JP2003519641A - Topical medicinal bioadhesive composition, and methods of use and preparation thereof - Google Patents

Abstract

  (57) [Summary] A film-forming gel that adheres to mucosal surfaces and body tissues and provides localized delivery of the drug to the treatment site. The gel contains a film-forming component containing a water-soluble cellulose polymer and a bioadhesive polymer. The gel also contains a volatile solvent and a drug.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION

  The present invention relates to topical medicated bioadhesive compositions.

In particular, the invention relates to such compositions, which are particularly adapted for use in the administration of topical agents to human tissue.

In a further aspect, the invention relates to a method of preparing such a bioadhesive composition.

[0004]

BACKGROUND OF THE INVENTION

For many years before the mid-1980s, medical and dental clinicians have been strongly adherent to human tissue, especially mucosal tissue, and are chemically compatible with a wide variety of agents,
And they have sought a local carrier in which such agents would be bioavailable to the underlying tissue. For example, Stoughton, Ann. .Pharrnacol. Toxicol,
1989, 29: 55-69.

[0005]

[Prior art]

In the mid-1980s, a topical biomedical adhesive product became commercially available and distributed under the registered trademark "ZILACTIN®". US Patent No. 5,081 as Pomerantz
These compositions, disclosed in U.S. Pat. No. 5,157,158 and U.S. Pat. No. 5,081,158, formed a medicated film on body tissue. The composition adhered strongly to moist mucosal tissue for up to several hours. The components of these film-forming compositions were chemically compatible with a wide variety of drugs, which were readily bioavailable from in situ deposited films.

The compositions disclosed in the Pomerantz patent include esterification reagents (eg salicylic acid, and / or salicylic acid, and / or hydroxypropylcellulose, an esterification reagent that reacts with HPC to form an insoluble reaction product in body fluids such as saliva. Tannic acid), and non-toxic volatile solvents for HPC and reaction products.

Commercial products such as ZILACTIN® products, as well as active agents such as topical analgesics (eg benzocaine) and topical mouth erosives (eg benzyl alcohol), using Pomerantz technology The product sold under the trademark "PRABASE GEL", which was prescribed between 1994-1996, was widely and rapidly accepted in the "prescription" drug market.

More recently, a similar product has emerged that uses ethyl cellulose instead of the esterified HPC of the Pomerantz formulation as a film forming agent. However, this product still contains compounds such as salicylic acid and tannic acid. It is not known what reaction occurs between salicylic acid and tannic acid in these more recent products and ethyl cellulose. See, for example, Chrch et al., US Pat. No. 5,885,611, which claims that salicylic acid is a "keratolytic agent" and tannic acid is a "astringent."

More recently, a combination of ethyl cellulose and bioadhesive polymer was used in a formulation to form a topical medicated film in combination with an alcoholic solvent and a pharmaceutical ingredient disclosed in US Pat. No. 5,955,097 to Tapolsky et al. Was done. Whether such formulations have the same tissue adhesion as Pomerantz, these carrier formulations
It is not known if they are chemically compatible with a wide variety of drugs, or if the drugs contained in these formulations are readily available locally to the body.

Topical carriers known to those of ordinary skill in the art include gels, pastes, tablets and membranes. However, these products would lack one or several favorable properties for devising an efficient and commercially acceptable pharmaceutical delivery. Some of the properties desired as a topical carrier include water solubility, ease of handling, and use with minimal foreign body sensation at the treatment site. Other properties desired for efficacy, user-friendly products for treating mucosal surfaces include use of pharmaceutically acceptable ingredients or substances, initial adhesion to the mucosal surface used, affected tissue. Increased residence time for protection or delivery of the pharmaceutical ingredient and ease of removal from the diseased tissue or natural dissolution at the delivery site of said delivery means is desired.

Gels for use on mucosal tissues and especially the oral cavity are known to the person skilled in the art. For example, US Pat. No. 5,192,802 discloses a gum gel made by mixing sodium carboxymethyl cellulose and xanthane gum. The gel is
It could also have potential use for erosion of the mouth, febrile herpes, and hemorrhoids. However, this type of pharmaceutical carrier has a very limited residence time, and body fluids such as saliva quickly wash it off the treatment site. Topical gels are also disclosed in US Pat. Nos. 5,314,914; 5,298,258; and 5,642,749. In those patents, the gels disclosed therein do not use water-soluble or oily media and use different types of gelling agents.

Denture “adhesive” pastes are also known to those skilled in the art. However, agents such as local narcotics would be used as pastes to relieve erosion in the mouth, but in these formulations, rather than to protect tissues or to deliver the medication locally, Its adhesiveness is mainly used to bond the denture and the gum. U.S. Pat. Nos. 4,894,232 and 4,518,721 disclose denture adhesive pastes. The '721 patent discloses the combined use of sodium carboxymethyl cellulose and polyethylene oxide in polyethylene glycerol.

Pastes have also been used as protective materials and as drug delivery systems. One of such pastes is a product commercialized under the name Orabase (R) -B. This product is a thick paste containing benzocaine to reduce sores in the mouth. Ingredients include guar gum, sodium carboxymethyl cellulose, tragacanth gum, and pectin. It paralyzes the applied area, but the paste was easily excluded from the area and had a limited residence time.

Adhesive tablets are disclosed in US Pat. No. 4,915,948. The water-soluble adhesive material used in the present invention is xanthan gum or pectin together with an adhesion-enhancing material such as polyol. Residue times were improved upon use of bioadhesive tablets, but they were not user friendly, especially for oral use, and were associated with their hardness, size and slow dissolution time. Discomfort is given. Adhesive tablets are also disclosed in U.S. Pat. Nos. 4,226,848; 4,292,299; and 4,250,163, which are single or double layer devices having an average thickness of 0.2 to 2.5 mm. The adhesive tablets disclosed in these patents are
It is used as a binder in non-adhesive components such as cellulose ethers, bioadhesive components such as polyacrylic acid, sodium carboxymethylcellulose, or polyvinylpyrrolidone, and in tableting applications. The cellulose derivative may or may not be water soluble. The cellulosic materials claimed in the '299 patent are methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

The use of thinner, softer, and therefore foreign-film sensation, laminate film "plasters" is disclosed in US Pat. Nos. 3,996,934 and 4,286,592. These products are used to deliver drugs across the skin or mucous membranes. The laminated film typically includes an adhesive layer, a storage layer, and a support layer. Designed to release the drug through the skin in any proportion over time, these devices are usually not water-soluble and do not dissolve or are not washed away by body fluids.

In addition to membrane systems for delivery of drugs through the skin, membrane delivery systems for use on mucosal surfaces are also known. These types of systems, which are insoluble in water and are usually in the form of preformed and laminated, extruded or synthetic membranes, have been described in U.S. Patents 4,517,173; 4,572,832; 4,713,243. No. 4,900,554; and No. 5,137,72 9. The '173 patent discloses and claims a film adhesive film comprising at least three layers. The membrane comprises a pharmaceutical layer, a poorly water soluble layer made by the combination of one or more cellulose derivatives with poorly water soluble soluble fatty acids, and an intermediate layer made of a cellulose derivative.
The '832 patent relates to a soft membrane for buccal delivery. The film is made by using water-soluble proteins, polyols, and polyhydrogenated alcohols such as cellulose, and polysaccharides in combination, and the use of coloring or flavoring agents is also taught. In the '243 patent, 40-95% water soluble hydroxypropyl cellulose, 5-60% water insoluble ethylene oxide, 0-10% water insoluble ethyl cellulose, propyl cellulose, polyethylene or polypropylene, and Disclosed are single or multi-layered thin films made from a drug. The membrane is a tri-layer stack including an adhesive layer, a reservoir layer, and a water-insoluble protective outer layer.

[0017] In the '729 patent, a soft, adhesive composition containing a systemic drug and applicable to the oral mucosa containing a mixture of vinyl acetate, a water-insoluble homopolymer, an acrylic acid polymer, and a cellulose derivative. Teaches the membrane. Finally, in the '554 patent, the oral cavity has an adhesive layer containing a mixture of an acrylic acid polymer, a water-insoluble cellulose derivative, and a pharmaceutical formulation, and a water-insoluble or slightly soluble backing layer. A device for use is disclosed. An adhesive layer containing the drug and applicable to the mucosal surface delivers the drug to the underlying tissue.

A composition comprising hydroxypropyl cellulose, a non-toxic volatile solvent, a reaction product that reacts with hydroxypropyl cellulose to form a reaction product that is soluble in said solvent, but is insoluble in body fluids at body temperature, and a pharmaceutical ingredient. But US Patent 5,081,
No. 157 and No. 5,081,158. Cross-linking reagents may be used.
After use and air drying, the film is formed in situ. As mentioned in the '158 patent, "alkyl or hydroxyl substituted cellulose is not a suitable replacement for hydroxyl propyl cellulose" to form an adhesive film in body tissue (column 2, Lanes 28-31).

Although the '158 patent advises the inclusion of an esterifying agent in the composition effective for film formation, the present invention does not require the use of an esterifying agent to be applied to the treatment site. Provide a membranous, film-forming pharmaceutical formulation for use on mucosal surfaces and body tissues to provide effective drug delivery to the treatment site, tissue perimeter, and other bodily fluids. The film-forming composition is a water-soluble cellulose polymer, preferably hydroxypropyl cellulose, and a bioadhesive polymer.

[0020]

[Outline of the Invention]

The present invention applies to mucosal surfaces and other body tissues utilizing volatile or diffusible solvents, water soluble polymers, bioadhesive polymers, and pharmaceutically effective amounts of active pharmaceutical ingredients. To a mucoadhesive gel for Typically, the composition will contain at least one water soluble hydroxyalkyl cellulose, a bioadhesive polymer, a volatile non-water soluble solvent, and at least one active pharmaceutical agent. In use, the gel forms an adherent, firm and sticky film to provide protection at the treatment site. The carrier composition is chemically compatible with a wide variety of drugs. The drug is derived from the bioavailable drug for delivering the drug below the treatment site, surrounding body tissue, and bodily fluids. Also provided are methods for protecting the mucosal surface or body tissue to deliver the drug locally. The gel provides a membrane that has an effective residence time and is easy to apply and use.

[0021]

Detailed Description of the Invention

In the present invention, the novel gel carrier composition is formed from hydroxypropyl cellulose and a bioadhesive polymer that adheres to wet body tissue, the gel composition acts as a pharmaceutical carrier and also adheres to mucosal surfaces and body tissue. One or more biologically active pharmaceutical compounds are incorporated into the gel.

The present invention has particular application in the localized treatment of body tissues such as mucosal surfaces and skin. When applied to mucosal surfaces or skin, volatile or non-aqueous solvents evaporate, diffuse, or penetrate surrounding tissues to form a film. This membrane provides protection to the treatment site as well as providing effective drug delivery to the treatment site, surrounding body tissue, and body fluids. Over time, the film gradually peels off.

The desired properties of the present invention are achieved by the combination of hydroxypropyl cellulose or another pharmaceutically acceptable bioadhesive polymer, a volatile pharmaceutically acceptable solvent and an active agent. In addition, thickeners, colorants, fragrances, or plasticizers may be used. Upon application, the solvent evaporates, diffuses, or penetrates the surrounding tissue to form a film.

Unlike certain gels and pastes known in the art which have a very limited residence time and tend to be washed out of the treatment site by body fluids such as saliva, the present invention provides The film's durability and adhesion and its non-aqueous composition provide increased residence time. For example, Orabase (R) gel is a water-based system so that the film that forms when applied is quickly washed off in seconds. Unlike the Pomerantz '158 patent, which relies on the chemical reaction of the components used, the present invention provides a water-soluble, selected water-soluble compound selected for their desirable adhesion and / or film-forming properties in a suitable solvent. And depends on the particular combination of bioadhesive polymers. Importantly, Pomerantz's '157 and' 158 patents teach that the use of hydroxypropylcellulose is inconsistent unless esterified, and the mechanism of film formation is hydroxypropylcellulose + and esterification. It teaches that it is specific to the agent. Notwithstanding this teaching, the present invention does not require the use of esterifying agents, but in fact, soluble alkyls such as hydroxypropyl cellulose with bioadhesive polymers as film-forming components in non-toxic volatile solvents. Utilizes a cellulose derivative.

[0025] Mucoadhesive tablets known in the art that also provide effective residence time, but have the disadvantages of discomfort and discomfort for use in the oral cavity due to their solidity, bulkiness and slow dissolution rate. In contrast to the present invention, the physical discomfort is very limited,
Alternatively, the gel is almost nonexistent.

The residence time of the film that forms when the solvent disappears depends on several factors, including the amount of gel applied and the components used to make the composition and their relative proportions. To do. The use of polymers with different molecular weights or different chemical reactivities can, for example, affect the dissolution rate of the membrane. In the present invention, residence times of up to several hours have been achieved depending on the particular formulation. The preferred residence time for effective drug delivery depends on the properties of the particular drug, but is at least 1-2 hours. The rate of drug release depends on the properties of the carrier gel and the relative proportions of its components, the total amount of drug incorporated into the gel, the particular site of application, and the physical and chemical properties of the particular drug or drug combination. .

The drug component of the present invention may comprise a single drug or a combination of drugs,
Drugs that can be used, alone or in combination, include anti-inflammatory analgesics, steroidal anti-inflammatory agents, antihistamines, local anesthetics, bactericides and disinfectants, vasoconstrictors, hemostatic agents,
It includes chemotherapeutic agents, antibiotics, keratolytic agents, cauterizing agents, and antiviral agents.

Examples of anti-inflammatory analgesics include acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefanaminic acid, flufenamic acid, indomethacin, diclofenac, alcofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprone. Fen, fenoprofen, sulindac, fenclofenac, sridanak, flurbiprofen, fentisak, bufexomac, piroxicam, phenylbutazone, oxyfenbutazone, clofezone, pentazocine, mepyrizole, tiaramid hydrochloride and the like are included.

Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chloropheniramine hydrochloride, chloropheniramine maleate, triperenamine hydrochloride, promethazine hydrochloride, metzirazine hydrochloride and the like.

Examples of local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid (2-diethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, hydrochloric acid. Examples include chloroprocaine, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine dihydrochloride, dyclonine, and dyclonine hydrochloride.

Examples of fungicides and disinfectants include thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorobesidine, povidone, cetylpyridinium chloride, eugenol, trimethylammonium bromide and the like.

Examples of the vasoconstrictor include nafazonil nitrate, tetrahitozoline hydrochloride, oxymetazoline hydrochloride, phenylephyrin hydrochloride, tramazoline hydrochloride and the like.

Examples of hemostatic agents include thrombin, phylonadione, protamine sulfate, aminocapronsan, tranexamic acid, carbazochrome, carboxoxochrome, sodium sulfonate, rutin, hesperidin and the like.

Examples of chemotherapeutic agents include sulfamine, sulfathiazole, sulfazidine,
It includes homosulfamine, sulfaoxazone, sulfaomidine, sulfamethizole, nitrofurazone and the like. Examples of antibiotics include penicillin, methicillin, oxacillin, cephalothin, cephalorzin, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacillin, chloramphenicol, kanamycin, streptomycin,
Gentamicin, bacitracin, cycloserine and the like are included.

Examples of keratolytic agents include salicylic acid, pod membrane resins, podrifox, and cantharidin.

[0036]   Examples of cauterizing agents include chloroacetic acid and silver nitrate.

Examples of antiviral agents include protease inhibitors, thiazine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and absorption inhibitors, and acyclovir, penciclovir, valacyclovir and ganciclovir. Such nucleoside analogs are included.

A variety of suitable polymers known in the art for bioadhesive properties are incorporated into the compositions of the present invention. The polymer must be pharmacologically acceptable. Some polymers for use in the present invention include crosslinked or non-crosslinked polyacrylic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose (respectively alone or in combination).

Penetration enhancers may be used to improve the absorption of the drug at the treatment site. Penetration enhancers for use in the present invention include sodium lauryl sulfate, sodium glycophosphate, Azone, EDTA, sodium cholate, 5-
Includes sodium methoxysalicylate, and other penetration enhancers known in the art.

The relative percentages of the component materials of the present invention may vary depending on the drug or combination of drugs used, the particular target therapeutic site, the solvent, and the particular polymer. Preferably, the solvent or combination of solvents is 50-80% by weight of the composition. The active drug or combination of drugs is 0.1-25% by weight, more preferably 0.2-
20% by weight. The film-forming gel component should be about 1-25% by weight, more preferably 1-10% by weight. Any perfume, colorant, or thickening agent and / or penetration enhancer should be 0-3% by weight, more preferably 0.5-2.5% by weight.

The properties of the film formed when the gel is applied (eg, thickness, tensile strength, and peel rate) are determined by the properties of the tissue to which the gel is applied, the amount of gel applied, the treatment site or surrounding area. It can vary greatly depending on the amount of saliva or other body fluids in the, contact surface, and other physiological factors. However, the properties of the film obtained in vivo may be controlled by the gel formulation and the addition of plasticizers, the use of cross-linking agents, or the amount of residual solvent.

To make the gels of the present invention, various components are dissolved in the solvent of choice. A suspension may be formed as one or more components may not be present in solution. The process of gelation may occur at any time and may be induced by the addition of special ingredients, pH changes, temperature changes, or the passage of time. Solutions and gels may be prepared by various methods known in the art. The gel may be applied to the treatment site by spraying, dipping, or it may be applied directly from a suitable dispenser or by finger or swab.

Methods of treating mucosal surfaces and body tissues using the pharmaceutical carriers of the invention are also provided. In one embodiment, the method for protection against mucosal surfaces or body tissues and localized delivery of a medicament comprises at least one water-soluble cellulose polymer, such as hydroxypropyl cellulose, bioadhesive polymer, volatile non-aqueous solvent, and at least The method comprises the steps of preparing a film-forming pharmaceutical carrier having one active pharmaceutical ingredient and applying the pharmaceutical carrier to mucosal surfaces or body tissues by spraying, dipping, or direct application. In a preferred embodiment,
The method further comprises the use of a mixture of hydroxypropyl cellulose, polyacrylic acid, 95% ethanol and water; and a local anesthetic.

Example 1 65% by weight 95% ethyl alcohol; 0.8% by weight mint flavor; 8% by weight hydroxypropyl cellulose; 2.2% by weight polyacrylic acid; 5% water USP; 15% benzocaine USP; and 4 A gel based on ethyl alcohol is prepared using wt% menthol USP. A transparent yellow gel with film-forming ability is formed.

Example 2 55% by weight 95% ethyl alcohol; 1% by weight mint flavor; 8% by weight hydroxypropyl cellulose; 2% by weight polyacrylic acid; 15% by weight ethoxydiglycol; 15% by weight benzocaine USP And with 4 wt% menthol USP,
A gel based on ethyl alcohol / ethoxydiglycol is prepared. Here, the two phase demanding solvents influence the film formation time. The film formation rate of this gel is slow compared to Example 1 where the solvent is a mixture of 95% ethyl alcohol and water.

Example 3 Using 75% by weight ethyl alcohol, 1% by weight mint flavor, 4% by weight hydroxypropyl cellulose, 3% polyacrylic acid, 9% by weight ethoxydiglycol; and 4% by weight dyclonine. Prepare a gel based on ethyl alcohol. This results in a gel that is harder and has a higher concentration of consistency, slightly increasing discomfort.

Example 4 55% by weight ethyl alcohol; 1.5% by weight mint flavor; 26% by weight 1-methyl-
2-pyrrolidone; 6 wt% hydroxypropyl cellulose; 2.5 wt% polyacrylic acid; 5 wt% water; and 4 wt% menthol USP, based on ethyl alcohol / 1-methyl-2-pyrrolidone To prepare a gel. Methylpyrrolidone has an undesired taste, so higher proportions of perfume are used to taste. The diffusion rate of this gel is appropriate and allows effective film formation.

Example 5 An ethyl alcohol-based gel is prepared using polyvinylpyrrolidone as the bioadhesive polymer. The ingredients are 65 wt% 95 ethanol, 0.8 wt% mint flavor, 6.2 wt% hydroxypropylcellulose, 4 wt% polyvinylpyrrolidone, 5 wt% water USP, 15 wt% benzocaine USP, and 4 wt%.
It is the menthol USP. The use of polyvinylpyrrolidone as the bioadhesive polymer instead of polyacrylic acid results in effective film formation, but the adhesion is weaker than that achieved using polyacrylic acid.

Example 6 An ethyl alcohol-based gel is prepared using sodium carboxymethylcellulose as the bioadhesive polymer. The ingredients are 75% by weight 95% ethyl alcohol, 1% by weight mint flavor, 8% by weight hydroxypropyl cellulose, 4% by weight sodium carboxymethyl cellulose, 8% by weight water USP, and 4% by weight menthol USP. . The use of sodium carboxymethyl cellulose instead of polyacrylic acid as the bioadhesive polymer results in effective film formation, but the adhesion is weaker than that achieved using polyacrylic acid.

Example 7 An ethyl alcohol-based gel is prepared using the following ingredients: 78
Wt% 95% ethanol, 1 wt% mint flavor, 8 wt% hydroxypropyl cellulose, 3 wt% polyacrylic acid, 6 wt% water USP, 0.1 wt% sodium lauryl sulfate, and 3.9 wt% Dyclonine USP. The gel formed is comparable to that formed in Example 1. However, the use of different anesthetics (ie dyclonine instead of benzocaine) produces a weaker paralytic effect.

Example 8 A gel according to the formulation of Example 1 is prepared and administered to 8 healthy volunteers. Participants are instructed to apply a tiny amount of gel to one fingertip and then quickly spread and rub the gel in one place in the oral cavity. Volunteers are asked to describe the ease of handling the gel, and its paralyzing effect, on a scale of 0-3 (3 is very good, 2 is good, 1 is normal, 0 is bad). Volunteers are also asked to describe the time required to form a film at the application site, as well as their residence time, and whether they have experienced any discomfort. In addition, volunteers are asked to describe the taste and overall efficacy of the gels, as well as their overall impression as positive (+) or negative (-). The results are shown in Table 1 below.

[0052]

[Table 1] The formulation of Example 1 is easy to apply and forms a film quickly, while providing only minimal discomfort to the user. The membrane remains in place for a long enough time to provide effective drug delivery and provides effective paralysis to the treatment site and surrounding tissues.

The present invention has been described in detail so that those skilled in the art can understand and implement the present invention, and the presently preferred embodiments are specified. The invention is as described in the claims.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/38 A61K 47/38 A61P 17/02 A61P 17/02 23/02 23/02 F term (reference) 4C076 AA09 BB22 BB31 CC01 DD37A EE09A EE09P EE16A EE16P EE32A EE32P FF35 FF68 4C086 AA01 AA02 BC21 MA03 MA05 MA28 MA57 MA63 NA10 ZA21 ZA89 4C206 AA01 AA02 FA36 MA03 MA63 MA10 MA28 MA28 MA28 MA57

Claims (7)

[Claims] 1. A film-forming gel that adheres to mucosal surfaces and body tissues and provides localized delivery of a medicament to treat the site, the film-forming gel comprising at least one water-soluble alkyl cellulose or water-soluble hydroxyalkyl cellulose. A film-forming gel containing a bioadhesive polymer, a non-aqueous solvent, and at least one active pharmaceutical ingredient. 2. The gel according to claim 1, wherein the water-soluble hydroxyalkyl cellulose is hydroxypropyl cellulose. 3. The gel according to claim 1, wherein the solvent comprises 95% ethanol and 5% water. 4. The gel of claim 1, wherein the pharmaceutical ingredient is a local anesthetic. 5. The gel according to claim 1, wherein the pharmaceutical ingredient is a topical medicine for heat blisters and cold injuries. 6. The gel according to claim 1, wherein the bioadhesive polymer is polyacrylic acid. 7. The gel according to claim 1, wherein the bioadhesive polymer is polyvinylpyrrolidone.