Stable, viscous, mucoadhesive aqueous compositions which are useful for the prevention and treatment of ulcerative, inflammatory, and/or erosive disorders of mucous membranes, especially mucositis.

Description of the Invention

SUMMARY OF THE INVENTION

It is an aim of the present invention to provide viscous, mucoadhesive liquid and mucoadhesive gel formulations to be used for the prevention and treatment of mucocutaneous disorders. The formulation may be used with or without one or more active pharmaceutical agents. These formulations are especially beneficial in diseases and conditions in which a wide area of the mucosal surface requires treatment, but the formulations may also be used in treating small areas of the mucosal surface.

In order that mucocutaneous disorders are treated effectively, it is preferred that the lesion is in contact with the liquid or gel, mucoadhesive formulation for the period of time required to derive benefit. To grant such benefit, this invention describes mucoadhesive, viscous liquid and mucoadhesive gel formulations which may or may not contain one or more pharmaceutically active ingredients. The liquid can readily be applied to the affected region of the mucosa by methods known in the art, while the high viscosity and mucoadhesion will cause liquid or gel to remain in contact with the lesion for extended periods. The formulations of the present invention may be applied to treat mucocutaneous lesions in a variety of body compartments, including, but not limited to, the oral cavity, the nasal cavity, the esophagus, the rectum, the bladder, and the vagina.

The present invention involves a composition for the treatment and prevention of mucocutaneous disorders. This composition of the present invention, in one embodiment, comprises an amount of a mucoadhesive effective to coat the mucocutaneous area being treated and also a therapeutically or prophylactically active drug for a mucocutaneous disorder. In an important embodiment, the mucoadhesive is at a viscosity-inducing concentration. In another embodiment of the present invention, the mucosal drug delivery composition useable in the treatment or prevention of a mucocutaneous disorder is described. This composition comprises an amount of a mucoadhesive to form an effective coat in the mucocutaneous area being treated, a viscosity-inducing agent and a therapeutic or prophylactic drug for mucocutaneous disorders. The mucoadhesive of the present invention in one embodiment may be a natural or synthetic linear or cross linked polymer. This mucoadhesive can be for example a linear or cross-linked polyacrylic acid, carboxymethylcellulose, hydroxyalkylcellulose, polyvinylpyrrolidone dextran sulfate, dermatan sulfate, a water-soluble vinyl polymer, guar gum, xanthan gum tragacanth gum and pectin or chitosan. In the composition of the present invention a mucoadhesive is generally at a concentration between about 0.1 w/w % and about 3.0 w/w %. In preferred embodiments, the mucoadhesive of the present invention will contain cross-linked polyacrylic acid hydrogels plus optional linear polyacrylate and/or polymethacrylate and/or linear copolymers derived from acrylate and methacrylate monomers. Useable viscosity-inducing agents are many and include agar, bentonite, glycerin, providone, kaolin, tragacanth, sodium alginate and cross-linked polyacrylic acids. The composition of the present invention is preferably at a pH between about 6.5 and about 9.5.

Among the mucocutaneous disorders treatable by their methods and compositions of the present invention are: mucositis, Bechet's disease, apthous ulcer, bullous pemphigoid, chemical cystitis, radiation cystitis, erythema multiforme, esophagitis, interstitial cystitis, oral Lichen planus, pemphigus, radiation proctitis, or ulcerative colitis.

An important aspect to the present invention involves a method for the prevention or treatment of mucocutaneous disorders. This method involves identifying a patient having or possibly developing a mucocutaneous disorder. Next in this method is the administration to the patient of a formulation comprising a mucoadhesive agent in an amount effective to prevent or treat the mucocutaneous disorder. Of course, this formulation may and often does include a viscosity-inducing agent and/or a viscosity-enhancing concentration of mucoadhesive. Mucocutaneous disorders treatable by this method are described above. The liquid formulation of this invention are often more useful when possessing pseudoplastic behavior, which provides for reduced viscosity during application, allowing the liquid to cover the mucosa more readily, and for increased viscosity of the liquid when in place on a mucocutaneous area. In terms of the length of treatment, this will vary according to the severity and type of disorder. It is expected that the alleviation of mucocutaneous disorders should be visible to anyone treating the patient and that the method of treatment should continue until recovery is clear. This may take from hours to days to weeks, depending upon the situation. Preferred mucoadhesive agents for this method are described above. Likewise, for viscosity-inducing agents.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention describes formulations for the prevention and treatment of disorders of mucous membranes in humans and animals. The liquid or gel formulations of the present invention are ideally suited to treat diseases and disorders which affect a wide area of the mucosal surface, but they also provide the opportunity to treat discrete, localized lesions, especially in the oral cavity. The mucous membranes which may be treated by the compositions described in this patent include, but are not limited to, those in the oral cavity, the nasal cavity, the gastrointestinal and respiratory tracts, the vagina, and the bladder. Inflammatory, erosive, and/or ulcerative diseases which can be treated by topical application of the compositions described in this patent include, but are not limited to, aphthous ulcers, Behget syndrome, bullous pemphigoid, chemical or radiation-induced cystitis, erythema multiforme, esophagitis, interstitial cystitis, mucositis, oral lichen planus, pemphigus, and radiation proctitis. In conditions such as aphthous ulcers, chemical or radiation-induced cystitis, mucositis, and radiation proctitis, when the onset of the inflammatory, erosive, and/or ulcerative condition may be forecast (for example, by prodromal sensations in the case of aphthous ulcers, and by initiation of chemotherapy and/or radiation therapy in the treatment of cancer), the compositions of this invention might be applied prior to the formation of lesions, or at the commencement of therapy to prevent or delay the onset of inflammatory, erosive, and/or ulcerative lesions. While a mucoprotective agent may be a mucoadhesive alone, a viscous mucoadhesive liquid or mucoadhesive gel arepreferred particularly when a pharmaceutical agent is present to be selectively transmitted to a mucosal target.

As described later in the Examples section, one of the viscous, mucoadhesive formulations of the current invention, a viscous liquid which is composed entirely of pharmaceutically-accepted excipients, demonstrated a surprising result in a clinical study. This study examined the degree of mucositis in patients receiving radiotherapy for head and neck cancer. The mean and median mucositis scores for patients rinsing six times a day with one of the viscous, mucoadhesive solutions of the current invention for the duration of radiation therapy (6 7 weeks), with or without concombinant chemotherapy, were much lower than the scores for patients who did not use this rinse.

Furthermore, mucoadhesive liquid/gel formulations of the current invention which are also composed entirely of pharmaceutically-accepted excipients, demonstrated a surprising results in a hamster model of radiation induced mucositis.

There is currently no complete explanation of why the viscous, mucoadhesive liquids and gels of the current invention without a known active pharmaceutical ingredient should provide such benefit to patients. The following are considered viable possibilities, but this invention should not be considered as limited to any one of these possibilities:

A viscous, mucoadhesive solutions provides a layer on the surface of the mucosa for an extended period, and this may have a beneficial effect, for example, a moisturizing or barrier effect, so limiting the damage to the mucosal surface caused by disease, or injury from ionizing radiation and/or chemotherapeutic agents. Thus, it is envisioned that any aqueous formulation which is formulated with non-toxic and non-irritating excipients and providing a liquid or gel-which is both viscous and mucoadhesive might be expected to provide benefit to patients suffering a disease or disorder of the mucosa.

It is known that polyanionic carbohydrate polymers and oligomers can have a beneficial effect in the treatment of mucosal disorders. For example, pentosan polysulfate and hyaluronic acid are known to provide benefit to patients with interstital cystitis (Morales A, et al, Treatment of refractory interstitial cystitis, Int Urogynecol J Pelvic Floor Dysfunct 1996;7(4):215 20). It is quite possible that other polyanionic and polycationic compounds, whether carbohydrate, of natural origin or synthetic, may also provide benefit in the prevention and treatment of mucosal disorders. Linear and partially cross-linked polyanionic polymers are included in the formulation used in the product demonstrating benefit in the mucositis clinical study described in the examples.

Other components of the formulation used in the clinical study, benzyl alcohol, citric acid, glycerin, polysorbate 60, and saccharin, alone or in combination with each other and/or the other excipients of the formulation may have a beneficial effect. Other preservatives, humectants, emulsifying agents, antioxidants, antimicrobial agents, solubilizing agents, and other excipients known in the art in the formulation of liquid pharmaceutical products, alone or in combination, may also provide for, or enhance, the beneficial properties on mucosal surfaces, when formulated to provide a viscous, mucoadhesive solution.

Other components of the liquid/gel formulations used in the hamster model of mucositis (phenoxyethanol, glycine, glycerol, ethanol) alone or in combination with each other and/or the other excipients of the formulation may have a beneficial effect. Other preservatives, humectants, emulsifying agents, antioxidants, antimicrobial agents, solubilizing agents, and other excipients known in the art in the formulation of gel pharmaceutical products, alone or in combination, may also provide for, or enhance, the beneficial properties on mucosal surfaces, when formulated to provide a mucoadhesive gel.

Viscous, mucoadhesive formulations for the prevention and treatment of mucosal diseases and disorders may additionally be formulated with one or more compounds known to be pharmaceutically active. Addition of further pharmaceutically active compounds could provide greater benefit to patients in the prevention and treatment of mucosal disorders. Examples of pharmaceutically active compounds which could be incorporated in the viscous, mucoadhesive solutions of this invention as provided later in this section.

Aqueous solutions of pharmaceutically-active compounds are well known in the art as convenient drug delivery formulations. Such formulations are most useful for oral delivery, when the solution is swallowed, and the drug is presented to the stomach and gastrointestinal tract in a form which is amenable to rapid absorption. Aqueous solutions are also used to deliver drugs to mucosal tissue. In general, aqueous solutions used to deliver pharmaceuticals tend to be non-viscous and non-mucoadhesive. For oral delivery, this property is undesirable, as it minimizes the amount of drug which is retained in the oral cavity and esophagus, while maximizing that delivered to the stomach and gastrointestinal tract. One preferred drug for the treatment of mucocutaneous disorders is amlexanox.

For topical treatment of mucosal membranes, aqueous solutions of pharmaceutically-active compounds offer the advantage over other dosage forms in that a wide area of the mucosa can be readily covered with the solution, which is of benefit if the area to be treated is not a single, discrete region. Also, mucosa not readily accessible can be treated using aqueous solutions of pharmaceutically-active compounds and simple methods of application. However, formulations which are non-mucoadhesive and non-viscous are less than ideal for delivery of drugs to mucosal surfaces. Such solutions will be rapidly removed from the area being treated, for example, because the liquid flows from the site of application under the influence of gravity, and/or because the natural secretions of mucosal membranes carry the solution from the site of application.

The present invention involves a finding that neither high viscosity nor mucoadhesion alone confers ideal properties. A viscous but non-mucoadhesive liquid will not be held in place on the mucosal surface. Instead, a non-mucoadhesive solution will readily be lost from the point of application, for example, under the influence of gravity, and/or through natural movements of the membrane and surrounding structures, and/or the flow of natural secretions. In an aqueous liquid formulation which is mucoadhesive but has low viscosity, only a thin layer of the liquid which is adjacent to the mucosa may be held in place, but the bulk of the liquid might rapidly flow from the site of application under the influence of gravity and/or be readily removed by the natural secretions of mucosal membranes. In a mucoadhesive, viscous liquid formulation, the liquid will adhere to the mucosa, while the high viscosity of the liquid will reduce the rate of removal of the bulk of the liquid from the site of application. In some cases a low viscosity mucoadhesive may provide effective treatment, especially when pharmaceutical agents are not required. A mucoadhesive agent may itself be a viscosity-inducer and thus serve two purposes. The term "viscosity-inducing" is meant to mean enhancement of the aqueous mucoadhesive layer that adheres to mucosal areas.

For most liquids, viscosity remains constant over a wide range of shear rates. This phenomenon is known as Newtonian viscosity, and liquids which display this property are called Newtonian liquids. Liquids in which viscosity varies with shear rate are termed non-Newtonian. There are several known non-Newtonian profiles. One of these profiles is termed pseudoplastic, and liquids which fall into this category demonstrate a decrease in viscosity as shear rate increases. Preferred formulations of the current invention are pseudoplastic, and demonstrate a decrease in viscosity at low shear rates. Pseudoplasticity benefits the application of the formulations of the current invention by virtue of the fact that application of shear (for example, swishing the liquid in the mouth) reduces the viscosity, so allowing the liquid to flow and coat the mucoscal surface more readily. Once the shear forces are discontinued, the viscosity of the liquid increases, as required (in combination with mucoadhesion) for prolonged attachment to the mucosal surface.

Formulations of the current invention are viscous, free-flowing liquids or mobile gels that are either Newtonian or pseudoplastic. The ability to flow freely or be spread freely is advantageous in order to readily coat either a selected region or a wide area of the affected mucosal membrane, and to coat mucosal membranes not readily accessible to simple application. The solutions of the current invention will have viscosities at zero shear in the range 100 20,000 cP.

The stable, viscous, mucoadhesive liquid formulations of the present invention may be applied to mucosal membranes for the delivery of pharmaceutically active compounds to the mucosal membranes for prevention and/or treatment of disorders or diseases of these membranes. The liquid may be applied, e.g., to the following mucosal surfaces; the oral cavity, the nasal cavity, the gastrointestinal and respiratory tracts, the vagina, and/or the bladder. The formulations of the current invention may also be applied to other mucous membranes for the prevention and treatment of disorders and diseases. Many methods known in the art for the delivery of liquids to body compartments may be used.

For treatment of disorders and diseases of the oral cavity, the stable, viscous, mucoadhesive liquid formulations of the current invention may be taken by mouth and distributed throughout the oral cavity by a swishing action, or by the patient adopting a slow circulating movement of the head. Excess solution can either be swallowed or expelled. For treatment of disorders and diseases of the oral cavity, the stable, mucoadhesive gel formulations of the current invention may be taken by mouth and distributed throughout the oral cavity by the action of the tongue and/or use of a swab or similar device. Excess gel can either be swallowed or expelled.

For treatment of disorders and diseases of the esophagus, the stable mucoadhesive liquid and gel formulations of the current invention can be swallowed with minimal contact of the oral cavity, or administered by gavage, or by spraying the liquid into the throat.

For treatment of disorders and diseases of the nasal cavity, the stable mucoadhesive liquid and gel formulations of the current invention can be delivered as droplets or by spraying the liquid into the nose.

For treatment of disorders and diseases of the bladder, the stable, mucoadhesive liquid or gel formulations of the current invention can be delivered by intravesical administration.

For treatment of disorders and diseases of the rectum and lower gastrointestinal tract, the stable mucoadhesive liquid or gel formulations of the current invention can be administered by catheter or enema.

Other methods to apply the stable, viscous, mucoadhesive liquid formulations and stable mucoadhesive gel formulations of the current invention to mucosal tissues are known to those skilled in the art.

Pharmaceutically active compounds which may be formulated with the stable mucoadhesive liquid and gel formulations of the current invention for topical treatment of a mucosa can include, either alone or in combination, one or more of the following classes of drugs: anti-allergy compounds, anti-inflammatory analgesic agents, steroidal and non-steroidal anti-inflammatory agents, antioxidant compounds, analgesics, antihistamines, local anesthetics, bactericides and disinfectants, vasoconstrictors, hemostatics, antibiotics, keratolytics, cauterizing agents, antiviral drugs, growth factors, supplements and other potential agents for treatment of mucositis. Other classes of pharmaceutically active agents may also be formulated with the stable mucoadhesive liquid and gel formulations of the current invention.

Examples of anti-inflammatory analgesic agents include acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac, fenclofenac, clidanac, flurbiprofen, fentiazac, bufexarnac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepirizole, tiaramide hydrochloride, etc.

Examples of steroidal anti-inflammatory agents include hydrocortisone, predonisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, predonisolone acetate, methylpredonisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumetasone, fluorometholone, beclomethasone diproprionate, etc.

Examples of antioxidant compounds include ascorbic acid, dehydroascorbic acid, alpha-tocopherol, glutathione, beta-carotene, azelastine, N-acetyl-L-cysteine, allopurinol, flavanoids, etc.

Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate isothipendyl hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride, etc.

Examples of local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-buthylaminobenzoic acid 2-(di-ethylamino) ethyl ester hydrochloride, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dyclonine, dyclonine hydrochloride, etc.

Examples of bactericides and disinfectants include phenoxyethanol. triclosan, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridinium chloride, eugenol, trimethylammonium bromide, etc.

Examples of vasoconstrictors include naphazoline nitrate, tetrahydrazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, etc.

Examples of hemostatics include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfanate, rutin, hesperidin, etc.

Examples of antibiotics include penicillin, meticillin, oxacillin, cefalotin, cefalordin, erythromcycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, and clindamycin.

Examples of keratolytics include salicylic acid, podophyllum resin, podolifox, and cantharidin. Examples of cauterizing agents include the chloroacetic acids and silver nitrate.

Examples of antiviral drugs include protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.

Examples of anti-allergy compounds include alopatadine, astemizole, cromolyn, fenpiprane, repirinast, tranilast, traxanox, etc.

Examples of growth factors, supplements and other potential agents for treatment of mucositis includes keratinocyte growth factor, granulocyte-colony-stimulating factor, transforming growth factor-beta3, sucralfate, L-glutamine, aminoacids, lisofylline, IL-15, antimicrobial peptides and histamine.

The amount of pharmaceutically active compound(s) to be used depends on the desired treatment strength, although preferably, the pharmaceutical component comprises 0.001 to 30% by weight of the formulation, and more preferably between 0.005 and 20% by weight.

In addition to the preferred requirements of mucoadhesion and viscosity as described above, it is important, for use of the formulation for the prevention and treatment of mucosal diseases and disorders that the liquid or gel be stable, such that it can be stored at ambient temperatures for many months or years, even when subjected to brief periods of elevated or depressed temperatures, without physical or chemical degradation of the formulation. It is usually desirable to formulate the product without use of any organic solvents, the presence of which might irritate the mucosal lesions being treated, although liquid and gel formulations containing pharmaceutically-acceptable organic solvents are within the scope of this invention provided that the incorporation of such solvents does no harm to the mucosa, and possibly provides benefit; for example, as disinfectants, or to aid the solvation of the mucous membrane to provide more rapid mucoadhesion, or for concentration of the excipients (through evaporation of the solvent following application to the mucosa) to enhance mucoadhesion and/or viscosity following application. Furthermore, it is desirable to formulate the viscous, mucoadhesive solution using only excipients which are accepted by all major pharmaceutical regulating authorities as safe.

The following list provides examples of components of the stable, viscous, mucoadhesive formulations of the current invention:

A linear or cross-linked polymer polyanionic or polycationic polymer which may or may not already be known to provide mucoadhesion. Such polymers include (but are not limited to) linear polyacrylic acid, a cross-linked homopolymer based on acrylic acid, a crosslinked copolymer based on acrylic acid, linear methacrylic acid homopolymers and copolymers, carboxymethylcellulose, hydroxyalkylcellulose, dextran sulfate, dermatan sulfate, and hyaluronic acid. Other mucoadhesive polymers are well-known to those skilled in the art. The mucoadhesive formulations of the current invention can contain a single mucoadhesive component, or mixtures thereof. The preferred mucoadhesive polymers are cross-linked homopolymers and copolymers based on acrylic acid and methacrylic acid, especially the Carbopol and polycarbophil polymers supplied by B.F. Goodrich, and Eudragit polymers supplied by Rohm-Haas; most preferred are Carbopol.TM., (polymer of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol) Noveon AA1.RTM., (also called polycarbophil, a salt of polyacrylic acid cross-linked with polyether or divinyl glycol) and Eudragit L-100 (methacrylic acid-ethyl acrylate copolymer (1:1)).

Viscosity enhancement is provided by one or more of the above mentioned mucoadhesive polymers alone or in combination with agar, bentonite, glycerin, povidone, kaolin, and/or tragacanth and sodium alginate. Most preferred is Carbopol in combination with glycerin.

The pH of the solution is adjusted to the final desired pH with any pharmaceutically accepted acid or base. Most preferred is sodium or potassium hydroxide, phosphoric acid, or citric acid. A final pH of 6.5 to 9.5 is preferred.

To prevent microbial growth in the formulation during storage, it is desirable to include a preservative. Preservatives known in the art include benzyl alcohol, benzoate salts, phenoxyethanol, methylparaben, and propylparaben. Phenoxyethanol and benzyl alcohol are the most preferred preservatives.

A humectant is desirable to provide a pleasant mouth-feel in oral applications. Humectants known in the art include cholesterol, fatty acids, glycerin, lauric Acid, magnesium stearate, pentaerythritol, and propylene glycol. Glycerin is preferred.

An emulsifying agent might be necessary, for example to ensure complete dissolution of all excipients, especially hydrophobic components such as benzyl alcohol. Many emulsifiers are known in the art. The preferred emulsifier is polysorbate 60

For oral applications, it may be desirable to add a pharmaceutically acceptable flavoring agent, coloring agent and/or sweetener. Compounds such as saccharin, glycerin, simple syrup, and sorbitol are useful among those as sweeteners. Saccharin is preferred.

It may be desirable to include other ingredients; for example a pharmaceutically acceptable organic solvent, a buffering agent, an antioxidant, a free radical scavenger, an antimicrobial agent, and/or a coloring agent. The exact formulation of the above ingredients, and the method of manufacture, will be apparent to those skilled in the art. A number of texts provide assistance in the design and manufacture of pharmaceutical formulations, including Remington's Pharmaceutical Sciences, Mack Publishing Company Co., Easton, Pa., and Pharmaceutical dosage forms and drug delivery, Ansel et al, 1995, Williams and Wilkins, Malvern, Pa.
 

Claim 1 of 16 Claims

1. A pseudoplastic liquid composition for treating or inhibiting an oral mucocutaneous disorder, said pseudoplastic liquid composition having a zero shear viscosity at 37.+-.1 degrees Celsius of 100-20,000 centipoise, comprising 0.1 to 2.0 wt/wt% of one or more mucoadhesives, wherein the mucoadhesive(s) is/are selected from the group consisting of polyvinylpyrrolidone, carboxymethylcellulose, dextran sulfate, hydroxyalkylcellulose, dermatan sulfate, a water-soluble vinyl polymer, chitosan, guar gum, xanthan gum, tragacanth gum, pectin and polyacrylic acid; wherein said pseudoplastic viscous liquid composition, when administered to an oral mucosa: 1) remains liquid when shear is applied due to swishing the liquid in the mouth; and 2) attaches to and coats the oral mucosa upon discontinuance of said shear.

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