosslinker preferably contains complementary reactive functional groups at its ends, and has the ability to form a shell-like complex with at least one film-forming polymer or the similar non-covalent crosslinker. to stairs. Normally, the non-covalent, shell-like crosslinker is a hydrophilic oligomer with reactive groups at both ends of its short chain. One function of the shell-like crosslinker is to impart the adhesive properties to the hydrophilic polymer mixture. Suitable complementary reactive functional groups for the shell-like crosslinker include hydroxyl, carboxyl and amino groups, all of which have the ability to crosslink non-covalently the hydrophilic polymer mixture. Preferably, the non-covalent, shell-like crosslinker is terminated with hydroxyl, amino or carboxyl groups. Generally, the non-covalent, shell-like crosslinker will have a molecular weight in the range of from about 45 to about 800, preferably in the range of from about 45 to about 600. Example shell-like crosslinkers include, by way of illustration and not limitation, alkylenglycols monomeric and oligomeric comprising about 1 to 20 alkylene oxide units, in their chains such as polyalkylene glycols (for example, ethylene glycol, 1,2-propylene glycol (PG) and polyethylene glycol), which includes oligomeric carboxyl terminated alkylene glycols, such as carboxyl-terminated polyalkylene glycols and oligomeric amino-terminated alkylenglycols, such as amino-terminated polyalkylene glycols; polyalcohols such as low molecular kiss polyhydric alcohols (for example, glycerol or sorbitol); alkanediols of butanediol to octanediol; carbonic diacids; ether alcohols (eg, glycol ethers); and poly (alkylene glycol diacids). Preferred carcass-like crosslinkers are oligoalkylene glycols, such as polyethylene glycol (PEG), carboxyl-terminated oligo-alkylene glycols such as carboxyl-terminated poly (ethylene glycols), and polyhydric alcohols. Particularly preferred crosslinkers are polyalkylene glycols of low molecular weight (molecular weight 200 to 600) such as polyethylene glycol 400. The shell-like crosslinker can also serve as a low molecular weight plasticizer, for example, when the shell-like crosslinker is a compound such as polyethylene glycol 400. Said shell-like crosslinker plasticizers could preferably be miscible with the other components and have the ability to lower the glass transition temperature (Tg) and the modulus of elasticity of the composition. Alternatively, a different compound may be included as the low molecular weight plasticizer. The non-covalent, shell-like crosslinker typically has a glass transition temperature Tg in the range from about a temperature of -100 ° C to about a temperature of -30 ° C and a melting temperature Tm less than about a temperature of 20 ° C. The non-covalent, shell-like crosslinker can also be amorphous. The difference between the Tg values of the film-forming polymer and the non-covalent, shell-like crosslinker, the Tg value of the carcass-like non-covalent crosslinker is preferably a temperature greater than about 50 ° C, more preferably higher than a temperature of about 100 ° C, and more preferably within the range of a temperature from about 150 ° C to about 300 ° C. The film-forming polymer, the non-covalent, ladder-like crosslinker and the non-covalent, shell-like crosslinker must be compatible, that is, have the ability to form a homogeneous mixture. As it was raised in the Patent Application of E.U.A. Do not. 2002/0037977 for Feldstein et al., The proportion of the non-covalent crosslinker similar to carcass to the other components of the composition can affect both the adhesion strength and the cohesive force. For example, the carcass-like non-covalent crosslinker decreases the glass transition of the non-covalent film-forming polymer / carcass-like crosslinker mixture to a degree greater than that predicted by the Fox equation, which is obtained by the equation ( I) Where Tc is the glass transition temperature of the mixture, wpa is the weight fraction of the film-forming polymer in the mixture, wpi is the weight fraction of the non-covalent crosslinker similar to carcass in the mixture, tg poi is the glass transition temperature of the film-forming polymer, Ta p \ is the glass transition temperature of the carcass-like non-covalent crosslinker. As also explained in that patent application, an adhesive composition having optimized adhesion and cohesion strength can be prepared by selecting the film-forming polymer and the carcass-like non-covalent crosslinker, and their relative amounts to produce a previously determined deviation of Predicted Tg - Generally, to maximize adhesion, the previously determined deviation of expected Tg will be the maximum negative deviation, while to minimize adhesion, any expected negative deviation of Tg is minimized.

As noted above, the composition may also contain a second non-covalent, stair-like crosslinker having the ability to form a stair-like interpolymer complex with the film-forming polymer or the first stair-like cross-linker. When a second ladder-like crosslinker is included, the non-covalent, shell-like crosslinker may also have the ability to form a shell-like complex with the second ladder-like crosslinker. For example, an acrylate polymer (Eudragit E 100) can be selected as the film-forming polymer. The first stair-like cross-linker can be Eudragit L-100-55, which forms an interpolymeric stair-like complex with the film-forming polymer Eudragit E 100. The second stair-like cross-linker can be PVP, which forms an interpolymeric complex similar to staircase with the first Eudragit L-100-55 stair-like reticulator. The carcass-like crosslinker can be PEG, which forms a carcass-like complex with the second ladder-like crosslinker PVP.

Exemplary adhesive compositions An illustrative composition includes poly (N-vinyl-2-pyrrolidone) ("PVP") as the film-forming polymer and polyethylene glycol ("PEG") as the non-covalent, shell-like crosslinker. By mixing a PVP-PEG adhesive mixture with a non-covalent, stair-like crosslinker that is moderately hydrophilic or a water-insoluble polymer, it is The result is a decrease in the hydrophilicity of the mixture and the indicator of dissolution. In order to decrease the rate of dissolution further or to obtain insoluble mixtures, the PVP-PEG mixture can be mixed with polymers that support complementary reactive functional groups (with respect to PVP) in their repeating units. Because PVP contains carbonyl groups that accept protons in their repeating units, the complementary functional groups are preferably proton donor hydroxyl or carbonyl groups. Therefore, for use with PVP and PEG, suitable non-covalent crosslinkers similar to ladders are long chain polymers such as polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, polymaleic acids, homo and copolymers thereof, as well as sulfonic acid and alginic acid. Another illustrative composition utilizes a copolymer of methacrylic acid and methyl methacrylate as the non-covalent, ladder-like crosslinker with the PVP-PEG observed above. This composition is used to facilitate the understanding of the principles of the present invention. The PVP-PEG complex combines high cohesive strength (due to the H bond of PVP-PEG) with a large free volume (resulting from the considerable length and flexibility of the PEG chains). In order to emphasize the improved free volume in the PVP-PEG mix, this type of complex structure is defined as a "shell-like" structure (see Figure 1). The shell-like structure of the complex results from the location of the reactive functional groups at both ends of the short PEG chains. When the non-covalent, ladder-like crosslinker contains reactive functional groups in the repeating units of the axis, the resulting complex has the structure referred to as "stair-like" (see Figure 2). The ladder-like type of interpolymer rich complexes was first described by Kabanov et al. (1979) Vysokomol. Soed. 21 (A): 243-281). While the formation of the shell-like complex leads to an improved cohesion force and free volume (which determines the adhesive properties of the PVP-PEG mixtures), the formation of the stair-like complex shown in Figure 2 is accompanied by the loss of solubility of the mixture and the increase of the cohesion force coupled with the decrease in free volume. For this reason, the structure of the ladder-like complex does not provide adhesion. Due to the decrease in the free volume and the increase in the cohesion energy, the PVP-PEG mixture mixed with a long chain polymer results in the PVP-like ladder complex not providing initial bonding or this being insignificant. However, since the non-adhesive PVP-PEG blend with the long-chain polymer is plasticized by water, the glass transition temperature of the mixture changes to lower values, which are typically characteristic of pressure-sensitive adhesives. , and adhesion develops. There are certain preferred combinations of components in the adhesive composition. For example, when the film-forming polymer is a poly (N-vinyl lactam), such as poly (N-vinyl pyrrolidone) or poly (N-vinyl caprolactam), the ladder-like crosslinker preferably is polyacrylic acid, polymethacrylic acid, polymaleic acid, polyvinyl alcohol, poly (hydroxyalkyl acrylate); poly (hydroxyalkyl methacrylate), such as poly (hydroxyethyl methacrylate), methacrylic acid copolymer or any other carboxyl-containing Eudragit. Similarly, when the film-forming polymer is poly (dialkyl aminoalkyl acrylate) or poly (dialkyl aminoalkyl methacrylate), then the ladder-like crosslinker is usually a hydroxyl containing the polymer, such as polyacrylic acid, polymethacrylic acid or polymaleic acid . When the film-forming polymer is a polyvinyl alcohol, polyvinyl phenol or poly (hydroxyalkyl acrylate) such as poly (hydroxyethyl methacrylate) the ladder-like crosslinker is preferably poly (N-vinyl lactam) such as poly (N-vinyl pyrrolidone) or poly (N-vinyl caprolactam), as well as a homopolymer or copolymer of polyacrylic, polymethacrylic or polymaleic acid. When the film-forming polymer is polyethylene oxide, then the ladder-like crosslinkers are polyacids such as homopolymers and copolymers of acrylic, methacrylic and maleic acids. Copolymers of poly (N-dialkylamino alkyl acrylate) with monomeric alkyl acrylate, methacrylate or ethacrylate, a copolymer of poly (N-dialkylamino alkyl methacrylate) and monomeric alkyl acrylate, methacrylate or ethacrylate can be used in place of the homopolymers, as film-forming polymers or as ladder-like crosslinkers. For any of the combinations mentioned above, a carcass-like crosslinker is an oligomeric alkylene glycol comprising about 1 to 20 alkylene oxide units in its chain, such as polyethylene glycol, carboxyl-terminated oligomeric alkyl glycol such as poly (ethylene glycol) terminated at carboxyl, or polyhydric alcohols. Other examples of suitable mixtures are shown below: Eudragit E-100 is a copolymer of 2-dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate 2: 1: 1, commercially available from Rohm Pharma Polymers. As described in the patent of E.U.A. No. 6,576,712 To illustrate the method used in the present description, a mixture of PVP-PEG-Eudragit was used as a typical example, although the method is general and can easily be reproduced using other hydrophilic water-soluble polymers. The properties of the adhesive polymer blends were evaluated and are established in the examples. The behavior of these polymer blends was found to be typical of covalently crosslinked polymers. However, in contrast to covalently crosslinked systems, triple polymer blends that combine the shell-like and ladder-like non-covalent crosslinker can be easily prepared using a simple procedure, and additionally, provide film-forming properties that are unattainable using chemically crosslinked polymers. Another exemplary composition comprises: a film-forming polymer selected from water-insoluble polymers that dilate in water and water-soluble polymers; a non-covalent, ladder-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form an interpolymeric stair-like complex with the film-forming polymer; and a shell-like non-covalent crosslinker containing reactive functional groups at its ends, and has the ability to form a shell-like complex with at least one film-forming polymer or the crosslinker no covalent similar to ladder. The amount of the film-forming polymer is greater than the amount of any of the crosslinkers.

OPTIONAL COMPONENTS OF ADHESIVE COMPOSITIONS The adhesive compositions of the present invention are useful in any number of additional contexts, where the adhesion of a product to a body surface is required or desirable. These applications include, for example, drug delivery systems; wound coatings; conductive hydrogels; cushions that release pressure for application to a foot, which includes cushioning for heels, cushion for elbows, cushion for knees, cushion for forearm, hip cushion, cushion for fingers, cushion for corn, cushion for calluses, cushioning of blisters, cushioning for bunions and cushioning for toes, all of which may include active agents for the treatment of dicubitis, ulcers on the venous and diabetic feet and the like; intraoral applications, such as teeth whitening bands, breath freshening films for the treatment of halitosis, and oral care products for treating sore throat, mouth ulcers / canker irritation, gingivitis, periodontal and oral infections, periodontal lesions, decay or dental deterioration and other periodontal diseases; transmucosal applications, adhesives to fix medical devices, systems diagnosis and other devices to be fixed to a body surface; senators for ostomy devices, prosthetics and face masks, sound absorbing materials, vibration and impact; vehicles in cosmetic and cosmetic gel products; as well as many other known uses or already can be verified by those experts in the field, or not yet discovered. Depending on the particular intended use, there are numerous components that can be incorporated into the composition or combined with the composition to form a patch, bandage or medical device. These are detailed below.

ACTIVE AGENTS Any of the presently described compositions can be modified such that they contain an active agent, and thus act as an active agent delivery system when applied to a body surface in relation to the transmission of the active agent thereto. The release of active agents charged into the compositions normally involves both the absorption of water and the desorption of the agent by means of a controlled diffusion diffusion mechanism. The compositions containing the active agent can be used, for example, in transdermal drug delivery systems, in wound coatings, in formulations topical pharmaceuticals, in implanted drug delivery systems, in oral dosage forms, in teeth whitening bands and the like. Such agents could be present in a cosmetically or therapeutically effective amount. Suitable active agents that can be incorporated into the present compositions and administered in topical or systemic form (eg, with a transdermal, oral, or other dosage form suitable for systemic administration of a drug) include, but are not limited to: adrenergic agents; Adrenocortical steroids; adrenocortical suppressors; agents that prevent the consumption of alcohol; aldosterone antagonists; amino acids; ammonia detoxifiers; anabolic agents; analeptic agents; analgesic agents; androgenic agents; anesthetic agents; Anorectic compounds; anorexic agents; antagonists; activators of the anterior pituitary and suppressors of the anterior pituitary; anti-acne agents; anti-adrenergic agents; anti-allergic agents; anti-amébic agents; anti-androgenic agents; anti-anemic agents; anti-anginal agents; anti-anxiety agents; anti-arthritic agents; anti-asthmatic agents and other respiratory drugs; anti-arteriosclerotic agents; anti-bacterial agents; anti-carcinogenic agents, including antineoplastic drugs and anticancer complementary enhancement agents; anti-cholinergic; anti-cholelithogenic agents; anti-coagulants; anti-coccidial agents; anti-convulsants; anti-depressants; anti-aging agents diabetics; anti-diarrheic; anti-diuretics; antidotes; anti-dyskinetic agents; anti-emetic agents; anti-epileptic agents; anti-estrogen agents; anti-fibrinolytic agents; anti-fungal agents; anti-glaucoma agents; anthelmintics; agents; Anti-hemophilic factor; anti-hemorrhagic agents; antihistamines; anti-hyperlipidemic agents; anti-hyperlipoproteinemic agents; anti-hypertensive agents; anti-hypotensive; anti-infective agents, such as antibiotics and antivirals; anti-inflammatory agents, both spheroidal and non-steroidal; agents anti-keratinization agents; anti-malaria agents; antibacterial agents; anti-migraine agents; anti-mitotic agents; anti-fungal agents; antinausea; antineoplastic agents; anti-neutropenic agents; anti-obsessive agents; anti-parasitic agents; antiparkinsonism drugs; anti-pneumocystic agents; anti-proliferative agents; anti-hypertrophy prostatic drugs; anti-protozoal agents; anti-pruritic; anti-psoriatic agents; anti-psychotic; antipyretics; antispasmodics; anti-rheumatic agents; anti-schistosomal agents; anti-seborrheic agents; antispasmodic agents; anti-tartar and anti-calculus agents; anti-thrombotic agents; anti-tubercular agents; antitussive agents; anti-ulcerative agents; anti-urolithic agents; antiviral agents; anxiolytics; appetite suppressants; drugs for attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); bacteriostatic and bactericidal agents; agents for benign prostatic hyperplasia therapy; blood glucose regulators; bone resorption inhibitors; bronchodilators; carbonic anhydrase inhibitors; cardiovascular preparations including anti-angina agents, anti-arrhythmic agents, beta-blockers, calcium channel blockers, cardiac depressants, cardiovascular agents, cardioprotectors, cardiotonic agents; agents for the central nervous system (CNS); stimulants for the central nervous system; choleretic agents; cholinergic agents; cholinergic agonists; cholinesterase deactivators; coccidiostatic agents; cognition adjuvants and cognition enhancers; cough and cold preparations, which include decongestants; depressants; diagnostic aids; diuretics; dopaminergic agents; ectoparasiticides; emetic agents; enzymes which inhibit the formation of plaque, calculus or dental caries; enzyme inhibitors; estrogen; fibrinolytic agents; anti-caries / anti-decay fluoride agents; oxygen free radical scavengers; gastrointestinal motility agents; genetic materials; glucocorticoids; stimulating principles of the gonad; stimulants for hair growth; hemostatic agents; herbal remedies; histamine H2 receptor antagonists; hormones; hormones; hypnotics; haemostatic hypocholesterolemic; hypoglycemic agents; hypolipidemic agents; hypotensive agents; HMGCoA reductase inhibitors; immunizing agents; immunomodulators; immunoregulators; immunostimulants; immunosuppressants; adjuncts for impotence therapy; inhibitors; keratolytic agents; leukotriene inhibitors; LHRH agonists; treatments for liver diseases; luteolysin agents; adjuvants of memory; mental performance enhancers; metal burners, such as ethylenediaminetetraacetic acid, tetrasodium salt; mitotic inhibitors; mood regulators; mucolytics; mucosal protective agents; muscle relaxants; mydriatic agents; narcotic antagonists; nasal decongestants; neuroleptic agents; neuromuscular blocking agents; neuroprotective agents; nicotine; NMDA antagonists; non-hormonal esteral derivatives; nutritional agents, such as vitamins, essential amino acids and fatty acids; ophthalmic drugs, such as antiglaucoma agents; oxytocic agents; pain relieving agents; parasympatholytics; peptide drugs; plasminogen activators; platelet activation factor antagonists; inhibitors of platelet accumulation; post-infarction treatment and subsequent brain trauma; enhancers; progestins; prostaglandins; inhibitors of prostate growth; proteolytic enzymes; agents to clean wounds; protirotropin agents; psychostimulants; psychotropic agents; radioactive agents; regulators; relaxing; re-distribution agents; scabicides; sclerosis agents; sedatives; sedative-hypnotic agents; selective adenosine A1 antagonists; serotonin antagonists; serotonin inhibitors; serotonin receptor antagonists; steroids, which include progestogens, estrogens, corticosteroids, androgens and anabolics; agents to stop smoking; stimulants; suppressors; sympathomimetics; synergistic hormones for the thyroid; thyroid inhibitors; thyromimetic agents; tranquilizers; agents to desensitize the teeth; teeth whitening agents such as peroxides, metal chlorides, perborates, percarbonates, peroxyacids, and combinations thereof; unstable angina agents; uricosuric agents; vasoconstrictors; vasodilators that include general, peripheral and cerebral coronaries; vulnerary agents; agents for wound healing; xanthine oxidase inhibitors and the like. Specific active agents with which the adhesive compositions present are useful, include, without limitation, anabasine, capsaicin, oxybutynin, isosorbide dinitrate, aminostigmine, nitroglycerin, verapamil, propranolol, silabolin, fondone, clonidine, cystisin, phenazepam, nifedipine, fluoacizin and salbutamol. The composition can also include any cosmetically active agent. As used herein, a "cosmetically active agent" includes any substance that can be released from the composition to effect a desired change in the appearance of the skin, teeth or surrounding tissue, or which imparts a socially desirable characteristic to the user. , such as fresh breath. For example, a cosmetically active agent can be a breath freshener or an agent which performs bleaching or discoloration of the teeth. Recognizing that in some cultures or certain segments of Western society, the coloring of the teeth can be significant or desirable, the cosmetically active agent can also be any agent, which imparts a color or has teeth.

OTHER INGREDIENTS The compositions made by the methods described herein may also comprise conventional additives, such as absorbent fillers, preservatives, pH regulators, plasticizers, softeners, thickening agents, antioxidants, pigments, dyes, conductive species, refractive particles, stabilizers. , resistance agents, bonding agents or adhesives, agents to eliminate sticking, flavoring and sweeteners, antioxidants and permeation improvers. In those modalities where the adhesion will be reduced or eliminated, the conventional bond eliminating agents can be used. These additives, and the amounts thereof, are selected in such a way that they do not interfere significantly with the desired chemical and physical properties of the hydrogel composition. Absorbent padding materials can be advantageously incorporated to control the degree of hydration when the adhesive is on the skin or other body surface. Such fillers may include microcrystalline cellulosetalc, clay, lactose, guar gum, kaolin, manityl, colloidal silica, alumina, zinc oxide, titanium oxide, magnesium silicate, magnesium aluminum silicate, hydrophobic starch, calcium sulfate, calcium stearate, phosphate calcium, calcium phosphate dihydrate and woven paper, non-woven and cotton materials. Other suitable fillers are inert, i.e., substantially non-absorbent, and they include, for example, polyethylenes, polypropylenes, polyether polyurethane amide copolymers, polyesters and polyester, nylon and rayon copolymers. A preferred filler material is colloidal silica, for example, Cab-O-Sil® (available from Cabot Corporation, Boston MA). Preservatives include, by way of example, p-chloro-m-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methyl ester, 4-hydroxybenzoic acid propyl ester, benzalkonium chloride, cetylpyridinium chloride, diacetate or gluconate. of chlorosidine, ethanol and propylene glycol. The compounds useful as pH regulators include, but are not limited to, glycerol regulators, citrate regulators, phosphate regulators and citric acid-phosphate regulators, which can be included in such a way as to ensure that the pH of the composition It is compatible with that of a body surface of the individual. Additionally, when the composition will be applied to a surface of the teeth, the addition of a pH regulator can ensure that the pH of the composition is compatible with that of the mouth environment and will not filter minerals from the surface of the teeth; In order to optimize bleaching without the demineralization of the teeth, calcium and / or fluoride salts may be included in the composition. Suitable plasticizers and softeners include, by way of illustration and not limitation, alkyl and aryl phosphates, such as tributyl phosphate, trioactyl phosphate, trisolsyl phosphate and triphenyl phosphate; alkyl citrate and citrate esters such as trimethyl citrate, triethyl citrate of acetyl triethyl citrate, tributyl citrate and acetyl tributyl citrate, acetyl triethyl citrate and triethyl citrate; alkyl glycerolates; alkyl glycollates; dialkyl adipates such as dioctyl adipate (DOA, also referred to as bis (2-ethylhexyl) adipate), diethyl adipate, d, (2-methylethyl) adipate and dihexyl adipate; dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates and mixed alkyl aryl phthalates, including esters of italic acid, such as those represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, di (2-ethylhexyl) -phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate; dialkyl cebacates such as diethyl sebacate, dipropyl sebacate, dibutyl sebacate and dinonyl sebacate; dialkyl succinates such as diethyl succinate and dibutyl succinate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; glycol esters and glycerol esters, such as glycerol diacetate, glycerol triacetate (triacetin), glycerol monolactate diacetate, methyl phthalyl ethyl glycollate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol butyrate and triethylene glycol dipropionate; hydrophilic surfactants, preferably hydrophilic nonionic surfactants, such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol esters and polyethylene glycol sorbitan fatty acid esters, as well as also nonionic surfactants, such as ethylcellulose; lower alcohols of ethyl to octal; lower diols such as 1,2- and 1,3-propylene glycol; low molecular weight poly (alkylene oxides), such as polypropylene glycol and polyethylene glycol; polyhydric alcohols such as glycerol; sorbitol; esters of tartaric acid such as dibutyl tartrate and mixtures thereof. Because the non-covalent, shell-like crosslinker can itself act as a plasticizer, it is generally not necessary to incorporate an added plasticizer. However, the inclusion of an additional low molecular weight plasticizer in the composition may, in some cases, be advantageous. For example, both the adhesive and water absorption properties of the adhesive composition can be easily controlled by adding the appropriate amounts of a plasticizer. The plasticizing mechanism results in the increase of free volume. Increasing the free volume, the plasticizer modifies the balance between cohesion energy and free volume, which are a factor to control adhesion. Because the film-forming polymer, the ladder-like crosslinker and the shell-like crosslinker are preferably hydrophilic materials, suitable plasticizers are also preferably hydrophilic in nature. Preferred thickening agents are naturally occurring compounds or derivatives thereof, and include, by way of example, collagen, galactomannans, starches, starch derivatives and hydrolysates, cellulose derivatives, such as methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, acids colloidal silicas and sugars such as lactose, sucrose, fructose and glucose. Synthetic thickening agents, such as alcohol, can also be used polyvinyl, copolymers of vinylpyrrolidone-vinylacetate, polyethylene glycols and polypropylene glycols. Pigments and dyes of the type commonly used with a food, drug or cosmetic in connection with the human body, especially color additives allowed for use in food, which are classified as "certifiable" or "exempt from certification" , they can be used to color the composition. These color-forming compounds can be derived from natural sources such as plants, minerals or animals, or can be made from counterparts of natural derivatives. Coloring compounds currently certified under the Food, Drug and Cosmetic Act for use in ingested foods and drugs include dyes such as FD Red &Red No. 3 (sodium tetraiodofluorescein salt); food red 17 (disodium salt of 6-hydroxy-5-. {(2-methoxy-5-methyl-4-sulfophenyl) azo.} -2-naphthalenesulfonic acid); food yellow 13 (sodium salt of a mixture of the mono- and disulfonic acids of quinophthalones or 2- (2-quinolyl) indanedione); yellow FD &C No. 5 (sodium salt of 4-p-sulfophenylazo-1-p-sulfophenyl-5-hydroxypyrazole-3 carboxylic acid); yellow FD &C No. 6 (sodium salt of p-sulfophenylazo-B-naptol-6-monosulfonate); green FD &C No. 3 (disodium salt of 4-. {[[4- (N-ethyl-p-sulfobenzylamino) -phenyl] - (4-hydroxy-2-sulfono-phenyl) -m-ethylene}. - [1 - (N-ethyl-Np-sulfobenzyl) -3,5-cyclohexadienimine]); blue FD &C No. 1 (disodium salt of dibenzyldiethyl diaminotriphenylcarbinol trisulfonic acid anhydride); blue FD &C No. 2 (sodium salt of acid indigotine disulfonic); red FD &C No. 40; orange B; and Citrus Red No. 2; and combinations thereof in various proportions. Color compounds exempt from FDA certification include anatous extract; beta-apo-8'-carotenal; beta-carotene; beet powder; canthaxanthin; caramel color; carrot oil; cochineal extract (carmine); prepared, partially defatted, toasted cottonseed meal; ferrous gluconate; fruit juice; grape-colored extract; Grape peel extract (endocyanin); paprika; paprika oleoresin; riboflavin; saffron; saffron from india; saffron oleoresin from india; vegetable juices; and combinations thereof in various proportions. The form of the color-forming compound for use in the composition preferably includes additives in the form of a dye, although it may also include lacustrine forms, which are compatible with the materials used in the hydrogel compositions. Water soluble dyes, provided in the form of powders, granules, liquids and other forms of special purposes, can be used according to the present method. Preferably, the "lacustrine" or water-insoluble form of the dye is used. For example, if a suspension of a color compound will be used, a lacustrine-shaped additive may be employed. Water-insoluble lake dyes prepared by the extension of calcium or aluminum salts of the dyes FD &C green # 1 lake, FD &C Blue # 2 lake, FD &C R &D # 30 lake and FD &C # yellow 15 lacustrine Other suitable color rendering compounds include pigments inorganic insoluble in non-toxic water, such as titanium dioxide, chromium oxide greens, blues and pink groceries; and ferric oxides. Said pigments, preferably have a particle size in the range from about 5 to about 1000 microns, more preferably from about 250 to about 500 microns. The concentration of the compound for coloring in the composition is preferably from about 0.05 to 10% by weight, and more preferably from about 0.1 to 5% by weight. More than one compound may be present to give color, such that multiple colors are imparted therein. These multiple colors can have stripes pattern, points, spirals or any other design which a consumer may find enjoyable. The color compound can also be used with other improved appearance substances, such as shiny particles. The compositions can be converted electrically conductive for use with biomedical electrodes and in other electrotherapy contexts, that is, for attaching an electrode or other electrically conductive element to the body surface, by the inclusion of conductive species. For example, the composition, formulated in such a way as to exhibit pressure-sensitive adhesion, can be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode or an electrode EKG to a skin or mucous tissue of the patient. These applications involve the modification of the hydrogel composition, in such a way that they improve the conductivity and contain a conductive species. In order to improve the conductivity, it may be useful to add poly-2-acrylamido-2-methyl propane sulfonic acid or its use as the poly or the ladder-like crosslinker. Suitable conductive species with conductive electrolytes in ionic form, particularly those normally used in the manufacture of conductive adhesives used for applications to the skin or other body surface, and include inorganic salts that can be ionized, organic compounds or combinations thereof . Examples of conductive electrolytes in ionic form include, but are not limited to ammonium sulfate, ammonium acetate, monoethanolamine acetate, diethanolamine acetate, sodium lactate, sodium citrate, magnesium acetate, magnesium sulfate, sodium acetate , calcium chloride, magnesium chloride, calcium sulfate, lithium chloride, lithium perchlorate, sodium citrate, sodium chloride and potassium chloride and redox complexes such as a mixture of ferric and ferrous salts, such as sulfates and gluconates . Preferred salts are potassium chloride, sodium chloride, magnesium sulfate and magnesium acetate, and potassium chloride is most preferred for EKG applications. Although virtually any amount of electrolyte may be present in the adhesive compositions of the present invention, normally the electrolyte is present at a concentration within the range of about 0.1-15% by weight of the composition. Refractive particles are particles that refract and reflect the light that reaches the adhesive and the color of the reflected light changes as the angle at which the composition is seen changes. The example refractive particles are those made of aluminized polyester, embossed. Suitable stabilizers include parabens, such as methyl paraben and propyl paraben. The bonding agents or adhesives may also be included to improve the adhesive and bonding properties of the composition, which is particularly beneficial for maintaining adhesion when the composition is used in such a way that it is subjected to a large amount of mechanical stress . The mechanism underlying the improvement of bonding is the result of the large and hydrophobic character of the bonding molecules. When mixed with the interpolymeric complex composition, the bonding agent can increase the free volume, causing only a slight impact on the cohesion energy. Suitable bonding agents can be solid or liquid. Exemplary materials include sticky rubbers, such as polyisobutylene, polybutadiene, butyl rubber, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). Preferred adhesive agents include polyisobutylene and low molecular weight butyl rubber. Other examples of suitable bonding agents herein are those conventionally used with pressure sensitive adhesion, for example, rosins, rosin esters (eg, Sylvagum® RE 85K (formerly Zonester 85K Resin) available from Arizona Chemical), poly terpenes, and hydrogenated aromatic resins in which a very substantial, if not all, portion of the benzene rings are converted to cyclohexane rings (e.g. Regalrez resins manufactured by Hercules, such as Regalrez 1018, 1033, 1065, 1078 and 1126, and Regalite R-100, the Arkon resin family of Arakawa Chemical, such as Arkon P-85, P-100, P-15 and P-125) and hydrogenated polycyclic resins (typically, dicyclopentadiene resins, such as Escorez 5300, 5320, 5340 and 5380 manufactured by Exxon Chemical Co.). In those modalities where the adhesion is going to be reduced or eliminated, the agents that remove conventional bonding can also be used. Agents to remove the paste include, crosslinked polyvinylpyrrolidone, silica gel, bentonites and so on. For the compositions to be used in the oral cavity, any natural or synthetic flavorings or food additives, such as those described in Chemical used in food processing, pub. No. 1274, National Academy of Sciences, pages 63-258 may be included in the compositions of the present invention. Suitable flavors include, pyro, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, oils and flavor oleoresins, as are known in the art, as well as combinations thereof. The amount of flavoring normally employed is a matter of preference, subject to factors such as the type of flavor, the individual taste and the desired strength.

Preferably, the composition comprises from about 0.-1-5% by weight of flavor. Sweeteners may also be included, such as sucrose, fructose, aspartame, xylitol and saccharin. Preferably, the composition comprises sweeteners in an amount from about 0.001 -5.0% by weight. Heat, light, impurities and other factors can result in oxidation of the hydrogel composition. Therefore, antioxidants may be included in the composition to protect them from light-induced oxidation, chemically induced oxidation and thermally induced oxidative degradation during processing and / or storage. Oxidative degradation, as will be appreciated by those skilled in the art, involves the generation of peroxy radicals, which in turn react with organic materials to form hydroxyperoxides. The primary antioxidants are scavengers peroxy free radicals, while secondary antioxidants induce the decomposition of hydroperoxides, and thus protect a material from degradation by hydroxyperoxides. The most primary antioxidants are spherically inhibited phenols, and those preferred for such compounds to be used herein are tetrakis [methylene (3,5-di-tert-butyl-4-hydroxyhydrocinnamate)] methane methane (for example, Irganox® 1010). available from Ciba-Geigy Corp., Hawthorne, NY) and 1, 3,5-trimethyl-2,4,6-tris [3,5-di-t-butyl-4-hydroxy-benzyl] benzene (e.g. Ethanox® 330 available from Etil Corp.). A particularly preferred secondary antioxidant that can replacing or complementing a primary antioxidant is tris (2,4-di-tert-butylphenyl) phosphite (for example, Irgafos® 168 available from Ciba-Geigy Corp.). Other antioxidants are useful, including but not limited to multi-functional antioxidants. Multi-functional antioxidants serve as both primary and secondary antioxidants. Irganox® 1520 D, manufactured by Ciba-Geigy is an example of a multifunctional antioxidant. Antioxidants of Vitamin E, such as those sold by Ciba-Geigy as Irganox® E17, are also useful in the present compositions. Other suitable antioxidants include, without limitation, ascorbic acid, ascorbic palmitate, tocopherol acetate, propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), bis (1, 2,2,6,6-pentamethyl-4-piperidinyl) - (3,5-di-tert-butyl-4-hydroxybenzyl) butylpropanedioate, (available as Tinuvin® 144 from Ciba-Geigy Corp.) and a combination of octadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate ( also known as octadecyl 3- (3 ', 5'-di-tert-butyl-4'-hydroxyphenyl) propionate) (Naugard® 76 available from Uniroyal Chemical Co., Middlebury, CT) and bis (1, 2.2, 6,6-pentamethyl-4-piperidinylsebacate) (Tinuvin® 765 available from Ciba-Geigy Corp.). Preferably, the antioxidant is present in an amount of up to about 2% by weight of the hydrogel composition; Typically, the amount of antioxidant is in the range of about 0.05% by weight to 1.5% per powder. One or more permeation enhancers may be included in the compositions described herein. With some active agents, it may be desirable to administer the agent together with an enhancer of adequate permeation in order to achieve a therapeutically effective flow through the skin or mucosa. The selection of suitable permeation enhancers will depend on the agent being administered, as well as the compatibility of the improver with the other components of the composition. Exemplary permeation enhancers include, by way of illustration and not limitation, sulfoxides such as dimethylsulfoxide (DMSO) and decylmethisulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (commercially available as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween® (20, 40, 60, 80) and lecithin (US Patent No. 4,783,450) for Fawzi et al.); 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacicycloheptan-2-one (Azone® available from Nelson Research &Development Co., Irvine, CA; see U.S. Patent No. 4,557,934 to Cooper, and U.S. Patent Nos. 3,989,816, 4,316,893, and 4,405,616 for Rajadhyaksha); alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters, such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof, such as propylene glycol, ethylglycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML, see for example, U.S. Patent No. 4,568,343 to Leeper et al.); amides and other nitrogen compounds such as urea, dimethylacetamide, dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid; and mixtures thereof. A substrate can also be fixed to the composition. The substrate can be any surface to which the composition adheres during manufacture, and can be a permanent substrate (e.g., a support element) or a temporary substrate (e.g., a manufacturing tool or equipment surface or a release coating). Exemplary substrates include flexible, elastic materials, such as fabric and open cell foams, such as polyurethane, polystyrene and polyethylene foams; polyesters; polyethylene; Polypropylene; polyurethanes; polyether amides; and non-polymeric materials such as waxes (e.g., microcrystalline or paraffin waxes) or a wax / foam laminate. The substrate is usually within the range of about 15 microns to about 250 microns thick. The substrate can also be integrated or decorated with decorative items, such as beads, imitations of diamonds or the like, provided that these articles do not interfere with the visco-elastic properties of the substrate, required for adequate deformation of the composition on the body surface. . The substrate can also display letters, words or images designed to be pleasing or attractive to a consumer. The substrate can also be translucent, in such a way that the composition is not obstructive when it is carried. However, the substrate or composition may optionally have color, such that the composition is easily observed when it is carried. Preferably, if color is desired, the color will be present in the substrate. For example, the substrate may have color with bright or vibrant colors, which the consumer may find pleasing. The substrate can therefore comprise a compound for coloring, such as, for example, a dye, a pigment or a substance that can impart color when it is added to the material that forms the substrate. The composition may also be attached to a release liner, which is a disposable element that serves to protect the system before application. The release coating must be formed from a material impervious to any active agents, as well as the composition itself, and which is easily removed from the adhesive composition. The release coatings are usually treated with silicone or fluorocarbons, and is commonly made from polyesters or polyethylene terephthalate. The compositions of the present invention are also suitable for use in a delivery system or patch, for example, a transdermal drug delivery device. The example systems could contain a drug reservoir, an outward facing support layer, and a means for securing the system to a body surface. During the manufacture of such systems, the composition may be molded or extruded onto a support layer or release liner, and serves as the contact face with the skin of the system. The composition can also be used as an active agent reservoir within the interior of said system, with a conventional contact adhesive laminated thereon to secure the system to a surface of the patient's body. Systems for topical, transdermal or transmucosal administration of an active agent, can usually contain one or more of the following: a reservoir containing an effective amount of an active agent; an adhesive means for maintaining the system in the active agent it transmits in relation to a surface of the body; a support layer; an index controlling membrane; and a disposable release liner that otherwise covers the exposed adhesive, protecting the adhesive surface during storage and before use. In many such devices, the reservoir can also serve as the adhesive means, and the compositions of the present invention can be used as the reservoir and / or the adhesive means.

Processing Methods The properties of the composition of the present invention are easily controlled by adjusting one or more parameters during manufacture. For example, the adhesion strength of the composition can be controlled during manufacture in order to increase, decrease or eliminate adhesion This can be achieved by varying the type and / or quantity of the different components, or by changing the manufacturing mode. Also, with respect to the manufacturing process, the compositions prepared using a conventional melt extrusion process which generally, though not necessarily, in some manner have different performance properties than the compositions prepared using a solution casting technique. Additionally, the degree to which the composition will expand upon contact with water can be varied by material selection. The compositions may vary in appearance from clear, transparent to translucent to opaque. Additionally, certain compositions can be made translucent by changing the relative amounts of the components, or by changing the manufacturing method (translucent hydrogels are more easily obtained using solution casting than melt extrusion). In this form, the translucent composition allows the user to observe the therapeutic (wound healing) or cosmetic (eg, blanched) procedure while it is occurring and determine when the desired effect has been obtained. The compositions described herein can generally be melt extruded, and therefore can be prepared using a simple extrusion and melting process. The components of the composition are weighed and subsequently mixed, for example, using a Brabender or Baker Perkins Blender mixer, generally but not necessarily at an elevated temperature, for example, from approximately a temperature of 90 to 170 ° C, normally a temperature of 100 to 140 ° C. If desired, solvents or water can be added. The resulting composition can be extruded using a single or double extruder, or granulated. Alternatively, the individual components can be melted at the same time and subsequently mixed before extrusion. The composition can be extruded to a desired thickness directly on a suitable substrate or support element. The composition can also be extruded first, and subsequently pressed against a support element or laminated to a support element. A releasable coating can also be included. The thickness of the resulting film, for most purposes, may be within the range of from about 0.050 to 0.80 mm, more commonly within the range from about 0.37 to about 0.47 mm. Alternatively, the compositions can be prepared by molding a solution, mixing the components in a suitable solvent, for example, a volatile solvent such as ethyl acetate, or lower alkanes (eg, ethanol, isopropyl alcohol, etc.) are particularly preferred. , at a concentration normally within the range of from about 30 to 60% weight per volume. The solution is molded onto a substrate, support element or release coating, as indicated above. Both the mixing and the molding are preferably carried out at room temperature. He material coated with the film is then baked at a temperature in the range of about 80 to 100 ° C, optimally at a temperature of 90 ° C, for a period of time in the range of about one to four hours, optimally about two hours. hours. Accordingly, one embodiment of the present invention is a method for preparing a composition of the present invention, which involves the following steps: preparing a solution of the components in a solvent. ; depositing a layer of the solution on a substrate to provide a coating thereon; and heating the coated substrate to a temperature in the range of from about 80 to 100 ° C for a period of time in the range of from about 1 to about 4 hours, thereby providing an adhesive composition on a substrate. Therefore, one embodiment of the present invention is a method for manufacturing an adhesive composition. First, the materials are selected, subsequently mixed to form an adhesive composition by melt extrusion or solution casting. The selection of materials is as described above. A film-forming polymer is selected first. Subsequently, a non-covalent, ladder-like crosslinker is selected because (1) it contains complementary reactive functional groups in the repeating units of the axis, and (2) it has the ability to form an interpoiimeric stair-like complex with the selected film-forming polymer. . Finally, a crosslinker non-covalent shell-like is selected because (1) contains complementary reactive functional groups at its ends, and (2) has the ability to form a shell-like complex with at least one of the selected film-forming polymer or non-covalent crosslinker similar to selected staircase; and wherein the amount of the film-forming polymer is greater than the amount of the non-covalent, ladder-like crosslinker or the amount of the non-covalent, shell-like crosslinker. When sticky compositions are desired, solution molding is the preferred method. For the preparation of substantially non-tacky compositions, melt extrusion is preferred. The techniques, either melt extrusion or solution casting can be used to prepare translucent compositions, although solution casting is usually preferred for these embodiments. The active agents can be added to the film-forming polymer components, the non-covalent, ladder-like crosslinker and the non-covalent, shell-like crosslinker as they are mixed together. The active agent can be added as a solid or as a solution to the composition dissolved in the solvent. The mixture is then molded as usual on a suitable substrate and allowed to dry, although a lower drying temperature is desired when this charging method is used. The compositions prepared in this form can be dried at room temperature for a period of time ranging from about 1 hour to about several days.

Alternatively, the active agent can be added after the components are mixed and the composition is prepared. A method for loading the composition with the active agent comprises forming layers of a desired active agent, for example, the tooth whitening agent, in aqueous solution on the surface of the composition placed on a suitable substrate, or placing the active agent directly on the substrate. The release coating is then assembled onto the top of the composition, forming a sandwich structure, and the solution containing the active agent is absorbed into the composition due to its water expansion properties. Therefore, one embodiment of the present invention is a method for forming a composition containing the drug, which involves the following steps: melt processing of the components through an extruder to form an extruded composition; extruding the composition as a film of the desired thickness onto a suitable erodible support element; and when it is cooled, and the film is loaded with an aqueous solution of the active agent, for example, a peroxide. Alternatively, the layered composition on the substrate can be immersed in a solution containing the desired concentration of active agent, and the solution absorbed in the composition. By measuring the weight gain index on the absorption liquid, the percentage charge of the composition with the active agent can be determined and controlled. The present invention also contemplates having a system of multiple layers. For example, it may be desirable to include additional active agents that may not be compatible with the primary active agent during storage. In this way, one layer can be the layer that contains the primary active agent and the other layer (s) can contain additional assets. These other layers can be made from the composition of the present invention, or any other biocompatible formulation known in the art (eg, polyisobutylene, dimethyl siloxane, ethylene vinyl acetate, polyvinyl acetate, cellulose acetate, butyrate, propionate, ethyl cellulose and acrylates. insoluble in water). Additionally, depending on the order of the layers, it may be desirable to have a sticky layer, for example, the layer to be placed directly on the surface of the body, and a non-sticky layer, for example, the outer layer that is placed closer to the clothing or other area where contact is not desired. Another advantage of having a multi-layer system is that the proportion of the polymers used in the outermost layer can be varied to achieve a non-tacky layer, so as to avoid having to include a separate support layer in the product. . A typical film thickness is from about 0.050 to 0.80 mm, preferably from 0.25 to 0.50 mm. The thickness of the film is not critical, and can be varied according to the desired concentration of any active agent incorporated in the film, the length of time that the composition will be adhered to the body surface, or the desired level of comfort. the carrier, and so on.

Methods of use In practice, the compositions can be used simply by removing the product from its package, removing a release coating (when included) and applying the composition to the desired body surface, for example, applied to the desired teeth. whitening or placing on any body surface to be used as a wound covering or a drug delivery system. The composition of the present invention can be provided in a variety of sizes and configurations. A support element may be included, and may be formulated to be occlusive or impermeable to the active agent, such that it reduces or prevents leakage of the active agent, of the composition, while the user carries the composition for the amount of time desired, ie, the composition will then administer the drug unidirectionally, for example, only to the surface of the body to which it is attached, such as the mucosal tissue. Alternatively, the support element may be formulated to have a pre-determined permeability such that it is provided for bidirectional drug delivery, eg, to the mucosal surface as well as to the surrounding environment of the oral cavity. The level of permeability, that is, its selective nature, can also be used to control the relative rates of administration towards the binding surface and the surrounding environment.

The composition can be maintained at the desired location for as little as a few minutes, several hours, all day or at night, and then be removed when the therapeutic or cosmetic effect has been achieved. Alternatively, when placed in a humid environment, such as an oral cavity, the composition can be left in its place and allowed to erode in its entirety. Accordingly, in one embodiment of the present invention, a method for whitening teeth may simply comprise applying the composition to the teeth that need to be bleached, while in another embodiment, the method may further comprise removing the composition when the composition has been achieved. desired degree of bleaching. If desired, a translucent composition can be provided, and it is carried without being annoying or obvious to others. The system can also be designed without an active ingredient and finds utility as a protective coating for an oral surface, for example, as a coating for a wound. The composition may be carried for an extended period of time, although it will normally be carried for a predetermined period of time from about 10 minutes to about 24 hours, after which the composition may be removed or eroded. For teeth whitening applications, a preferred period of time is from about 10 minutes to about 8 hours (e.g., overnight), with from 30 minutes to about 1 hour, being a preferred embodiment. For other active agents, a therapeutically or cosmetically effective time can be easily determined based on the active agent that is being used, as well as the condition to be treated. In one embodiment, the composition is a solid and is attached to the support member during manufacture. Accordingly, the composition is applied in a single step. Alternatively, the composition can be a non-solid and be manufactured and packaged separately from the support element. In that case, the composition is first applied by the user, followed by the application of the user of the support element to the outer surface of the composition. In any embodiment, the user may form the composition on the body surface, for example, around the upper and lower teeth or other oral tissue, applying normal manual pressure to the support element with the tips of the fingers and thumbs, optionally, slightly moistening the composition or body surface before application. It is assumed that the surface area of the finger tip or thumb of the average adult is approximately one square centimeter, the normal pressure generated by the tips of the fingers and thumbs is approximately 100,000 to approximately 150,000 Pases (ie, approximately 3). pounds or 1.36 kg) per square centimeter. The pressure is normally applied to the composition for each fingertip and thumb for approximately one or two seconds.

Once the pressure applied to the support element by the tips of the fingers and thumbs is removed, the composition remains in the form of, and is adhered to, the body surface on which it was formed. When the user is ready to remove the composition, the composition can be removed, simply by removing it from the body surface. If desired, the composition can be adhered again during the additional treatment time. Any residue that leaves this one is minimal and can be removed using the conventional methods of washing, cleaning teeth or oral cavity. In one embodiment of the present invention, the composition is a solid and is a pressure sensitive adhesive and absorbs water. The composition can also be applied as a non-solid composition, for example, applied as a liquid or gel. For example, the user can extrude the composition from a tube on a finger for application to the teeth or other body surface, extrude the composition from a tube directly onto the teeth, apply the composition by means of a brush or other applicator, and so on The erodible support element can then be applied as a separate step after the liquid or gel is applied. After evaporation of the solvent, the liquid composition or the gel is dried to form a polymeric film similar to matrix or gel on the body surface. In one embodiment of this liquid film or gel forming composition, the composition contains sufficient water or other solvent to provide the flow property. In another embodiment of this composition, the polymeric components of the liquid or gel composition are soluble in an ethanol-water mixture both at room temperature and at refrigeration temperatures of about 4 ° C, and are miscible from the evaporation of the solvent. In yet another embodiment of this liquid or gel forming composition, the polymer composition has a critical solution temperature of less than about 36 ° C in an ethanol-water mixture. For use in the oral cavity, the resulting film (after evaporation of the solvent) is preferably insoluble or slowly soluble in the saliva at body temperature, so as to provide long-lasting contact between the composition and the tooth enamel . The following examples are set forth in such a way as to provide those skilled in the art with a disclosure and description of how to make and use the compounds of the present invention, and is not intended to limit the scope of what the inventors consider to be their invention. . Efforts have been made to ensure accuracy with respect to numbers (eg, quantities, temperatures, etc.) although some errors and deviations can be found. Unless stated otherwise, the parts are parts by weight, the temperature is in degrees Celsius (° C) and the pressure is at or near atmospheric pressure.

Abbreviations DMAEMA 2-dimethylaminoethyl methacrylate Eudragit E 100 methacrylic acid copolymer, (Rohm America Inc.) Eudragit L 100 methacrylic acid copolymer (Rohm America Inc.) Eudragit L 100-55 methacrylic acid copolymer (Rohm America Inc.) Eudragit S 100 methacrylic acid copolymer (Rohm America Inc.) Gantrez S-97 maleic acid copolymer methylvinyl ether (International Specialti Products) HPC hydroxypropylcellulose, MW = 1, 150,000 HPMCP polyethylene hydroxypropylmethylcellulose PEO phthalate, MW = 200,000 g / mol PG 1, 2-propylene glycol PVA Poly (vinyl) alcohol, MW = 75,000 PVP 90 Kollidon® 90F polyvinylpyrrolidone (BASF) PEG 400 polyethylene glycol 400 TBC tributyl citrate Triethyl citrate EXAMPLE 1 Preparation and properties of adhesive compositions based on the combination of types of crosslinking similar to ladder and similar to film-forming polymer casing First, PVP 90 was selected as the film-forming polymer. In this case, examples of complementary polymers that have the ability to crosslink PVP with covalent by the formation of an interpolymeric complex similar to water-insoluble ladder with PVP are: homopolymers or copolymers of polyacrylic acid (PAA), polymethacrylic acid (PMA) ), homopolymers or copolymers of maleic acid, homopolymers or copolymers of polyvinyl alcohol (PVA), homopolymers or copolymers of polyvinyl phenol, alginic acid and hydroxypropyl cellulose (HPC). A non-covalent crosslinker of PVP is a methacrylic acid polymer and ethyl acrylate (1: 1), commercially available from Rohm Pharma Polymers as Eudragit L 100-55. By mixing the Eudragit L 100-55 with a mixture of PVP 90-PEG 400 adhesive, the result was the formation of an insoluble homogeneous single phase mixture. Being insoluble in water, the triple PVP-PEG-Eudragit mixture was characterized in terms of Sun Fraction (%) and dilatation ratio, as shown in the table below and in Figures 4 and 5) Preparation of the films: 50 g of PEG 400 were dissolved in 200 g of ethanol. Under vigorous agitation, the Eudragit L 100-55 powder is added in the amounts indicated below. Under vigorous agitation, the PVP 90 powder was added in the amounts shown below. The mixture was stirred for 2 hours to obtain a homogeneous solution. The solution was stored for a period of 2-5 hours to allow the air bubbles to dissipate. The polymeric films were prepared by molding the solution on a PET support, followed by drying at room temperature for 3 days. Films of 0.20 ± 0.03 mm were obtained. The water content in the films obtained was measured in gravimetric form by weight loss at a temperature of 120 ° C. The water content in the film films was found within the range of 1 1 ± 1.5% by weight.

The dilation properties of the films were tested in gravimetric form. The samples were placed in a buffer solution of 0.1 M, at least 200 folds of solution amount were taken with respect to the weight of the sample. The samples were stored for 3 days at a temperature of 25 ° C. The dilated samples were then removed accurately and dried at a temperature of 1 10 ° C. The dilatation ratio and the Sun Fraction were calculated as follows: Dilation ratio = md / ms; Fraction Sol,% = 100 · (m0 - md) / m0, where m0 is the initial weight of the sample, ms is the weight of the dilated sample and md is the weight of the sample after drying. According to the data shown above, the higher the pH in the water, the higher the dilation ratio, while the fraction of the soluble mixture was only slightly affected by the pH. The higher the pH, the greater the degree of ionization of the carboxyl groups of Eudragit and the greater the dilatation of the ladder-like complex. These data imply that the solubility of the mixture in water (expressed in terms of the sol fraction) is controlled by the non-covalent crosslinking with the Eudragit and depends on the content of the crosslinker. Actually, with the increase in Eudragit concentration, the sun fraction decreased correspondingly (Figure 4). The value of the sol fraction was close to the PEG 400 content in the mixtures (Figure 5), whereas the PVP was mainly in the insoluble state due to the stair-like cross-linking with Eudragit. The rate of expansion is a measure of the degree of noncovalent crosslinking of the film-forming polymer (PVP). The higher the concentration of the ladder-like crosslinker, Eudragit L 100-55, the lower the dilatation ratio and the denser the PVP-Eudragit hydrogen bond network (Figure 4). The shell-like reticulator, PEG, caused the increase in both the expansion ratio and the sol fraction (Figure 5). It is this way the dilation and dissolution of the triple mixtures PVP-PEG- Eudragit can be easily changed by changing the composition of the mixture. By varying the ratio of film-forming polymer (PVP 90) to the ladder-like crosslinker (Eudragit L 100-55) and the content of the carcass-like crosslinker (PEG 500), it was found as a feasible tool for controlling the mechanical properties of the adhesive hydrogels. The elastic properties of the PVP-PEG-Eudragit hydrogels were typical for those of the cured rubber (Figure 6). Adding the non-covalent, ladder-like crosslinker, Eudragit, to the PVP-PEG adhesives described in the U.S. Patent. No. 6,576,712 for Feldstein et al., There was an acute gain in mechanical strength and loss of ductility. The ultimate elastic effort comes through an Eudragit content of 8%, while the maximum stretch in the rupture slightly decreased with the elevation of the Eudragit concentration for the single-phase mixtures. The two-phase compositions exemplified by the 36% Eudragit mixture exhibited an increase in light ductility, accompanied by the loss of cohesion force. The shell-like crosslinker, PEG, was a good plasticizer for the triple PVP-PEG-Eudragit mixtures. The elevation in the PEG content promoted the ductility of the hydrogel films (Figure 7).

EXAMPLE 2 Adhesive properties of hydrogels in dilated state This example demonstrates the adhesive properties of the PVP-PEG-Eudragit L 100-55 blend as a function of the degree of hydration. Preparation of the films: 30 g of PEG 400 were dissolved in 280 g of ethanol. Under vigorous stirring, 12 g of Eudragit L 100-55 powder was added. Under vigorous stirring, 58 g of PVP 90 was added. The mixture was stirred for 2 hours to obtain a homogeneous solution. The solution was stored for 5 hours to allow the bubbles to dissipate. The polymeric films were prepared by molding the solution on a PET support, followed by drying at room temperature for 1 day. The films were then dried in an oven at a temperature of 1 10 ° C overnight. Films with a size of 0.20 ± 0.04 mm were obtained. PVP-PEG-Eudragit L 100-55 films of a different degree of hydration were prepared by controlled spraying of quantities of distilled water on the surfaces of the films. The films were then covered with a PET release liner, sealed in aluminum bags and stored for 7 days to ensure even distribution of water within the film samples. The water content in the films obtained was measured in gravimetric form by weight loss at a temperature of 120 ° C. The films with a degree of hydration that varies between 1 1 and 40% by weight and greater, were prepared as indicated in the table below. The adhesive properties of the hydrated PVP-PEG-Eudragit films (Figures 8-10) were tested according to the ASTM D 2979 method using a TAXT2 Texture Analyzer Machine. A stainless steel probe with average resistance of 50 nm was used, the contact pressure was 0.8 MPa, the contact time was 1 second, the outcome index was 0.1 mm / sec.

The maximum stress value in the stress-strain curves of the probe is traditionally considered a measure of bonding. The maximum bonding was documented in approximately one degree of hydration between 15-17% (Figures 8 and 9). However, the most accurate measure of adhesion is the amount of total dissipated energy in the course of the outcome procedure (the outcome work). The outcome work is shown in Figure 10 as a function of the water content in the dilated hydrogel. As seen from the data in Figure 10, adhesion to the probe was high enough, even at a 40% degree of hydration. At comparatively low levels of hydration of the mixture, the type of adhesive bond failure was always adhesive. Made to measure that the absorbed water content exceeded 50%, the type of outcome became cohesive. In this sense, the PVP-PEG / Eudragit L 100-55 (12%) blends revealed the properties that are typical of both pressure-sensitive adhesives (high adhesion) and bioadhesives (improvement of adhesion in the course of dilation). in water). Such a unique high adhesion coupling with the ability to increase adhesion under hydration has never been reported before.

EXAMPLE 3 Effect of the composition of methacrylic acid copolymers on the performance properties of their mixtures with a PVP-PEG adhesive In the following example, PVP 90 was chosen as the film-forming polymer, while copolymers of methyl methacrylate and methacrylic acid (Eudragit L 100 and Eudragit S 100) served as the ladder-like crosslinkers. The PEG 400 was used as the shell-like crosslinker. The films were prepared and tested. The Eudragit L 100 differs from the Eudragit L 100-55 by the composition of the hydrophobic monomer, while the content of the monomeric units of methacrylic acid is the same (50%). In Eudragit L 100-55 hydrophobic monomer units are represented by ethyl acrylate, while Eudragit L 100 is a copolymer of methacrylic acid with methyl methacrylate. In turn, the Eudragit S 100 differs from the Eudragit L 100 for the decreased content of methacrylic acid units (33% instead of 50%), while methyl methacrylate is the hydrophobic monomer of both copolymers. Preparation of the films: 40 g of PEG 400 were dissolved in 280 g of a water / ethanol (1: 1) mixture. The required amount of sodium hydroxide dissolved (as indicated in the table below). Under vigorous stirring, 12 g of Eudragit L 100-55 powder was added. Under vigorous stirring, 58 g of PVP 90 powder was added. The mixture was stirred for 2 hours to obtain a homogeneous solution. The solution was stored for 5 hours to allow air bubbles to dissipate. The polymeric films were prepared by molding the solution on a PET support followed by drying at room temperature for 3 days. Films with a thickness of 0.20 ± 0.04 mm were obtained. The water content in the films was measured in gravimetric form by weight loss at a temperature of 120 ° C. Films with a degree of hydration of 10 ± 1.5% by weight were obtained. The adhesive properties of these PVP-PEG-Eudragit films are established below PVP-PEG mixes with Eudragit L 100 as a crosslinker Similar to ladder were found to be water soluble, while mixtures containing Eudragit S 100 as the stair-like reticulator were hydrogels that can be dilated in water.

EXAMPLE 4 Compositions containing copolymers of methacrylic acid as the film-forming polymer and PVP as the ladder-like crosslinker Whereas in Examples 1-3, the film-forming polymer was PVP and the stair-like crosslinker was either Eudragit L 100-55, L 100 or S 100, this example represents an inverted composition, wherein the Eudragit serves as the film-forming polymer and the ladder-like crosslinker is PVP. The sun fraction corresponded closely to the water-soluble carcass-like crosslinker content, PEG, indicating that the formation of the interpolymeric stair-like complex resulted in an insoluble product.

In this sense, varying the composition of the PVP-PEG-Eudragit L 100-55 mixtures, the adhesive materials of different degrees of hydrophilicity were obtained, where the values of the proportion of expansion They went from 2 to 60.

EXAMPLE 5 Dissolving and gradually expanding adhesive mixtures of PVP-PEG shell-like complex with stair-like crosslinkers not containing carboxyl acrylic The PVP was selected as the film-forming polymer and the PEG 400 was selected as the shell-like crosslinker and adhesion enhancer. The maleic acid copolymers and cellulose derivatives bearing carboxyl groups were then evaluated and determined as suitable ladder-like crosslinkers. One of the most illustrative examples of the use of maleic acid copolymers with methyl vinyl ether as the ladder-like crosslinker in the PVP-PEG complex is provided by the Gantrez S-97 copolymer. The PVP mixtures containing 40% by weight of PEG and 5, 10 and 15% of Gantrez were obtained by molding / drying in water-ethanol solutions (1: 1). All mixtures were soluble in water, although the time required for the complete dissolution of the films was achieved in linear relation to the contents of the ladder-like crosslinker (Gantrez). In contrast, the lower the Gantrez content in the mixtures, the greater the adhesion. Another typical example that supports the proposed carboxyl-containing polymers are suitable ladder-like crosslinkers of electron donor hydrophilic polymers such as PVP is provided by the HPMCP. PEG 400 was used as the shell-like crosslinker of PVP 90. Film preparation: 40 g of PEG 400 were dissolved in 240 g of ethanol / water mixture (80 parts by weight of ethanol: 20 parts by weight of water ). Subsequently, under vigorous stirring, the required amounts of HPMCP and PVP were dissolved. The mixture was stirred for 2 hours to obtain a homogeneous solution. The solution was stored for 5 hours to allow the bubbles to dissipate. The polymer films were prepared by molding the solution on a PET support, followed by drying at room temperature for 3 days. Films with a thickness of 0.20 ± 0.04 mm were obtained. The adhesive behavior of these dilated hydrogels followed the pattern exhibited by mixtures PVP-PEG-Eudragit L 100-55. The dilation and dissolution properties of the films are presented below.

EXAMPLE 6 Use of hydrophilic hydrophilic polymers as PVP ladder-like crosslinkers in adhesive hydrogels The list of suitable ladder-like crosslinkers of the electron-donating hydrophilic film-forming polymers, exemplified herein by PVP, are not extracted by polyacids. Other suitable hydrophilic polymers carry the hydroxyl group in their repeating units. This example demonstrates the suitability of PVA and hydroxyl-containing cellulose derivatives such as HPC as the PVP ladder-like crosslinkers. Mixtures of PVP 90 with PVA, with PEG, PG or glycerol as the shell-like crosslinker, can be prepared in the following manner. Under vigorous agitation, the required amount of PVA was dissolved in distilled water at a temperature of 95 ° C (9 parts by weight of water were taken to dissolve 1 part by weight of PVA). Subsequently, under vigorous agitation, the required amounts of PG and PVP were dissolved. The mixture was stirred for 2 hours at a temperature of 85 ° C to obtain a homogeneous solution. The polymeric films were prepared by molding the solution on a support element, followed by drying at room temperature for 3 days. Films with a thickness of 0.20 ± 0.02 mm were obtained. The adhesive properties of the films were similar to those observed with the mixtures PVP-PEG-Eudragit L 100-55. The results of sol-gel analysis are listed below.

Another suitable RRP-like ladder is HPC. The high molecular weight of PVP 90 (58.67% by weight), PEG 400 (29.33%) and HPC were dissolved in ethyl alcohol under stirring. The resulting solution was cast on a release coating and dried at a temperature of 50 ° C. An alternative method of blending production involves direct mixing of the components followed by extrusion of the mixture as indicated below in Example 11. The prepared mixture had a soluble fraction of 62% and an expansion ratio of 10.13. The adhesive behavior of the formulation follows the pattern shown by the PVP-PEG-Eudragit L 100-55 mixtures. An adhesive mixture containing 58.67% by weight of PVP 90, 29.33% by weight of PEG 400, 9.6% by weight of HPC and 2.4% by weight of Eudragit L 100-55 was prepared as indicated above. The properties of this composition were intermediate between those of the PVP-PEG-Eudragit L 100-55 and PVP-PEG-HPC mixtures. The sol fraction content was 48% and the dilatation ratio was 6.8.

EXAMPLE 7 PVP-free adhesive hydrogels based on interpolymeric complexes involving the combination of stair-like and shell-like cross-linking Although PVP is one of the most successful representatives of hydrophilic polymers suitable for serving as film-forming components in the adhesives of the present invention, other suitable film-forming polymers include PEO. PEO is a much weaker electron donor polymer compared to PVP. For this reason, PEO has the ability to form sufficiently strong hydrogen bonds with strong proton donor polymers such as polyacids. A mixture containing 68.2% by weight of PEO, 25% by weight of PG as the shell-like crosslinker and 6.8% by weight of Gantrez S-97 as the ladder-like crosslinker, was prepared by molding / drying a water solution The film prepared with a thickness of 0.2 mm was cohesively resistant (the last elastic stress was 5.0 MPa) indicating that the PEO is crosslinked due to the H bond with the carboxyl groups of Gantrez S-97. From the immersion of the film in water, the film dissolved in a period of time of 1-2 minutes. It was observed appreciable gluing for hydrated films in a moderate way. The maximum bonding (approximately 0.8 MPa) was observed with the film which contains 13% by weight of water.

EXAMPLE 8 Preparation and properties of adhesive compositions based on ladder-like interpolymer complexes While the hydrophilic adhesives presented above are formed due to the hydrogen bond between the polymeric components, the samples shown in the table below illustrate the properties of the hydrogels prepared by coupling the H bond and the electrostatic crosslinking of the polymer forming of film. The electrostatic interactions, as a rule, are stronger than the H bonds. Eudragit E-100 was used as the film-forming polymer, which is a copolymer of DMAEMA, butyl methacrylate and methyl methacrylate (2: 1: 1). The DMAEMA monomeric units have the ability to form electrostatic bonds with carboxy groups in the ladder-like crosslinker, Eudragit L 100-55.

EXAMPLE 9 Performance properties of adhesive compositions based on interpolymeric complexes compared to conventional pressure sensitive adhesives and bioadhesives The properties of the triple-blend hydrogels of the present invention (PVP-PEG-Eudragit L 100-55), were compared with those of: conventional pressure sensitive adhesives (PSA, DURO-TAK® 34-4230, National Starch and Chemicals); classic bioadhesives (polyacrylic acid polymers covalently cross-linked Carbopol® 974P and Noveon® AA1, both from B.F. Goodrich, Co.); the PVP-PEG binary mixtures described in the U.S. Patent. No. 6,576,712 for Feldstein et al .; and the hydrophilic adhesives of the present invention (Examples 1-7).

The PSAs, exemplified above by the SIS block copolymer based on DURO-TAK® 34-4230 adhesive, represent a special class of viscoelastic polymers. These have the ability to form a strong adhesive bond with various substrates under the application of a light external pressure for a short period of time (1-2 seconds). It is noteworthy that typical PSAs for human use mainly based on hydrophobic elastomers with low glass transition temperatures, ranging from a temperature of -120 to -30 ° C, which are normally increased by the addition of bonding resins. The common property of PSAs is a loss of adhesion as the surface of a substrate is wetted. For this reason, conventional PSAs can not be used for application to highly hydrated tissues and soft biological tissues, such as the oral mucosa. Hydrophilic bioadhesives are normally used for this purpose, which are generally not sticky in the dry state, although they adhere to wet substrates. The adhesive strength of these bioadhesives, however, is usually much lower than that of the PSAs. As seen from these data, the adhesives of the present invention share the properties of both pressure sensitive adhesives and bioadhesives. In fact, although their adhesion strength was normally that of the PSAs, they exhibited increased adhesion to wetted substrates such as bioadhesives. By varying the composition of the hydrogel, control can easily be provided Additional adhesive properties, water absorption and mechanical properties of hydrogel-based products cross-linked in non-covalent form (see Figures 3 to 7). The detachment adhesion to the skin of the dry and wet human forearm in vivo was evaluated for the conventional acrylic PSA and three grades of adhesives based on the interpolymeric complexes of the present invention. The data established that the adhesive properties of the water soluble PVP-PEG adhesives described in the U.S. Pat. No. 6,576,712 share the properties of PSAs and bioadhesives by the combination of high adhesion characterized by conventional PSAs with the ability to adhere to wet skin and the biological tissues typical of bioadhesives. The adhesive behavior of the water-soluble PVP-PEG adhesives and the PVP-PEG-Eudragit L 100.55 adhesives of the present invention were compared with the properties of two different grades of conventional PSAs: PSA DURO-TAK® 34-4230 based on SIS and acrylic PSA (3M). Expressed in terms of maximum effort under outcome, the bonding of adhesives based on interpolymeric complexes was found to be comparable with that of conventional PSAs. However, a distinctive feature of the adhesive blends of the present invention were the lower maximum elongation values that were the result of the non-covalent crosslinking of the film-forming polymer chains. Because the shell-like crosslinking is significantly more loose than ladder-like cross-linking, the water-soluble PVP-PEG adhesive showed greater stretching in the debonding test than was observed with adhesives having a similar type to crosslinking ladder. In this sense, it is pertinent to observe that the ladder-like crosslinking is the dilution of the network density due to the mixture of the carcass-like crosslinkers that function as plasticizers, in the course of the dilation in water, and also the decrease in the concentration of the stair-like reticulator.

EXAMPLE 10 Preparation of adhesive films by direct mixing of polymeric components followed by extrusion The behavior of the hydrophilic and amphiphilic adhesives of the present invention is typical of the covalently crosslinked polymers. In contrast to covalently crosslinked systems, however, adhesives based on interpolymer complexes can be readily prepared using a simpler mixing procedure, and additionally, provide film-forming properties that are impossible using the cross-linked polymers. Although the formulations described in the above examples were prepared by molding from the solutions followed by drying, the adhesive films of the present invention can also be produced by directly mixing the components in the dry state followed by the extrusion. Direct mixing was carried out using a Termo Haake Mixer, while the extrusion process was carried out with a Skania Single-Screw Extruder. The mixing and extrusion processes are described below.

Preparation of a composition PVP-PEG-Eudragit The mixture composition was as follows: 58.7% by weight of PVP 90; 9.33% by weight of PEG 400; and 12.0% by weight of Eudragit L 100-55. Mixing procedure: The total amounts of PEG and Eudragit were mixed at room temperature. An amount of PVP was then added at room temperature to reach the desired consistency, producing a pre-mix. This pre-mix was charged to the mixer under agitation at a speed of 40 rpm at a temperature of 55 ° C. The remaining PVP was then introduced in small portions, with an increase in the stirring intensity at 60 rpm. The mixing regime is presented below.

Extrusion process: the die with the cut thickness of 100 μm and a width of 6.5 cm was built to prepare the film with the thickness of -127 micrometers. Two temperature regimes, I and II, were used as shown below.

The formulation layer was then extruded (without any filter) between two PET anti-adhesion films and left at a linear velocity of -5-7 mm / c.

Preparation of a PVP-PEG-HPC composition The mixture composition was as follows: 58.67% by weight of PVP 90; 29.33% by weight of PEG 400; and 12.0% by weight of The extrusion process was as described above, and the scheme is presented below Preparation of a composition PVP-PEG-HPC-Eudragit The mixture composition was as follows: 58.67% by weight of PVP 90; 29.33% by weight of PEG 400; 9.60% by weight of HPC; and 2.40% by weight of Eudragit L 100-55. The mixing and extrusion procedures were as described above, and the regimes are presented below EXAMPLE 11 Coatings for wounds The following samples illustrate how the hydrogel compositions of the present invention can be used for silver-containing antibacterial wound coatings. The films for wound coatings were prepared from the following ingredients The antibacterial coating was insoluble in water and was exuded, although it can be dilated, thereby absorbing a large amount of exudate. The coating was initially sticky and maintained a good adhesion to wet wounds and they exude moderately, although it could be removed from the skin without pain by washing with a large amount of water. Accordingly, the coating is this example is useful for the treatment of pressure, diabetic, arterial and venous ulcers. The potentiometric method with a selective ion electrode Ag was used to study the release of silver from the coating. Aqueous solutions of silver nitrate in the concentration range of 2.5x10"6-10" 3 M were used to calibrate the selective electron of Ag ion.

Circular samples of (2.54 cm, 5 cm2 area) of the film were cut and laminated to glass plates by means of a two-sided tape. The glass plate with the Ag release side facing up was placed in a laboratory beaker and 50 ml of distilled water was poured into the beaker. The system was then covered with a Petri dish and placed in an oven, heated to a temperature of 25 ± 0.2 ° C. After the specified time points, the receptor solution in the beaker on the mixture was shaken and the silver concentration was measured with the Ag ion selective electrode. After the measurement, the receptor solution was removed and replaced with 50 my distilled water A cumulative Ag release was calculated and expressed in pg per cm 2 of the antibacterial coating. It was found that samples 11-1 administer a high amount of silver sulfate.

EXAMPLE 12 Bands for teeth whitening One embodiment of the tooth whitening composition was prepared from the following ingredients using the melt extrusion process: The ingredients were melt processed in a single screw extruder Brabender as follows. First the Eudragit L 100-55 was added to the extruder, followed by the PVP and PEG, at a temperature from 100 to 150 ° C. The composition was extruded to a thickness of 0.35 mm between two polyethylene terephthalate release liners. A solution of hydrogen peroxide was added to the extruded film. Being applied to the surface of the teeth, initially the adherent film immediately tacky to the tooth enamel, dilated and dissolved slowly in the saliva, releasing the hydrogen peroxide. Figure 11 compares the in-vi release profiles of hydrogen peroxide from a teeth whitening band based on the composition PVP-PEG-Eudragit L 100-55 and Crest's Whitestrips ™ (Procter & amp; amp;; Gamble Co., Cincinnati, OH; referred to as the "Crest Product" product). The Crest product contains 5.3% hydrogen peroxide on a Carbopol 956 gel on a thin polyethylene film. Carbopol is a classic representative of bioadhesive hydrogels made for covalent crosslinking of polyacrylic acid. The amount of hydrogen peroxide released in vivo was measured by the rest of hydrogen peroxide in the product removed from the surface of the teeth in a period of previously determined use. The composition of the present invention provided a prolonged release of hydrogen peroxide compared to the Crest product. In fact, compared to the Carbopol-based matrix in the Crest product, the PVP-PEG-Eudragit L 100-55 bioadhesive film in the present invention provided a delayed dissolution index. In turn, the prolonged release of hydrogen peroxide from the composition of the present invention, provided the improved bleaching effect of the present invention.

EXAMPLE 13 Liquid formulations for teeth whitening The adhesive mixtures described in the present invention can be applied either in the form of adhesive films or as solutions in suitable solvents, which have the ability to form the film from drying the application site. To prepare a liquid tooth whitener, the following components were mixed.

Eudragit RL is a copolymer of trimethylammonioethyl methacrylate chloride with ethylacrylate and methyl methacrylate (0.2: 1: 2), available from Rohm Pharma Polymers. Being insoluble in an aqueous medium, in the hydrogel composition, it serves to protect the hydrogel film from rapid dissolution. When applied to the surface of the teeth and allowed to dry for 30 seconds, the liquid compositions form a thin hydrogel film, which remains on the teeth for a period of time greater than 30 minutes, and provides a bleaching effect on the teeth. teeth.

EXAMPLE 14 Adhesive matrices with therapeutic agents The following compositions were prepared by dissolving in ethanol the components listed below, molding the solution and drying at a temperature of 50 ° C. The sample uses an acrylate polymer (Eudragit E 100) as the film-forming polymer. The Eudragit L-100-55 is the stair-like reticulator of Eudragit E 100, and the PVP is the shell-like reticulator of the L-100-55. PVP also helps increase the hydrophilicity of the mixture. The PEG is the similar reticulator housing of the PVP. The sample also includes an alkyl citrate (TEC) as the plasticizer.

EXAMPLE 15 Liquid bandages that form films In this example, adhesives were formulated with a soluble ladder-like crosslinker, together with a similar ladder and similar to a cell-like crosslinker for the soluble ladder-like crosslinker. The main component was an insoluble film-forming polymer, and a plasticizer was included. Samples 15-1 to 15-4 represent liquid compositions suitable for application to the skin as liquid advantages. Sample 15-1 is a liquid formulation for whitening teeth, which it contains the film-forming polymer (Eudragit RS) and the plasticizer for this tributyl citrate polymer (TBC). Eudragit RS is a copolymer of trimethylammonium methylmethacrylate chloride (0.1) with ethylacrilate (1) and methyl methacrylate (2), available from Rohm Pharma Polymers. Samples 15-2 to 15-4 do not contain a ladder-like crosslinker for the PVP ladder-like reticulator. The liquid benefit and cold wound compositions for skin applications may also contain active agents, such as local anesthetics. Suitable local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, penzocaine, p-butylaminobenzoic acid ester of 2- (diethylamino) ethyl hydrochloride; procaine hydrochloride; tetracaine hydrochloride; chloroprocaine hydrochloride; oxiprocaine hydrochloride; mepivacaine; cocaine hydrochloride; and piperocaine hydrochloride. Any natural or synthetic flavors such as those described in the publication Chemicals Used in Food Processing, Pub. No. 1274, National Academy of Sciences, pages 63-258, may be included in the compositions of the present invention. Suitable flavors include pyrol, mint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils (clove oil) and oleoresins, as are known in the art, as well as combinations thereof. The amount of flavoring normally used is a matter of preference, which is subject to factors such as taste type, taste individual and desired strength. Sample 15-3 also contains a skin softening agent such as glycerol monooleate (Peceol, Gattefossé, France).

The practice of the present invention will employ, unless otherwise indicated, the conventional techniques of polymer chemistry, adhesive manufacturing and hydrogel preparation, which are within the skills of the art. These techniques are fully explained in the literature. It will be understood that although the present invention has been described in conjunction with the preferred specific embodiments, the description and examples that are presented above are intended to illustrate and not to limit the scope of the present invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which the present invention pertains.

Claims (44)

NOVELTY OF THE INVENTION CLAIMS

1. - An adhesive composition, characterized in that it comprises: a film-forming polymer selected from water-insoluble polymers that dilate in water and water-soluble polymers; a non-covalent, ladder-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form an interpolymeric stair-like complex with the film-forming polymer; and a non-covalent, shell-like crosslinker containing reactive functional groups at its ends and having the ability to form a shell-like complex with at least one of the film-forming polymer or the non-covalent, stair-like crosslinker; wherein the amount of the film-forming polymer is greater than the amount of the non-covalent, ladder-like crosslinker or the amount of the non-covalent, shell-like crosslinker.

2. The composition according to claim 1, further characterized in that it comprises about 20 to 95% by weight of the film-forming polymer.

3. The composition according to claim 1, further characterized in that it comprises approximately e! 0.5 to 40% by weight of the stair-like reticulator.

4. - The composition according to claim 1, further characterized in that it comprises approximately 0.5 to 60% by weight of the shell-like crosslinker.

5. The composition according to claim 1, further characterized in that the water-insoluble polymer that expands in water is selected from cellulose derivatives, and acrylate-based polymers and copolymers.

6. - The composition according to claim 5, further characterized in that the cellulose derivative is a cellulose polymeric ester containing unesterified cellulose monomer units, cellulose acetate monomer units, and either monomeric butyrate units of cellulose or monomeric units of cellulose propionate.

7. - The composition according to claim 5, further characterized in that the cellulose derivative is a polymer containing monomeric units of hydroxyalkylcellulose or monomeric units of carboxyalkylcellulose.

8. The composition according to claim 5, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate.

9. - The composition according to claim 1, further characterized in that the water-soluble polymer is selected from water-soluble cellulose-derived polymers, homopolymers and copolymers of vinyl alcohols, homopolymers and copolymers of vinyl phenols, homopolymers and copolymers of ethylene oxides, homopolymers and copolymers of maleic acid, collagen, gelatin, alginates, starches and polysaccharides of natural occurrence.

10. The composition according to claim 9, further characterized in that the polymer derived from water soluble cellulose is selected from hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydratecellulose and hydroxypropylmethylcellulose.

11. - The composition according to claim 9, further characterized in that the polysaccharide of natural occurrence is selected from agars, alginates, alginic acid derivatives, carrageen, chitin, chitosan, glucomannan, gellan gum, gelatin, guar gum, arabic gum , ghatti gum, karaya gum, tragacanth gum, locust bean gum, pectins, pululan, starches and starch derivatives, tamarind gum and xanthans.

12. - The composition according to claim 1, further characterized in that the non-covalent crosslinker similar to ladder is selected from hydrophilic polymers, water-insoluble polymers that dilate in water, water-soluble polymers, hydrophilic and hydrophobic monomeric copolymers and combinations thereof.

13. - The composition according to claim 12, further characterized in that the hydrophilic polymer is selected from poly (dialkyl aminoalkyl acrylates), poly (dialkyl aminoalkyl methacrylates), polyamines, polyvinylamines, poly (alkylene imines), polyacrylic acids, polymethacrylic acids, acids polymaleaics, polysulfonic acids, poly (N-vinyl lactams), polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates), poly (N-vinyl-acrylamides), poly (N-alkyl acrylamides) , polar cellulose derivatives containing hydroxyl and carboxyl groups, alginic acid, chitosan, gelatin, combinations and copolymers thereof.

14. The composition according to claim 12, further characterized in that the water-insoluble polymer that expands in water is selected from cellulose derivatives, acrylate-based polymers and copolymers and combinations thereof.

15. The composition according to claim 14, further characterized in that the cellulose derivative is a cellulose polymeric ester containing unesterified cellulose monomer units, monomer units of cellulose acetate, and either monomeric butyrate units of cellulose or monomeric units of cellulose propionate.

16. The composition according to claim 14, further characterized in that the cellulose derivative is a polymer that contains monomeric units of hydroxyalkylcellulose or monomeric units of carboxyalkylcellulose. 7.

The composition according to claim 14, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate.

18. - The composition according to claim 12, further characterized in that the water-soluble polymer is selected from water-soluble cellulose-derived polymers, homopolymer and copolymers of polyvinyl alcohols, homopolymer and copolymers of vinyl phenols, homopolymer and copolymers of oxides of ethylene, homopolymer and copolymers of maleic acid, collagen, gelatin, alginates, starches, polysaccharides of natural occurrence and combinations thereof.

19. The composition according to claim 1, further characterized in that the non-covalent crosslinker similar to carcass is selected monomeric and oligomeric alkylen glycols comprising from about 1 to 20 units of alkylene oxide in their chains, polyalcohols, alkanediols, carbonic diacids , ether alcohols, poly (alkylene glycol diacids) and combinations thereof.

20. The composition according to claim 1, further characterized in that it additionally comprises at least one active agent.

21. - The composition according to claim 1, further characterized in that it additionally comprises at least one additive selected from absorbent fillers, pH regulators, plasticizers, softeners, thickening agents, antioxidants, pigments, dyes, conductive species, refractive particles, stabilizers, resistance agents, peelers, flavorings and sweeteners, antioxidants and permeation enhancers.

22. The composition according to claim 1, further characterized in that the film-forming polymer is an acrylate polymer, the ladder-like crosslinker is a poly (N-vinyl lactam), and the shell-like crosslinker is an alkylene glycol oligomeric comprising approximately 1 to 20 units of alkylene oxide in its chain.

23. - The composition according to claim 1, further characterized in that it additionally comprises a second non-covalent, stair-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and has the ability to form an interpolymeric complex similar to ladder with the film-forming polymer or the first non-covalent reticulator similar to ladder; and wherein the non-covalent, shell-like crosslinker has the ability to form a shell-like complex with at least one of the film-forming polymer, the first non-covalent, stair-like crosslinker or the second non-covalent, stair-like crosslinker.

24. - The composition according to claim 23, further characterized in that the second non-covalent crosslinker similar to ladder has the ability to form an interpolymeric complex similar to ladder with the first non-covalent crosslinker similar to ladder and the non-covalent crosslinker similar to casing has the ability to form a shell-like complex with the second non-covalent, stair-like crosslinker.

25. - The composition according to claim 24, further characterized in that the film-forming polymer and the first stair-like crosslinker are acrylate polymers, the second stair-like crosslinker is a poly (N-vinyl lactam), and the The shell-like crosslinker is an oligomeric alkylene glycol comprising approximately 1 to 20 alkylene oxide units in its chain.

26. - A method for selecting polymeric components for use in an adhesive composition, characterized in that it comprises: (a) selecting a film-forming polymer; (b) selecting a non-covalent, ladder-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form an interpolymeric stair-like complex with the selected film-forming polymer; and (c) selecting a carcass-like non-covalent crosslinker containing complementary reactive functional groups at its ends, and having the ability to form a carcass-like complex with at least one of the selected film-forming polymer or non-covalent crosslinker similar to selected staircase; and wherein the amount of the film-forming polymer is greater than the amount of the non-covalent, ladder-like crosslinker or the amount of the non-covalent, shell-like crosslinker.

27. The method according to claim 26, further characterized in that the amount of the film-forming polymer is from about 20 to 95% by weight of the composition, the amount of the ladder-like crosslinker is from about 0.5 to 40. % by weight of the composition, and the amount of the shell-like crosslinker is from about 0.5 to 60% by weight of the composition.

28. - The method according to claim 26, further characterized in that the film-forming polymer is selected from hydrophilic polymers, water-insoluble polymers that dilate in water, water-soluble polymers and hydrophilic and hydrophobic monomeric copolymers.

29. - The method according to claim 28, further characterized in that the hydrophilic polymer is selected from poly (dialkyl aminoalkyl acrylates), poly (d-alkyl aminoalkyl methacrylates), polyamines, polyvinyl amines, poly (alkylene imines), polyacrylic acids , polymethacrylic acids, polymaleic acids, polfonic acids, poly (N-vinyl lactams), polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates), poly (N-vinyl acrylamides), poly ( N-alkyl acrylamides), polar cellulose derivatives that they contain hydroxyl and carboxyl groups, alginic acid, chitosan, gelatin and copolymers thereof.

30. - The method according to claim 28, further characterized in that the water-insoluble polymer that expands in water is selected from cellulose derivatives and acrylate-based polymers and copolymers.

31. - The method according to claim 30, further characterized in that the cellulose derivative is a cellulose polymeric ester containing unesterified cellulose monomer units, cellulose acetate monomer units, and either monomeric butyrate units of cellulose or monomeric units of cellulose propionate.

32. - The method according to claim 30, further characterized in that the cellulose derivative is a polymer containing monomeric units of hydroxyalkylcellulose or monomeric units of carboxyalkylcellulose.

33. - The method according to claim 30, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate.

34. - The method according to claim 28, further characterized in that the water-soluble polymer is selected from water-soluble cellulose-derived polymers, homopolymer and copolymers of vinyl alcohols, homopolymer and copolymers of vinyl phenols, homopolymer and copolymers of ethylene oxides, homopolymer and copolymers of maleic acid, collagen, gelatin, alginates, starches and polysaccharides of natural occurrence.

35. The method according to claim 26, further characterized in that the non-covalent grating similar to ladder is selected from hydrophilic polymers, water-insoluble polymers that dilate in water, water-soluble polymers, hydrophilic and hydrophobic monomeric copolymers, and combinations thereof.

36. The method according to claim 34, further characterized in that the hydrophilic polymer is selected from poly (dialkyl aminoalkyl acrylates), poly (dialkyl aminoalkyl methacrylates), polyamines, polyvinyl amines, poly (alkylene imines), polyacrylic acids, acids polymethacrylics, polymaleic acids, polysulfonic acids, poly (N-vinyl lactams), polyalkylene oxides, polyvinyl alcohols, polyvinyl phenols, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates), poly (N-vinyl acrylamides), poly (N-) alkyl acrylamides), polar cellulose derivatives containing hydroxyl and carboxyl groups, alginic acid, chitosan, gelatin, combinations and copolymers thereof.

37. The method according to claim 35, further characterized in that the water-insoluble polymer that expands in water is selected from cellulose derivatives, polymers and acrylate-based copolymers and combinations thereof.

38. - The method according to claim 37, further characterized in that the cellulose derivative is a polymeric cellulose ester containing unesterified cellulose monomer units, monomer cellulose acetate units, and either monomer units of cellulose butyrate or units monomeric cellulose propionate.

39. - The method according to claim 37, further characterized in that the cellulose derivative is a polymer containing monomeric units of hydroxyalkylcellulose or monomeric units of carboxyalkylcellulose.

40. The method according to claim 37, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate.

41.- The method according to claim 35, further characterized in that the water-soluble polymer is selected from water-soluble cellulose-derived polymers, homopolymers and copolymers of vinyl alcohols, homopolymer and copolymers of vinyl phenols, homopolymer and copolymers of oxides of ethylene, homopolymers and copolymers of maleic acid, collagen, gelatin, alginates, starches, polysaccharides of natural occurrence and combinations thereof.

42. - The method according to claim 35, further characterized in that it additionally comprises selecting one or more additional non-covalent crosslinkers similar to ladders.

43. The method according to claim 26, further characterized in that the non-covalent, shell-like crosslinker is selected from monomeric and oligomeric alkylenglycols comprising from about 1 to 20 alkylene oxide units in their chains, polyalcohols, alkanediols, diacids carbon atoms, ether alcohols, poly (alkylene glycol diacids) and combinations thereof.

44. The method according to claim 43, further characterized in that it additionally comprises selecting one or more additional shell-like non-covalent crosslinkers. 45.- A method for manufacturing an adhesive composition, characterized in that it comprises: (a) (i) selecting a film-forming polymer; (ii) selecting a non-covalent, ladder-like crosslinker containing complementary reactive functional groups in the repeating units of the axis, and having the ability to form an interpolymeric stair-like complex with the selected film-forming polymer; and (iii) selecting a carcass-like non-covalent crosslinker containing complementary reactive functional groups at its ends, and having the ability to form a carcass-like complex with at least one of the selected film-forming polymer or the similar non-covalent crosslinker. to selected staircase; and wherein the amount of the polymer forming film is greater than the amount of the non-covalent crosslinker similar to ladder or the amount of the non-covalent crosslinker similar to carcass; (b) mixing the film-forming polymer, the non-covalent, ladder-like crosslinker and the non-covalent, shell-like crosslinker; and (c) forming an adhesive composition by melt extrusion or solution casting.