MXPA00003491A - Method and compositions for in situ - Google Patents

Abstract

Methods and compositions for forming protective and/or medicated films on body tissue. Liquid compositions contain a hydrophobically modified polymer, other than an esterified lower-hydroxyalkyl-subsituted cellulose, suspended or dissolved in a solven. The modified polymer is soluble in the solvent but insoluble in body fluids. The compositions may optionally contain a separate medicinal component, i.e., one which is present in addition to any medications, if any, present in the solvent, in the modified polymer and in any other additive components such as flavors, skin penetrants, preservatives, other solvents for the additives, etc. A protective and/or medicated film is formed in situ upon body tissue by applying the liquid composition to the tissue and separating the solvent from the composition, e.g., by vaporization.

Description

METHOD AND COMPOSITIONS FOR IN S1TU TRAINING PROTECTIVE AND / OR MEDICAL FILMS ON BODY TISSUES This invention relates to methods for the in situ formation of protective films on body tissues. Furthermore, the invention relates to compositions that form medical films in situ on body tissues. In another aspect, the invention provides methods and compositions for in situ formation of protective and / or medical films on body tissues. According to another aspect, the invention provides methods and compositions for the in situ formation of films on body tissues, films that provide slow or sustained release of topical medicaments and / or provide a protective coating for the underlying tissues. Pharmacologists have long sought to provide methods and compositions for the in situ formation of protective and / or medical films on body tissues, so that a protective film can be formed and maintained in specific locations on or within the human body. or animal The underlying body tissue may have a cut, abrasion, wound or injury, or it may become infected. Such a protective film can prevent the attack of the underlying wound or injury by external substances, germs, etc., or prevent the infection of healthy surrounding tissue, preventing the spread of infection, for example by viral diffusion. Alternatively, the body tissue, to which a medicinal film is applied, may be healthy, but it is desired to administer a drug for absorption through the skin or the surface of an internal organ. In particular, medicines, such as topical anesthetics, corticosteroids, bactericidal and virucidal sterilizing agent and the like, are difficult to maintain in proper contact with the various tissues of the body, due to the physical movement of the underlying or adjacent tissues or the abrasion of such tissues by the movement of wound bandages, clothing, etc. It is especially difficult to maintain the protective and / or medicinal films on moist or wet tissues, such as mucosal tissues, and on other tissues of the body, which exude or secrete blood, sweat or other aqueous fluids from the body. In the case of mucosal tissue, it is considered practically impossible to reliably maintain a protective or medicinal treatment composition at the treatment site. The mucosal tissues are hairless and moist initially, which interferes with such compositions in their intended locations. The use of topical anesthetics to reduce pain is known. For example, commercially available preparations containing benzocaine or corticosteroids and various thickeners are widely used. However, they do not form coherent, persistent films in the mouth and move easily from the site of the ulcer by saliva and physical movement of the tissues that surround it. An intra-oral ointment base in the oral cavity has been supplied, which consists essentially of sodium carboxymethyl cellulose and pectin. However, such ointments are not considered sufficiently persistent to solve the basic problem of forming a protective film on an oral injury and / or maintaining a topical analgesic or other medicament in contact with an ulcer for up to several hours. The dose of topical adhesive for mucosal ulcers or lesions has been proposed in the form of a two-phase tablet, which has a preformed, peripheral adhesive film of hydroxypropylcellulose (hereinafter referred to as "HPC") with a medicament in an oleaginous core of cocoa butter, which is immediately behind the underlying tissue. This device is reported to adhere to the mucous of dogs for thirty minutes up to six hours. Mixtures of HPC and polyvinyl acetate have been proposed as carriers for the formation of films for medicines, but, according to our knowledge, the use of such systems for the intra-oral application of topical medicines has not been successful. The previously molded films of analgesics carrying HPC and antibiotics have been reported, anecdotally, for the treatment of leukoplak pain. The alkylcellulose and / or cellulose ether compounds have been used as thickeners or ointment bases for a wide variety of drugs. For example, hydroxyethyl cellulose (hereinafter "HEC") and / or HPC were used to form a gel for the application of topical acne medicaments in U.S. Patent No. 4,244,948 to Boghosian et al. The HEC was used to form a water soluble lotion or gel in a cold sore / fever blister medicament, sold as "Kan -A®", a registered trademark of Blistex, Inc., a water soluble film, formed from HPC was used as the carrier for a bactericide, in an immersion composition of bovine tits, in U.S. Patent No. 4,434,181 to Marks, et al. So far, it has been known that the pain associated with cold sores, fever blisters and recurrent aphthous stomatitis lesions (RAS) was temporarily alleviated by Tinnell's medicinal composition, US Patent No. 4,381,296, in a carrier of HPC-water, esterified with alcohol. However, the clinical tests did not show that the pain reduction was due to the action of the drugs, but rather that the main analgesic effect is believed to be due to the formation of a protective film, which formed on the lesions. This film, which persists over the injury for several hours, acts as a barrier to attacks by air, food, saliva, etc. This composition was first sold by Zila Pharmaceuticals, Inc., in the early 1980s, under the trade name "HERPAWAY11 and then sold, until 1993, under the trademark of" ZILACTIN "®. Later, in the mid 1980s, discovered that the ability to form the film of HERPAWAY and ZILACTIN® compositions was due to the partial esterification of the HPC component by the medicinal components of the Tinnell '296 patent, rather than by the simple deposit of a material of the HPC without modification, per se on the lesion, in the vaporization of the alcoholic solvent.

Later, a gel-like product has been sold, which is believed to contain hydroxyethyl cellulose (HEC), salicylic acid, ethyl alcohol and benzocaine. The composition forms a film on body tissues, but there are indications that it causes irritation of the underlying tissue. It is not known that the sliciloyl ester of the HEC is present or is formed in this composition. It is also known (Stoughton, Arch. Dermatol, 1962, 86, 608-610, Stoughton, Arch Dermatol, 1985, 121, 63-67) to enhance the effects of topical medicaments by first applying a quantity of the medicament to the body tissue (epidermis). ), usually in a lotion or gel carrier, and then cover the site treated with the medicament with a waterproof, preformed elastic film or membrane. The membrane keeps the medication in contact with the tissue, to which it has been applied and prevents the physical dislocation of the medication by the fluids of the body, for example, washing the medication and separating it during the normal bath, dislocation by the movement of the underlying tissue and / or dislocation by abrasion of the medicament by clothing or contact with other body tissues or objects. Until our invention, there is only one known composition that provides the same results of potentiating the drug as those described by Stoughton, but which achieves those results by the direct in situ formation of a drug film on the body tissue, by applying a liquid composition which contains the drug. This composition was described by Pomerantz in U.S. Patent Nos. 5,081,158 and 5,081,157. The composition was a liquid (gel) comprising an HPC partially esterified in a volatile solvent (the original HERPAWAY / ZILACTIN), plus a medicinal component, ie separate, and in addition to any other medication, if any, which can be distributed of the original compositions of HERPAWAY / ZILACTIN. By applying these compositions to the body tissue and "drying" the liquid composition (gel) (by volatilization of the solvent), these compositions formed a coherent, adherent medicinal film deposited in situ containing the separate medicament on the tissue of the body. body, even on the moist mucosal tissue, and effectively distributes the separated medication to the underlying body tissue. Therefore, last versions of the original ZILACTIN® product, sold since 1993-94, containing separate medications, ie benzocaine (ZILACTIN®-B) and benzyl alcohol (ZILACTIN®), components recognized as effective for the treatment of cold sores and fever blisters.

Subsequent unpublished research has confirmed that the original ZILACTIN® films include very small amounts of HPC esterified by the salicylic and / or tannic acid components. This conclusion was supported by published literature, by Landoll, which confirms that water-soluble HPC normally becomes insoluble in water if it is modified by the binding of very small amounts (as low as 0.9-1.3% by weight) of water. hydrophobic groups (long chain hydrocarbons), through ether link, to the HPC backbone. The insoluble polymer modified by a hydrophobe, however, is soluble in aqueous ethanol. J. Polym. Sci. Polymer Chemistry Ed., 20, 443-455 (Wiley, 1982). Long before the publication of the Landoll document, it was known that hydrophobic groups impart water insolubility to chemical substances, while hydrophilic groups impart water solubility. In particular, the water solubility of the polymers is strongly dependent on the hydrophilicity and hydrophobicity of the repeating units of the polymer. For example, it is known from the prior art that the copolymer, poly (vinyl acetate - co-vinyl alcohol) contains both a hydrophilic substituent (hydroxyl group) and a hydrophobic substituent (the methyl group of the acetate), and more than 30 mole% of the monomer containing the methyl group, the copolymer is insoluble in water. It is also known from the Landoll document that the hydrophobic modification of hydrophilic (i.e., water-soluble) polymers such as HPC makes the modified polymer insoluble in water at body temperatures, even at low levels of modifier introduction. hydrophobic. For example, the introduction of only about three hydrophobic groups (eg, C12) per polymer chain of the HPC (molecular weight of 50,000) makes the modified polymer insoluble in water. The theoretical explanations of this phenomenon consider the formation of three dimensional networks of polymer molecules formed by the hydrophobic link or "association", of the limited number of hydrophobic groups attached to the polymer chains. These "linkages" between molecules serve to greatly increase the effective molecular weight of the polymer, drastically reducing its solubility. The increased viscosity is also observed for aqueous solutions of less extensively modified polymers. We have now discovered that the principle of hydrophobic modification of polymers is effectively employed to produce new liquid compositions to form films in situ in body tissues. These compositions are formed of a polymer and an agent ("interaction agent") that interacts with the polymer to form a product ("interaction product") which is substantially insoluble at normal body temperatures in water or aqueous body fluids, but that is soluble in a non-toxic volatile solvent. The application of this interaction product, dissolved in a non-toxic volatile solvent, will result in the in situ formation of a film of the interaction product on the body tissue, which includes wet surfaces such as mucosal tissues, in the evaporation of the volatile solvent , and the film is persistent because it is substantially insoluble in the body fluids of aqueous base. Depending on the chemistry of the specific method used to prepare the interaction product, it can be prepared separately and then dissolved in a suitable volatile solvent or, alternatively, if the reagents used to prepare the interaction product, and the reaction by-products, are pharmacologically acceptable, The interaction product can be prepared in situ in our liquid compositions. The interaction between the polymer and the interaction agent can occur during the manufacture or storage of the liquid compositions, during the application of the liquid compositions to the tissues of the body, or even during the "drying" of the liquid compositions by vaporization of the solvent volatile or during only some or all stages.

Also, because substantially the same result is obtained by the copolymerization of monomers with the hydrophilic and hydrophobic groups, those copolymer compositions and methods for the preparation are included as specific embodiments of the general principles of this invention. In this case, the agent that interacts (copolymerizes) with the polymer to form the water insoluble interaction product is itself another polymer, copolymer, modified polymer or modified copolymer. In short, therefore, according to our invention, we provide a method for forming a film in situ on the tissue of the body. Our method comprises the steps of (a) applying to the body tissue a liquid composition that includes a non-toxic volatile solvent and a polymer modified in solubility, in addition to an esterified HPC (from the Pomerantz patents), or a copolymer, the Lime is soluble in the solvent, but insoluble in body fluxes; and (b) separating the solvent from the liquid composition to form a persistent film. The film may act merely as a protective "bandage" film, which excludes air, bodily fluids and other foreign materials from the underlying lesion, or which prevents the escape of substances, eg, viruses, from an underlying film lesion, which can spread from the infection to or irritation of the surrounding healthy tissue. These liquid compositions of the invention may also contain additional medicinal components (ie, in addition to those components, if any, of the compositions forming the film, which may have an incidental medicinal effect) that are effectively distributed from these liquid compositions and / o of the films deposited in situ formed there. As will be apparent to those skilled in the art, the liquid compositions of the invention may also include additive components to modify the characteristics of the liquid compositions and / or facilitate the manufacture of the compositions, including, without limitation, the agents generally used in the same, as flavor agents, plasticizers, dermal penetrants, preservatives as well as other "secondary" solvents, which are used to dissolve these interaction agents and other additive components. If any of these additive components have any incidental medicinal effect, the term "separate" medicinal component is intended to mean a medicinal component in addition to those present in the primary solvent, in the modified polymer or copolymer in the additive components. The method of the invention also considers the steps of: (a) forming an interaction product by the interaction of a polymer (which may include HPC) and at least one interaction agent, in addition to the esterification agent (as in patent '158 of Pomerantz), which interacts with the polymer (and possibly with other components of the interaction mixture), to form an interaction product. The interaction agent is soluble in a solvent, but insoluble in bodily fluids; (b) solubilizing the interaction product in the solvent; and (c) forming a film in situ on the tissue of the body, applying the solvent solution of the interaction product to the body tissue and (d) separating the solvent from the liquid composition. As previously described, the interaction product can be manufactured separately and then solubilized in the solvent or, alternatively, the interaction product can be formed in situ, during the manufacture and / or storage of the liquid composition or during the drying of the application of the liquid composition on the tissue of the body, or both. Our invention also considers a liquid composition that forms a medical film in situ on the body tissue, which comprises: (a) a solvent; (b) an interaction product formed by the interaction between a polymer and an agent, in addition to an esterification agent, which is soluble in the solvent, but insoluble in body fluids; and (c) a medicinal component, in addition to any other medicament, if any, in the polymer, the interaction agents, the interaction product and the other functional additives in the composition. Likewise, the invention considers such a liquid composition, which contains such a separate medicament, but in which the substrate polymer is a polymer in addition to a cellulose substituted by lower hydroxyalkyl, in this case, the interaction agent may include esterification agents. The solvent for the interaction product is preferably a volatile solvent, such as, for example, volatile polar solvents. As used herein, the term "volatile" solvent means a solvent which evaporates (vaporizes) from the liquid compositions, after they are applied to the body tissue, at a rate which is sufficient to cause the formation of the liquid. film in the body tissue, within a practical period of time, for example from 30 seconds to 5 minutes. This allows the application of the liquid compositions by people with limited medical experience, for example technicians or even the patients themselves. The application site can be substantially immobilized, and abrasion of the site by other body parts, clothing, etc., and irrigation by body fluids can normally be suspended or eliminated during this appropriate short period of time, to allow the film formation. After the film is formed on the fabric, this film is sufficiently adherent and coherent, so it is persistent at the site of application for a sufficient time to allow the film to perform its intended function, that is to temporarily relieve the pain, forming a physical barrier over the site of application, and / or allowing the film to retain a separate medicament against the tissue (injury, wound, etc.) for a period of time sufficient to achieve practical therapeutic effects, for example 15 to 30 minutes until as much as 4 to 6 hours. The particular solvent for forming the liquid composition is selected by its ability to dissolve the components of the liquid composition, the ability to maintain the interaction product in solution or suspension until the application of the composition to the treatment site and the ability to separate quickly. of the composition after application to the body tissue, for example by vaporization, extraction, etc., as well as for its non-toxic characteristics when the composition is applied in the amount and for the time necessary to form a protective film and / or medicinal. Obviously, the solvent must not be toxic to the body in the amounts and contact times employed and must be chemically compatible with the other components of the liquid compositions, ie, these solvents are those which are "pharmacologically acceptable". Suitable solvents will be readily identified by those skilled in the art taking into account the present disclosure, for example, volatile polar solvents, which are medicinally compatible with the body tissue and which are chemically compatible with the other components of the liquid compositions, i.e. , these solvents that are "pharmacologically acceptable". Advantageously, the solvent is a lower alkyl alcohol, for example, preferably ethyl alcohol or isopropyl alcohol. Ethyl alcohol is preferred when the film is to be deposited in the oral cavity, while isopropyl alcohol is suitable for use in depositing films on the skin. The term "liquid" composition includes those liquids with a viscosity that varies from that of a "flowing" liquid to a viscous lotion or even a self-supporting, disseminable gel. Advantageously, in order to allow a more accurate application of the liquid to a specific treatment site, for example, a fever blister or a cold sore or a small wound, the liquid composition is preferably in the form of a spreadable gel, which can be conveniently filled into flexible dispensable tubes, which can be tightened to distribute the gel directly on the application site or on an applicator, such as at the tip of the finger or a plug, from which it is applied to the body tissue. The term "soluble" (in the solvent) means that the components of the liquid composition are either completely dissolved in or at least substantially, dissolved or suspended uniformly or dispersed substantially uniformly in the liquid composition, so that the The liquid composition is sufficiently stable to withstand the separation of one or more of its components, until the liquid composition can be applied to the body tissue. This can vary from a period of time of only a few minutes (in the case of liquid compositions that are to be applied soon after the formulation), to several years (for products sold through normal ethics or on counter-channels). The shelf life can be determined by accelerated aging tests, well known and accepted in the art. The term "insoluble" 11 in body fluids means that the interaction product is sufficiently resistant to solubilization or other actions that destroy the film or fluids of the body, for example saliva, sweat, blood and the like, to enable the film deposited in situ remains adhered to the tissue of the body and is sufficiently coherent to allow the film to perform its intended function, i.e. act as a physical protective coating for the underlying tissue, and / or distribute the medicament separated therefrom. The term "non-toxic" means that a component is not detrimental to the tissues of the body or to the functions of the body at the concentrations employed and / or for the time that the component is in contact with the tissue. of the solvent from the liquid composition means the removal of the solvent from the liquid composition, after application to the tissue of the body, by any suitable technique, such that the interaction product is deposited as an adherent, coherent film on the fabric, for example, simply by air drying the applied liquid composition, drying in the accelerated air (as by heating the composition liquid applied with hot air or a heat lamp) or preferably extracting the solvent from the liquid composition by the moderate irrigation of the application site with an aqueous solvent, which dissolves part or all of the volatile solvent and simultaneously helps in precipitating the product from insoluble interaction in water and / or the drug separated, as a coherent, persistent film. The terms of in situ film formation or in situ film formation on the corporeal tissue means that the film autogenously forms on the body tissue in the separation of the solvent component from the liquid compositions, in distinction from the films that are previously formed, for example, by molding, extrusion or thermal compression or molding and then applied to body tissues. The term "over" the corporeal one, does not exclude the possibility that an intermediate film of another chemical or physical nature can be placed between at least part of the film of the interaction product of the body tissue. For example, the application of a liquid composition containing ethyl alcohol as the solvent to the wet mucosal tissue causes the more or less immediate denaturation of the saliva and / or tissue proteins that are underlying the film deposited in situ described herein. Such an intermediate denatured protein film does not appear to degrade the effectiveness of the interaction product, either as a protective barrier or as a carrier, for a separate medication. In fact, such a layer or intermediate material actually appears to aid in the adhesion of the film of the interaction product deposited in situ to the underlying tissue. In accordance with the presently preferred embodiments of the invention, the interaction product component of the compositions of the invention are present in the composition in an amount of about 1 to 10% by weight of the final composition. The ratio of the interaction product in the composition affects the time required for the composition to air dry and form a firm adhesive film. With lower contents of the interaction product, the compositions dry more slowly, but the resulting film is more coherent and resistant to abrasion. With higher contents, the film is formed more rapidly by air drying, but the resulting film is less coherent and adhesive due to the fact that the portion of the film on the surface of the applied composition and the surface of the body tissue dry to different regimes At present, it is preferred to employ sufficient interaction product and solvent in the final composition to supply an easily applied gel, which dries to form the film deposited in situ in a practical period of time, in distinction from a liquid or lotion that runs. , which is difficult to maintain over the treatment site attempted for a sufficient time to form the film deposited in situ and which may take too long a time to form the film. Similarly, the amount of the interaction product should not be so great or the amount of the solvent so small as to form a rigid gel, which may be difficult to distribute or disseminate on the application site. This optimum amount may vary depending on the exact chemical composition of the interaction product and the nature of the other components of the final compositions. However, this optimum amount can be easily determined by the person skilled in the art, without undue experimentation, taking into account this description. The invention can be visualized according to the use of an interaction product, comprising a three-part molecule, composed of a polymer, an "interlayer" and a hydrophobic group, schematically represented as: (polymer) - (interlaced) - (hydrophobic group) in which the interleaver may or may not contain atoms that are originally part of the polymer and / or the hydrophobic group. These major constituents of the interaction product consist of:) a polymer, which includes synthetic polymers, natural polymers and synthetically modified natural polymers, including homopolymers, like block polymers, alternatively, and random copolymers; ) a "linker", which may consist of organic functional groups known to come together in different domains of complex organic molecules, including, but not limited to, the ethers (0 = C-0) and their sulfur derivatives [ that is, derivatives thio (S = C-0), thiolo (0 = CS), and dithio (S = CS)], ethers (-0-) and their derivatives thio (-S-), urethanes [0- ( C = 0) -N] and its derivatives thio (for example xanthanatoses), carbonates [0- (C = 0) -0] and its derivatives thio, amides (0 = CN) and imides and their derivatives thio, ureas [N - (- C = 0) -N] and its derivatives thio, amines (CN), imines (C = N), acetals and semiacetals [RCH (0R ') 0R ") and RCH (0R') (OH)] and its derivatives thio, ketals and semicetals [RR'C) OR "(OR1 • ') and RR'C (0R") 0H)] and its derivatives thio, sulfonates [-S (= 0) 2-0], sulphinates [ -S (= 0) -0], sulfonamides [S- (= 0) 2-N], sulfinamides [S (= 0) -N], disulfides (.-SS-) and their various mono- and poly-oxides , sulfoxides (RS (= 0) - R1], sulfones [RS (= 0) 2-R '], simple or multiple carbon-to-carbon bonds, alcohols [RC (0H) R '], ketones [R- (C = 0) -R'] and thioketones [R- (C = S) -R1], phosphate esters [R0-P (= 0) 0 ~ ) -OR1 and R0- P (= 0) (OR ") (OR")], phosphamides [RO-P (= 0) (0 ~) -NR 'and RO- P (= 0) (OR') ( NR ") and RO-P (= 0) (NR ') NR") and 0 = P (NR) (NR1) (NR ") and their less substuted analogs, for example, R0-P (= 0) (NR1 ) (NH2)], phosphonate esters [RP (= 0) (0") - 0R!] And phosphonamides [RP (= 0) (0 ~) -NR and R- P (= 0) (NR1) NR" and its less substituted derivatives], phosphinate esters (RP (= 0) -OR '] and phosphinemides [R- P (= 0) -NR'] or combinations thereof. in which the various groups R, R1, R "and R * '• are groups of polymers and / or hydrophobes that bind. 3) a hydrophobic group that can derive primarily its hydrophobicity from a hydrocarbon group, which includes unsaturated hydrocarbon chains (e.g., terpenes) and rings (i.e. cycloalkyls) and combinations thereof (e.g., steroids), which may contain one or more heteroatoms in the chains and / or rings, or fats, oils, waxes or a haloalkyl group, such as the fully fluoro-substituted alkyl chain [eg, (CF) n (CF3)] or ring or its combinations, such groups typically exhibit higher hydrophobicity than the affluent unsubstituted hydrocarbon of comparable length, or of an aromatic or aralkyl group (i.e., aromatic and aliphatic constituents combined) or heterocyclic groups (eg, furyl, thienyl) or of a silicone ( for example one or more dimethylsiloxane units) or another hydrophobic group containing heteroatoms, and including any other group with a generally recognized hydrophobic character.

Various embodiments of the invention, which are chosen to illustrate the practice of the invention and which are not intended as limitations of the scope thereof, include: 1) HPC (HPC-OH), a synthetically modified natural polymer, hydrophobically modified by the covalent attachment of a large hydrocarbon chain, via a urethane linkage to a hydroxyl group of the HPC, as, for example, through the reaction of HPC-OH with octadecyl isocyanate, shown below: HPC-OH + 0 = C = N- (CH2) i7CH3? HPC-O-C (= 0) -NH- (CH2) 17CH3, 2) carboxymethylcellulose, a synthetically modified natural polymer, hydrophobically modified by the covalent attachment of a hydrocarbon chain via an amide bond, for example, through the reaction of carboxymethylcellulose with a condensing agent and the N- hydroxysuccinimide, to thereby produce an active ester [CMC-C (= 0) -X], followed by treatment with a large chain amine (e.g. octadecylamine), as shown below: CMC-C (= 0) -X + CH3 (CH2)? 7NH2-CMC-C (= 0) -NH (CH2) 17CH3 poly (vinyl alcohol - co-vinyl acetate), a synthetic vinyl polymer, hydrophobically modified by the covalent attachment of a hydrocarbon chain via an ester linkage, such as, for example, through the reaction of a polymer with a fatty acid chloride, in the presence of a base, shown below (in the block polymer, randomly or alternatively the copolymer, does not mean this involved by the structural representation: polyiminodiacetamide, a synthetic polyether, hydrophobically modified by the covalent attachment of a perfluoroalkyl chain via a sulfonamide linkage, as, for example, through the reaction of amine functional groups linked to the polymer with perfluoro fluoride -1- octansulfonyl, shown below: H C? 3IC? Z ^ SOJP H The preparation of the hydrophobically modified polymers, described above, can be carried out in a homogeneous solution by the use of a suitable solvent or by emulsion techniques, in which the phase containing the polymer is mixed with the phase containing a hydrophobic reagent for bond formation in the two-phase mixture.

The following specific examples are presented to illustrate the preparation of compositions that are useful in accordance with the various embodiments of the invention. They do not attempt to indicate or limit the scope of the invention, which is pointed out only in the appended claims.

Example 1 Synthesis of Hydrophobically Modified HPC A urethane linkage was employed in the hydrophobically modified polymer described in this example. To a solution of 5.0 g of HPC (molecular weight of 50,000 and molar substitution = 3.0) in 575 ml of tetrahydrofuran (or an appropriate volume of another suitably non-reactive solvent, such as dioxane or pyridine) under an inert atmosphere, a solution of octadecyl isocyanate was added slowly with stirring. in 50 ml of the same solvent. To achieve approximately 1% of the link modifier, the amount of the octadecyl isocyanate must be 0.05 g in excess of the amount destroyed by any moisture contained in the HPC. After a reaction time of 1 day, the reaction mixture was carefully poured into cold water to cancel the reaction and precipitate the product. This product was collected by filtration or centrifugation, washed with water and dried in the air. The degree of substitution was determined by nitrogen analysis. The variation of the modified binding amount, when required to optimize the water solubility of the interaction product, can be achieved by varying the reaction time, temperature and / or ratio of the reactants.

Example 2 Synthesis of carboxymethylcellulose ,. hydrophobically modified An amide bond was employed in the hydrophobically modified polymer described in this example. To a suspension of 5 g of carboxymethylcellulose in ml of dioxane, which contains 0.1 g of the N-hydroxysuccinimide, was added 3 g of the 1,3-dicyclohexylcarbodiimide. The reaction mixture was stirred for 4 hours to allow formation of the active ester of the carboxyl groups bonded to the polymer. This polymer was collected by filtration, washed with dioxane and transferred to a solution of 0.05 g of octadecylamine in 25 ml of dioxane, to achieve about 1% bound modifier. After a reaction time of 1 day, the reaction mixture was poured into aqueous acid to suppress the reaction, solubilize any remaining amine and precipitate the product. This product was collected by centrifugation, washed with water and dried in air. The degree of substitution was determined by nitrogen analysis. To optimize the solubility of the water of the modified polymer, some variation in the amount of the linker of the modifier may be required, which may be achieved by varying the reaction time, temperature, and / or the ratio of the reactants.

Example 3 Synthesis of hydrophobically modified polyvinyl alcohol-co-vinyl acetate An ester linkage was employed in the hydrophobically modified polymer described in this example. To 5 g of the polyvinyl alcohol-co vinyl acetate, whose content of vinyl acetate is less than 30 mol%, prepared by the controlled saponification of the polyvinyl acetate, 50 ml of pidirine was added, and the mixture was stirred overnight. To this stirred mixture, 0.057 g of palmityl chloride, dissolved in 5 ml of pyridine, was added to achieve about 1% of the linker modifier. After a reaction time of 1 day, the mixture was added to aqueous hydrochloric acid to precipitate the product. This product was collected by filtration, washed with water, and redissolved in ethyl alcohol and reprecipitated with water, for purification, and air-dried. The degree of substitution was determined by saponification and analysis of fatty acids. For the solubility of the optimal modified polymer, the variation of the amount of the linked modifier can be achieved by varying the reaction time, temperature and / or ratio of the reactants.

Example 4 Synthesis of hydrophobically modified polyiminodiacetamide A sulfonamide linkage was employed in the hydrophobically modified polymer described in this example. To a solution of 5 g of the polyiminodiacetamide in 25 ml of toluene, 0.05 g of perfluoro-1-octansulfonyl fluoride, dissolved in 5 ml of toluene, was added to achieve about 1% of the linker modifier. After a reaction time of 1 day, the mixture was carefully added to cold water, to suppress the reaction and precipitate the product. The finely divided silica can be advantageously added as a catalyst, and the product was collected by filtration, washed with water and air dried. The degree of substitution was determined by the analysis of fluorine and sulfur. For optimum properties of the water solubility of the modified polymer, the variation of the ligand amount of the modifier was achieved by varying the reaction time, temperature and / or reagent ratio.

Example 5 Synthesis of Hydrophobically Modified Hydroxyethyl Cellulose (HEC) An ester bond was employed in the hydrophobically modified polymer in this example. To 5 g of the HEC in 50 ml of pyridine, were added 0. 057 g of palmitoyl chloride, dissolved in 5 ml of pyridine, to achieve approximately 1% of the binding modifier. After a reaction time of 1 day, the mixture was added to aqueous hydrochloric acid to precipitate the product. This product was collected by centrifugation, washed with water and redissolved in isopropyl alcohol and reprecipitated with water, for purification, and air dried. The degree of substitution was determined by saponification and analysis of fatty acids. For the optimum properties of the water solubility of the modified polymer, the variation of the ligand amount of the modifier can be achieved by the variation of the time of the reaction time, temperature and / or ratio of the reactants.

Example 6 Preparation of the hydrophobically modified HE. during the manufacture / storage of a film-forming composition In this example, the HEC modified hydrophobically by the ester linkage was prepared during the manufacture / storage of the final composition forming the film. To 1 g of the HEC in 5 g of polyethylene glycol, 0.035 g of octadecenylsuccinic anhydride and 0.015 g of triethanolamine were added. After a reaction time of 1 day, 13.95 g of aqueous ethanol was added to the mixture to destroy any unreacted anhydride and dissolve the modified HEC. By adjusting the substitution taste, optimum water solubility properties of the film, the amount of HEC, anhydride, triethanolamine and polyethylene glycol are obtained, as well as the reaction time, temperature and H can be varied. 10% by weight benzocaine was added to the modified modified HEC. The resulting composition is self-stable and effectively works to treat the pain of cold sores, fever blisters and RAS lesions, by a combination of "bandage" film "Protective, formed in situ after the application of the composition to the site of the lesions and the anesthetic effect of benzocaine. The film remained in place over the injury, for several hours.

Example 7 Other compositions that form films. containing a separate medicament Therapeutically effective amounts of several topical medicines were incorporated into ethanol solutions containing from 2 to 8% by weight of the modified polymers of Examples 1 to 6. The resulting mixtures are self-stable and were applied topically to tissues of the body and air dried, forming coherent, adherent films, which contain the medicines. The drugs migrated to the treatment site to effectively achieve the desired therapeutic result Anesthetics Benzocaine Dyclonine hydrochloride Hexylcaine hydrochloride Pramoxine hydrochloride Butamben picrate Tetracaine hydroiodide Anti-inflammatory agents Hydrocortisone acetate Betamethasone valerate Triamcinolone acetonide Fluocinonide Dexamethasone Methylprednisone acetate Antibiotics Clindamycin 10 Erythromycin Meclocycline sulfosalicylate Tetracycline Chlorhexidine Neomycin 15 Polymyxin Sulfate Bacitracin Sulfadoxine Antifungal Agents Clotrimazole 20 Miconazole Nystatine Acyclovir Interferon Vidarabine 25 Betadine Topical Agents Miscellaneous Salicylic Acid Isotretinoin Aloe Vera Alclometason Dipropionate Caprylic Acid Lindane Having described the invention in such terms as to enable a person skilled in the art to understand and practice the same and having identified the best currently preferred modes of the invention, WE CLAIM :

Claims (6)

R E IVI N D I C T I O N S

1. A method for forming an in situ film on body tissues, this method comprises: a.) Applying a liquid composition to the tissues of the body, which includes: (i) a solvent, (ii) a polymer, in addition to a cellulose of lower hydroxyalkyl, esterified, which is soluble in the solvent, but insoluble in body fluids; And b.) Separate the solvent from the liquid composition.

2. A method for forming an in situ film on body tissues, this method comprises: a.) Applying a liquid composition to the tissues of the body, which includes: (i) a solvent, (ii) a polymer, in addition to a cellulose of lower hydroxyalkyl, which is soluble in said solvent, and (iii) at least one interaction agent, in addition to an etherification agent, which interacts with the polymer to form an interaction product, which is soluble in the solvent , but insoluble in body fluids; And b.) Separate the solvent from the liquid composition.

3. A method for forming an in situ film on body tissues, this method comprises: a.) Applying a liquid composition to the tissues of the body, which includes: (i) a solvent, (ii) a polymer, which is soluble in the solvent, and (iii) at least one interaction agent, in addition to the esterification agent, which interacts with the polymer to form an interaction product, which is soluble in the solvent, but insoluble in body fluids; And b.) Separate the solvent from the liquid composition.

4. A composition, which forms a medical film in situ on body tissues, this composition comprises: a.) A first solvent; b.) a polymer, in addition to the hydroxyalkyl lower cellulose, which is soluble in the first solvent; c.) at least one interaction agent, which interacts to form an interaction product, this interaction product is soluble in the first solvent, but insoluble in body fluids; And d. ) at least one additive component, selected from the group consisting of flavoring agents, plasticizers, dermal penetrants, preservatives and second solvents for the interaction agent and the additive component; e.) a medicinal component, in addition to any other medication, if any, in components (a), (b), (c) and (d).

5. A composition, which forms a medical film in situ on body tissues, this composition comprises: a.) A first solvent; b.) a polymer, hydrophobically modified, which is soluble in the first solvent, but insoluble in body fluids, this modified polymer is formed by the interaction with at least one interaction agent, in addition to the esterification agent, this polymer modified is soluble in the first solvent, but insoluble in body fluids; c.) at least one additive component, selected from the group consisting of flavor agents, plasticizers, dermal penetrants, preservatives and second solvents, if any, for the interaction agent and the additive component; d.) a separate medicinal component, in addition to any other medication, if any, in components (a), (b) and c).

6. A composition, which forms a medical film in situ on body tissues, this composition comprises: a.) A first solvent; b.) a modified polymer, in addition to the modified lower hydroxyalkyl cellulose, which is soluble in the first solvent, but insoluble in the body fluids, this modified polymer is formed by the interaction of a polymer with at least one agent of interaction, this modified polymer is soluble in the first solvent, but insoluble in body fluids; c.) at least one additive component, selected from the group consisting of flavoring agents, plasticizers, dermal penetrants, preservatives and second solvents, if any, for the interaction agent and the additive component; d. ) a medicinal component, in addition to any other medication, if any, in components (a), (b) and (c).