Dry powder effervescent formulation for drug delivery across mucous membranes - Patents.com

Abstract

The embodiments include formulations and methods for oral mucosal administration of dry powder to create topical foam compositions for delivery of drugs to internal mucosal spaces such as the oral cavity, nasal cavity, rectal cavity, vaginal cavity or esophagus. The active drug can be amifostine, an antibiotic, an antifungal, a nonsteroidal anti-inflammatory drug or a steroidal anti-inflammatory drug. Oral mucosal delivery allows for targeting of oral epithelial cells. The embodiments also include methods for treating mucositis. Conventional formulations and methods are generally ineffective due to the inability to direct drugs to the epithelial cells of the GI, which are most susceptible to mucositis. The formulations described herein increase the concentration, permeability and residence time at the target site. The formulations also allow for a stable form of amifostine, avoiding the difficulties associated with drug storage, dosing and administration.

Description

[Technical field]

[0001] The present invention relates to therapeutic formulations, and more particularly to the use of dry powders to create topical foam pharmaceutical compositions for the delivery of small molecule drugs. [Background technology]

[0002] Cancer can be defined as a group of diseases involving abnormal cell growth that has the potential to invade or spread to other parts of the body. Despite technological advances, cancer remains a significant cause of death and causes immense suffering. Cancer is the second most common cause of death in the United States. Patients with cancer often have limited treatment options. Treatments may include a combination of surgery, radiation therapy, chemotherapy, and targeted therapy. Despite advances in research, these treatments have remained relatively unchanged for the last few decades. Radiation and chemotherapy typically result in multiple side effects, including damage to epithelial cells.

[0003] Oral mucositis is a common debilitating complication of chemotherapy and radiation. Mucositis occurs when cancer treatment destroys the rapidly dividing epithelial cells lining the gastrointestinal tract (from the mouth to the anus), leaving the mucosal tissue susceptible to ulceration and infection. It may be defined as an acute inflammation of the oral mucosa in response to systemic tumor therapy and / or radiation to areas including the oral cavity. Clinical manifestations range from a general erythematous oral mucosa to erosive lesions and frank ulceration. Lesions are often very painful, can impair nutrition and oral hygiene, and can increase the risk of local and systemic infection. Furthermore, severe oral mucositis may require undesirable dose reductions and / or interruptions of cancer treatment. Mucositis is therefore a crucial complication of cancer treatment and may affect patient prognosis.

[0004] The pathogenesis of oral mucositis is thought to involve direct and indirect mechanisms. Direct toxic effects of cytostatics on the rapidly dividing cells of the oral epithelium can result in mucosal atrophy, erythema and ulceration. Indirect orotoxic effects are caused by the release of inflammatory mediators, loss of protective salivary components and treatment-induced neutropenia. Bacteria, fungi and viruses can superimpose secondary infections on the damaged mucosa. Mucositis can be described in four successive phases: a) inflammatory / vascular phase (release of free radicals and cytokines); b) epithelial phase with atrophy and ulceration (reduced epithelial regeneration); c) ulcerative / bacterial phase with further tissue damage due to cytokine stimulation (colonization of mixed bacterial flora, causing endotoxin release); d) healing phase.

[0005] There are few options for treating mucositis. Oncologists may attempt to minimize the side effects of cancer therapy through dose reduction. Other regimens for mucositis prevention are primarily palliative. Local and systemic analgesics are applied for pain relief, and antibacterial agents are applied for bacterial or fungal infections or for prevention. Amifostine (S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate) can be administered as a cytoprotective adjuvant. Amifostine, sold under the trade name Ethyol, is often administered in combination with cancer chemotherapy, including DNA-binding chemotherapy agents, and radiation therapy.

[0006] Amifostine was originally developed as a radioprotectant. Amifostine and its derivatives exert their protective effects without significantly affecting the beneficial properties of the administered therapeutic agent. This is due, in part, to the selective incorporation of the protective thiol into normal tissues. Amifostine is commercially available as a lyophilized powder of amifostine trihydrate for reconstitution and subsequent delivery by intravenous infusion. Although FDA approved, amifostine has limitations and many patients do not realize benefit from the use of the drug. In a recent study, patients with epirubicin-induced oral mucositis were administered amifostine as a mouthwash. There were no significant differences between these patients and those receiving controls (see, e.g., Stokman et al., Anticancer Res. 2004 Sep-Oct;24(5B):3263-7).

[0007] Several factors limit the effectiveness of amifostine. Amifostine is a soluble, highly polar molecule that is ionized in the physiological pH range. However, it is hydrolyzed at gastric pH. This results in decreased intestinal permeability and poor oral absorption. Therefore, amifostine is traditionally administered intravenously prior to chemotherapy or radiation therapy. Although intravenous amifostine is an FDA-approved treatment, it is not in widespread use due to systemic toxicity.

[0008] Certain drug compounds, such as amifostine, act locally in the oral cavity, pharyngeal cavity, nasal cavity, rectal cavity, vaginal cavity or esophagus. Providing a delivery mechanism that provides increased concentration, permeability and increased residence time at the target site is essential for the effectiveness of the product. Examples of drugs used in this way include amifostine in the oropharyngeal or rectal cavity in the prevention of radiation damage and oral mucositis or rectal bleeding, antibiotics for the treatment of gum disease, antifungals for the treatment of thrush / candidiasis in immunocompromised and HIV patients, and steroidal corticosteroids in the nose for the treatment of polyps or in the esophagus for the treatment of eosinophilic esophagitis.

[0009] After intravenous administration, amifostine is rapidly cleared from plasma. The rapid clearance of amifostine is mainly due to the rapid conversion of amifostine to its active metabolite, WR-1065. Animal studies have shown that maximum tissue concentrations of WR-1065 occurred within 5-15 min after amifostine injection. These results suggest that amifostine should be applied for a short period (e.g., 15-30 min) prior to chemotherapy. Another limitation of amifostine may be due to its low cellular concentration due to low uptake of WR-1065. Summary of the Invention [Problem to be solved by the invention]

[0010] Thus, there is a need for a means to prevent and / or treat mucositis, which may be achieved by improving the formulation and administration of amifostine to locally target the oral epithelial cells most susceptible to mucositis for efficacy without toxicity.

[0011] Embodiments of the present invention include novel formulations and improved methods of administering amifostine, antibiotics, antifungals and corticosteroids, as well as other small molecules. [Means for solving the problem]

[0012] The invention described and claimed herein has many attributes and embodiments, including but not limited to those described or illustrated or referenced in this brief summary. The invention described and claimed herein is not limited to or by the features or embodiments identified in this summary, which are included for purposes of example only and not limitation.

[0013] Embodiments include solid foaming and expanding powder pharmaceutical carrier compositions that have good and consistent flow properties as a powder, are easily dispersible in the mouth, and achieve a taste-masking effect that facilitates ingestion, allowing patients and healthcare professionals to accurately measure doses and administer medications safely.

[0014] Thus, one embodiment is a moisture-controlled, stable form of amifostine that avoids the difficulties associated with handling known amifostine: it is difficult to control the moisture content of amifostine trihydrate during drying procedures and storage to meet the pharmacopoeia limits of 19.2-21.2%.

[0015] One embodiment is a storage-stable amifostine or other small molecule composition suitable for oral mucosal, rectal or vaginal delivery.

[0016] One embodiment is a small molecule composition such as amifostine suitable for oral mucosal use and delivery to the larynx and esophagus.

[0017] One embodiment is a non-aqueous (or substantially non-aqueous) formulation for oral mucosal administration of amifostine. The formulation may include amifostine (5%-40% w / w), a polyol (5%-30% w / w), a base (5%-30% w / w) and an acid (15%-50% w / w). The formulation may also include a sweetener (e.g., sucralose). The base may be sodium bicarbonate and the acid may be succinic acid. In aspects, the formulation also includes a penetration enhancer and / or a film-forming agent.

[0018] The formulation can be administered as a mouthwash for the prevention, treatment or amelioration of diseases such as oral mucositis. The formulation can expand when exposed to bodily fluids such as saliva. In an embodiment, the volume of the formulation increases as it foams. The formulation can retain the increased volume for more than 30 seconds, which can increase the concentration, permeability and residence time in the oral cavity. At least a portion of the acid or base can be coated for sustained generation of foam. The formulation can be a sticky foam in the oral cavity. Similarly, it can be a sticky firm foam or a very sticky very firm adhesive foam.

[0019] The formulation may be administered concomitantly with radiation or chemotherapy exposure. In embodiments, the formulation is administered within about one hour prior to radiation exposure or chemotherapy.

[0020] Another embodiment is a non-aqueous (or substantially non-aqueous) formulation for administering budesonide. The formulation can include budesonide (5%-40% w / w), polyol (5%-30% w / w), base (5%-30% w / w) and acid (15%-50% w / w). The formulation can be administered rectally to treat ulcerative colitis. The formulation can expand upon exposure to bodily fluids. In an aspect, the volume of the formulation increases as it foams. The formulation can retain the increased volume for more than 30 seconds, which can increase the concentration, permeability and residence time in the rectal cavity. At least a portion of the acid or base can be coated for sustained generation of foam. The formulation can be a sticky foam in the oral cavity. Similarly, it can be a sticky firm foam or a very sticky very firm adhesive foam.

[0021] In aspects, the formulations described herein can be used to treat other diseases, such as eosinophilic esophagitis.

[0022] Another embodiment is a free-flowing powder formulation of a small molecule active agent, such as amifostine. In an aspect, the powder comprises an effective amount of a dispersing agent.

[0023] Although a free-flowing powder may be preferred, small molecules such as amifostine may have alternative formulations (eg, tablets, orally disintegrating tablets, capsules, lozenges, gummies, suppositories and other solid dosage forms).

[0024] Another embodiment is a self-foaming composition, optionally in the form of a free-flowing powder, further comprising chitosan. In an aspect, a patient ingests the composition orally as a rinse.

[0025] Another embodiment is an amifostine or other small molecule composition that is non-aqueous (or substantially non-aqueous) and administered without water. Such compositions and formulations can be referred to as "self-foaming" insofar as the composition foams without administration of water or other fluids and relies on bodily fluids in situ.

[0026] Another embodiment is amifostine (or other small molecule composition) in the form of a free-flowing powder, and water or other liquid is administered to the patient separately from the free-flowing powder.Another embodiment is amifostine (or other small molecule composition) in the form of a powder, and the powder is mixed with water or other liquid immediately prior to administration to the mucosal cavity of the subject.

[0027] Another embodiment is an amifostine (or other small molecule composition) in the form of a flowable powder in a unit dose package. Another embodiment is an amifostine (or other small molecule) composition that is effervescent (i.e., foams) when administered into a mucosal cavity.

[0028] Another embodiment is a formulation for mucosal delivery of amifostine or other small molecules, comprising the following components: amifostine or other small molecules (5%-40% w / w), dispersing agent (polyol and / or surfactant) (5%-30% w / w), base (5%-30% w / w), negatively charged component (chitosan or gelatin) (5%-30% w / w), dicarboxylic acid (15%-50% w / w) and sweetener (0.5%-10% w / w). In one embodiment, the base is sodium bicarbonate. In one embodiment, the base is sodium carbonate or a mixture of sodium bicarbonate and sodium carbonate. In one embodiment, the dicarboxylic acid is succinic acid.

[0029] In certain non-limiting embodiments, the weight of a flowable powder dose is between 50 mg and 5 grams, preferably between 250 mg and 2 grams, more preferably between 300 mg and 1.2 grams, and most preferably between 400 mg and 900 mg. In embodiments in which the powder or other solid is mixed with a solvent prior to administration to the patient, the aforementioned weights may be exceeded.

[0030] Another embodiment is a method of mucosally delivering a therapeutic amount of amifostine. Another embodiment is a method of mucosally delivering a therapeutic amount of amifostine as a radioprotectant. Another embodiment is a method of mucosally delivering a therapeutic amount of amifostine as a cytoprotectant. Another embodiment is a method of mucosally delivering a therapeutic amount of amifostine as an adjunct to chemotherapy.

[0031] One embodiment is a method of mucosally delivering a therapeutic amount of amifostine, where the duration of the therapeutic amount is between 15 minutes and 4 hours. Another embodiment is a method of mucosally delivering a therapeutic amount of amifostine to treat oral mucositis.

[0032] Another embodiment is a method of delivering a therapeutic amount of amifostine that provides a thin film of amifostine throughout, or substantially throughout, or generally throughout a mucosal cavity (oral, rectal or vaginal).

[0033] Another embodiment is a method of delivering a therapeutic amount of amifostine (or other small molecule) that provides a thin film of amifostine or other small molecule throughout, or substantially throughout, or generally throughout the oral cavity, pharynx, larynx and / or esophagus, nasal cavity, rectal cavity or vaginal cavity.

[0034] Another embodiment relates to an effervescent composition that foams, optionally without the administration of water or other administered liquid.

[0035] Another embodiment relates to a foamable composition that uses saliva alone (or substantially alone) or other mucosal or bodily derived fluids to create a foam.

[0036] Another embodiment relates to a foamable composition that creates a foam using saliva or other mucosal derived fluids having a volume of more than 20 ml, preferably more than 30 ml. The volume can be measured according to the method described in Example 1.

[0037] Another embodiment relates to a foamable composition that uses saliva or other mucosal derived fluids having a volume greater than 30 mL to create a foam, said foam volume remaining greater than 30 mL for at least 30 seconds within the mucosal cavity.

[0038] Another embodiment relates to a foamable composition that uses saliva or other mucosal derived fluids having a volume greater than 30 ml to create a foam, said foam volume remaining greater than 30 ml within the mucosal cavity for at least 45 seconds.

[0039] Another embodiment relates to a foamable composition that uses saliva or other mucosal derived fluids having a volume greater than 30 mL to create a foam, said foam volume remaining greater than 30 ml for at least 60 seconds within the mucosal cavity.

[0040] Another embodiment relates to a foamable composition that creates a foam containing amifostine (or other drug), said foam having a pH between 4.5 and 6.0.

[0041] Another embodiment relates to an effervescent composition that produces a substantial amount of firm foam (defined below) from a powder formulation upon exposure to saliva or other mucosal-derived or other bodily fluids.

[0042] Another embodiment relates to an effervescent composition that creates a substantial amount of firm foam (or very firm foam) (as defined below) from a powder formulation exposed to saliva or other mucosal derived fluid, said foam resisting substantial degradation within the mucosal cavity.

[0043] Another embodiment relates to a foamable composition that creates an adhesive foam or a very adhesive foam (both terms defined below), where the active ingredient-containing foam adheres to mucous membranes or other body surfaces.

[0044] Another embodiment relates to a foamable composition in which the powder is delivered intranasally or intranasally and utilizes nasal secretions to form a foam within the nasal cavity.

[0045] Another embodiment relates to nasal compositions for the topical treatment of the nasal or intranasal cavities.

[0046] Another embodiment relates to an effervescent composition for intranasal delivery.One embodiment relates to an effervescent composition for intranasal delivery for systemic absorption.

[0047] Another embodiment relates to an effervescent composition for mucosal and gastrointestinal (GI) systemic absorption.

[0048] Another embodiment relates to a foamable composition for vaginal delivery.One embodiment relates to a foamable composition capable of coating the pelvic diaphragm.

[0049] Another embodiment of the invention relates to a foamable composition for vaginal delivery that is capable of coating the vaginal opening.

[0050] Another embodiment relates to an effervescent composition for vaginal delivery for absorption into the uterus via the uterine first pass effect.

[0051] Another embodiment of the present invention relates to a vaginal foamable composition that produces a foam upon exposure to vaginal secretions, optionally including menstrual fluid.

[0052] Another embodiment relates to a sustained release effervescent composition, in which some (or all) of the acid or base is coated to provide sustained foam production for 1 second to 15 minutes, preferably 30 seconds to 8 minutes, more preferably 2 minutes to 6 minutes.

[0053] Another embodiment relates to a dental foamable composition.

[0054] It is an object of certain embodiments of the present invention to coat the roof of the mouth (hard palate) with a composition and one or more active agents contained therein.

[0055] It is an object of certain embodiments of the present invention to coat the soft palate with a composition and one or more active agents contained therein.

[0056] It is an objective of certain embodiments of the present invention to coat the floor of the mouth and / or the lingual side of the gums with the composition and one or more active agents contained therein.

[0057] It is an objective of certain embodiments of the present invention to coat the oropharynx (tonsils and base of tongue), nares, and / or postcricoid area with the composition and one or more active agents contained therein.

[0058] It is an object of certain embodiments of the present invention to coat the pyriform sinuses and / or aryepiglottic folds with the composition and one or more active agents contained therein.

[0059] It is an objective of certain embodiments of the present invention to coat the subglottic area (the area below the vocal cords) with a composition and one or more active agents contained therein.

[0060] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.

[0061] The accompanying drawings illustrate aspects of the present invention. [Brief description of the drawings]

[0062] [Figure 1] 1 is a flow chart showing the conversion of amifostine (WR-2721) to WR-1065.

[0063] [Diagram 2] 1 is a flow chart showing steps for preparing an amifostine solution for oromucosal administration.

[0064] [Diagram 3] 1 is a table listing various compositions and conditions used in the preparation of foams along with output data that quantitatively describes each condition and preparation.

[0065] definition Reference herein to "one embodiment / aspect" or "embodiment / aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the present disclosure. Use of the phrase "in one embodiment / aspect" or "in another embodiment / aspect" in various places herein does not necessarily all refer to the same embodiment / aspect, nor to separate or alternative embodiments / aspects that are mutually exclusive with other embodiments / aspects. Furthermore, various features are described that may be exhibited by some embodiments / aspects and not exhibited by others. Similarly, various requirements are described that may be requirements of some embodiments / aspects but not other embodiments / aspects. Embodiments and aspects may be used interchangeably in some cases.

[0066] The terms used in this specification generally have their usual meaning in the art, within the context of this disclosure, and within the specific context in which each term is used.Specific terms used to describe this disclosure are explained below or elsewhere in this specification, in order to provide practitioners with additional guidance regarding the description of this disclosure.It will be understood that the same thing can be said in more than one way.

[0067] Thus, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is there any special meaning to a term whether it is detailed or discussed herein. Synonyms of certain terms are provided. The listing of one or more synonyms does not preclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term discussed herein, is illustrative only and is not intended to further limit the scope and meaning of the disclosure or any exemplified term. Similarly, this disclosure is not limited to the various embodiments provided herein.

[0068] Without intending to further limit the scope of the present disclosure, the following examples of instruments, devices, methods and their related results according to the embodiments of the present disclosure are given. Please note that in the examples, titles or subtitles may be used for the convenience of the reader, and should not limit the scope of the present disclosure in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, the present document, including definitions, shall prevail.

[0069] The term "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect on a subject to which it is administered. In other words, an "active agent" or "active ingredient" refers to one or more components of a composition to which all or part of the composition's effect is attributable. An active agent may be a primary active agent, or in other words, a component of a composition to which all or part of the composition's effect is attributable. An active agent may be a secondary active agent, or in other words, an additional portion of the composition and / or a component of a composition to which other effects are attributable.

[0070] A "pharmaceutical composition" can include a combination of an active agent, such as a therapeutic molecule, with an inert or active carrier in a sterile composition suitable for in vitro, in vivo or ex vivo diagnostic or therapeutic use.

[0071] The term "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0072] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable carriers.

[0073] As used herein, the term "prevention" refers to any action whereby the onset of a disease is inhibited, ameliorated, or delayed.

[0074] The term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition or disorder (i.e., arresting further progression of the pathology and / or symptom); (2) ameliorating a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition or disorder (i.e., reversing the pathology and / or symptom), e.g., reducing the severity of the disease.

[0075] The term "administration" refers to the introduction of a certain amount of a given substance into a patient by a specific appropriate method. The compositions disclosed herein can be administered via any of the common routes, such as, but not limited to, inhalation, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, pulmonary, or rectal administration, as long as they can reach the desired tissue.

[0076] The term "subject" or "patient" refers to the one intended to be treated with active agent. Optionally, the subject is a person susceptible to mucositis, or a person suspected of having or diagnosed with mucositis. However, it includes, but is not limited to, any subject treated with the pharmaceutical composition disclosed herein. In certain embodiments, the pharmaceutical composition disclosed herein is administered to a subject to prevent and / or treat mucositis.

[0077] Where applicable, the terms "about" or "approximately" as used herein and in the appended claims mean a margin of + / - 20% unless otherwise indicated. Also, where applicable, the term "substantially" as used herein and in the appended claims means a margin of + / - 10% unless otherwise indicated. It is to be understood that not all uses of the above terms can be quantified to allow the application of the referenced range.

[0078] The term "budesonide" refers to a corticosteroid drug. It is often administered using a metered-dose inhaler or nebulizer. It is also available as a pill, nasal spray, and rectal suppository. The inhaled form is used for the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The nasal spray is used for allergic rhinitis and nasal polyps. The suppository pill is formulated for delayed release and can be used for inflammatory bowel disease, including Crohn's disease, ulcerative colitis, and microscopic colitis.

[0079] The term "mucosa" refers to the soft tissue lining the body's tubes and organs in the digestive, respiratory and reproductive systems. It may also be called the mucosa. The mucosa has three layers: the epithelium, the lamina propria and the muscularis mucosa.

[0080] The term "polyol" refers to an organic compound containing multiple hydroxyl groups. Polyols commonly used in the art include sorbitol, mannitol, xylitol, maltitol, maltitol syrup, lactitol, erythritol, and isomalt. Sugar alcohols are polyols derived from sugars.

[0081] The term "alkaline phosphatase" or "ALP" refers to a hydrolytic intracellular enzyme involved in cellular metabolic processes. Amifostine can be classified as a prodrug that is activated upon dephosphorylation by ALP to its active metabolite WR-1065.

[0082] The term "GRAS" refers to "Generally Recognized as Safe." "GRAS acids" can be, for example, glycocholic acid, hydrochloric acid, lactic acid, linoleic acid, malic acid, pectic acid, sorbic acid, succinic acid, tannic acid, tartaric acid, taurocholic acid, and thiodipropionic acid. The acid component can be used to target an average pH in saliva of 4.5 to 6.5.

[0083] The term "oromucosal use" or "oromucosal administration" refers to the application of a drug or pharmaceutical agent via the oral mucosa, including one or more of the nasopharynx, oropharynx, or larynopharynx, specifically the oral cavity and / or pharynx.

[0084] The term "intranasal use" or "intranasal administration" refers to the application of a drug or medicinal agent to the nose, nasal cavity and / or nasopharynx.

[0085] The esophagus may also be targeted using embodiments of the present invention.

[0086] The terms "rectal use" or "rectal administration" or "rectal use" or "rectal administration" refer to the application of a drug or pharmaceutical agent to the rectal cavity.

[0087] The terms "vaginal use" or "vaginal administration" refer to the application of a drug or medication to the vaginal cavity.

[0088] The term "stick pack" refers to a set of cylindrical pouches, each used for one dose of medication. As used herein, a single dose of amifostine formulation (or other agent) can be packaged in a stick pack for administration to a patient.

[0089] The term "free-flowing powder" refers to a powder that has the ability to move with the flow that characterizes fluids and loose particulate solids. A free-flowing powder material has low caking and low cohesion. Cohesion is the tendency of the particles of a powder to stick together and agglomerate (generating larger clusters of particles). A Powder Flowability Analyzer (PFA) can be used to evaluate the flow behavior of a powder.

[0090] The term "dispersing medium" or "dispersing agent" refers to a substance, typically a surfactant, added to a suspension of solid or liquid particles in a liquid (e.g., a colloid or emulsion) to improve separation of the particles and prevent their settling or agglomeration. An effective amount of a flow agent can be used to promote flow. Acceptable silicates are preferred (but not limiting) flow agents.

[0091] The term "ion pair" refers to naturally occurring species formed in solution by electrostatic interactions between opposite charge states that are often sufficiently lipophilic to dissolve in non-aqueous solvents.

[0092] The term "ion pairing" refers to an approach to improve the lipophilicity and subsequently the transport rate of a drug (i.e., amifostine) across lipid membranes. Lipophilization (esterification of the lipophilic moiety) of ionizable drugs with high aqueous solubility by ion pairing with appropriate counterions has proven successful in this regard. Ion pairs are a pair of oppositely charged ions held together by Coulombic attraction without forming covalent bonds. They behave like a single unit and can partition into the membrane as a more lipophilic unit. This strategy involves coadministering an excess concentration of counterion. Counterions used with amifostine for ion pairing include succinate, phthalate and benzoate.

[0093] The therapeutic agent in the pharmaceutical composition can be formulated in a "therapeutically effective amount" or a "prophylactically effective amount". A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount of the recombinant vector may vary depending on the condition being treated, the severity and course of the condition, the mode of administration, whether the peptide or agent is administered for prophylactic or therapeutic purposes, the bioavailability of the particular agent, the ability of the agent to induce the desired response in the individual, previous treatments, the age, weight, and sex of the patient, the patient's medical history and response to the agent, the type of therapeutic agent used, the discretion of the attending physician, and the like. A therapeutically effective amount is also an amount in which any toxic or harmful effects of the recombinant vector are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

[0094] Many known useful compounds are listed in Remington's Pharmaceutical Sciences (13 th Ed), Mack Publishing Company, Easton, PA--standard reference texts for various types of administration. As used herein, the term "formulation" means a combination of at least one active ingredient with one or more other ingredients, generally also called excipients, which may be independently active or inactive. The term "formulation" may or may not refer to a pharma- ceutically acceptable composition for administration to humans or animals, and may include compositions that are useful intermediates for storage or research purposes.

[0095] Other technical terms used herein convey their ordinary meaning in the art in which they are used, as exemplified by various technical dictionaries. The specific values ​​and configurations discussed in these non-limiting examples may vary and are cited only to illustrate at least one embodiment and are not intended to limit its scope. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0096] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the claimed subject matter. Additional features and advantages of the subject technology will be set forth in the following description, and in part will be obvious from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the specification and claims.

[0097] Amifostine is a prodrug, which is active as a protective agent when dephosphorylated by alkaline phosphatase to its active metabolite WR-1065, as shown in Figure 1. WR-1065 is preferentially taken up by normal cells over neoplastic cells due to the higher alkaline phosphatase activity, better angiogenesis and higher pH of normal tissues. Once inside the cells, WR-1065 protects against chemotherapy and radiation-induced damage by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and direct binding to and inactivating cytotoxic drugs. Intravenous administration of amifostine can provide protection against a broad range of cytotoxic agents. Reduction of hematological or non-hematological toxicity has been described for cisplatin, carboplatin, doxorubicin, paclitaxel and 5-fluorouracil. Prevention of mucositis has been described, primarily in head and neck cancer patients treated with radiation therapy.

[0098] Amifostine is a water-soluble, moderately acidic compound. Conversion of amifostine to WR-1065 by alkaline phosphatase is pH-dependent and occurs more rapidly at alkaline pH. Alkaline phosphatase is a hydrolytic intracellular enzyme involved in cellular metabolic processes. Elevated salivary alkaline phosphatase (ALP) levels often reflect inflammation and destruction of healthy tissue. ALP is a key enzyme in periodontal tissues as it is part of the normal turnover of the periodontal ligament, root cementum and bone homeostasis. Both healthy and inflamed mouths have sufficient levels of ALP, and it is not a significant rate-limiting step in the process of WR-2721 conversion or resorption.

[0099] This split pKa between parent and metabolite presents a challenge in that an acidic environment is required to convert WR-2721 to WR-1065. Similarly, a basic environment confers stability to WR-2721. An environment that is too acidic reduces the amount of WR-1065 that is absorbed. An overly acidic environment may also increase acid-catalyzed hydrolysis of the ester bond prior to absorption. The resulting WR-1065 is likely further metabolized to an inactive compound, resulting in loss of radioprotective activity.

[0100] For example, amifostine is unstable at intragastric pH (i.e., pH between 1 and 3). Amifostine is hydrolyzed to WR-1065 under these acidic conditions. The hydrolysis reaction of amifostine is pH- and temperature-dependent but appears to be nonenzymatic and proceeds by cleavage of PS bonds to yield a thiol (WR-1065) and inorganic phosphate (i.e., H2N(CH2)3NH(CH2)2SPO3H2+H2O→H2N(CH2)3NH(CH2)2SH+H3PO4). The maximum rate of hydrolysis occurs at pH 3.0.

[0101] However, amifostine remains stable at neutral pH. In a recent study, no detectable hydrolysis occurred over 4 hours at room temperature at neutral pH. Thus, the drug is stable in saliva, which has a normal pH range of 6.2 to 7.6 (6.7 being the average). The resting pH of the oral cavity does not fall below 6.3. In the oral cavity, saliva maintains the pH near neutral (6.7 to 7.3).

[0102] Applicants have developed dynamic buffer systems as a solution to a difficult problem. Ongoing saliva production in the oral cavity (or other body cavity) during administration of the drug and during the intended absorption period is taken into account. Buffers that can be used to control pH include, for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, dipotassium phosphate, potassium citrate, and sodium phosphate. Buffer systems can be designed to dynamically control the pH of the product to account for the effects of saliva during use (i.e., dynamic buffer systems). Examples of buffer systems to obtain a preferred pH include dibasic sodium phosphate and monobasic sodium phosphate. Both are FDA approved buffer materials for use and are listed on the inactive ingredients list. For example, nicotine absorption is enhanced at Ph 7-8. For pH 7, the monobasic / dibasic ratio can be 4.6 / 8.6. For pH 7.5, the monobasic / dibasic ratio can be 1.9 / 11.9. For pH 8.0, the monobasic / dibasic ratio can be 0.6 / 13.4. These are mathematically calculated buffer values ​​that can be adjusted with other ingredients added to the formulation. They can also be adjusted for the length of time designed for dissolution of the dosage form in the target cavity.

[0103] One or more acids can be added to the dry powder formulation to achieve an appropriate pH for both conversion and absorption. Acids included in the FDA SCOGS (Select Committee on GRAS Substances) database include glycocholic acid, hydrochloric acid, lactic acid, linoleic acid, malic acid, pectic acid, sorbic acid, succinic acid, tannic acid, tartaric acid, taurocholic acid and thiodipropionic acid. The acid component can be used to target an average pH in saliva of 4.5 to 6.5, optionally over a period ranging from 1 minute. Preferably, the acid is GRAS.

[0104] In embodiments, the formulations described herein also include a penetration enhancer, which is a substance that enhances absorption through mucous membranes, mucosal coatings, and epithelia (otherwise known as "permeation enhancers" or "penetration enhancers," see, e.g., U.S. Patent Application Publication No. 2006 / 0257463). Mucosal absorption enhancers include, but are not limited to, polyethylene glycol (PEG), diethylene glycol monoethyl ether (Transcutol), 23-lauryl ether, aprotinin, Azone, benzalcomine chloride, cetylperidium chloride, cetylmethylammonium bromide, dextran sulfate, lauric acid, laurate / propylene glycol, lysophosphatidylcholine, menthol, methoxysalicylic acid, oleic acid, phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides, and various alkyl glycosides, or bile salts such as those described in U.S. Patent Application Publication No. 2006 / 0257463, e.g., sodium deoxycholate. These include sodium thorium, sodium glycodeoxycholate, sodium taurocholate and sodium glycocholate, surfactants such as sodium lauryl sulfate, polysorbate 80, laureth-9, benzalkonium chloride, cetylpyridinium chloride and polyoxyethylene monoalkyl ethers such as the BRIJ® and MYRJ® series, benzoic acids such as sodium salicylate and methoxy salicylate, fatty acids such as lauric acid, oleic acid, undecanoic acid and methyl oleate, fatty alcohols such as octanol and nonanol, laurocapram, polyols, propylene glycol and glycerin, cyclodextrins, sulfoxides such as dimethyl sulfoxide and dodecyl methyl sulfoxide, terpenes such as menthol, thymol and limonene, urea, chitosan and other natural and synthetic polymers.Preferably, the mucosal absorption enhancer is a polyol, such as polyethylene glycol (PEG), glycerin, maltitol, sorbitol, or diethylene glycol monoethyl ether (Transcutol). This list of penetration enhancers is not limiting.

[0105] In embodiments, the formulations described herein also include a "film former" or "film former" to improve the adhesion of the composition to the intended body surface. The film former can include, for example, one or more combinations of water-soluble, water-insoluble, or water-soluble or water-insoluble polymers. The polymer can include cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include pullulan, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, and combinations thereof. Specific examples of useful water-insoluble polymers include ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and combinations thereof. Other polymers useful for incorporation into the film include biodegradable polymers, copolymers, block polymers, and combinations thereof. Known useful polymers or classes of polymers that meet the above criteria include poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanones, polyoxalates, poly(α-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Further useful polymers include stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propanoic acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, poly(lactic acid) / poly(glycolic acid) / polyethylene glycol copolymers, copolymers of polyurethane and poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of alpha-amino acids, copolymers of alpha-amino acids and caproic acid, copolymers of alpha-benzyl glutamate and polyethylene glycol, copolymers of succinic acid and poly(glycol), polyphosphazenes, polyhydroxyalkanoates, and mixtures thereof. Binary and ternary systems are contemplated. Other useful and specific polymers include those sold under the trademarks Medisorb and Biodel. Medisorb materials are sold by the Dupont Company and are generally identified as "lactide / glycolide copolymers" containing "2-hydroxypolymers with propanoic acid, hydroxyacetic acid, and other hydroxypolymers." Four such polymers include lactide / glycolide, which is believed to be 100% lactide having a melting point within the range of 338-347°F (170-175°C); lactide / glycolide 100L, which is believed to be 100% glycolide having a melting point within the range of 437-455°F (225-235°C); lactide / glycolide 50 / 50, which is believed to be 85% lactide and 15% glycolide and has a melting point within the range of 338-347°F (170-175°C); and lactide / glycolide 50 / 50, which is believed to be a copolymer of 50% lactide and 50% glycolide and has a melting point within the range of 338-347°F (170-175°C).

[0106] Amifostine oral mucosal delivery formulation Mucositis often occurs when radiation or chemotherapy agents destroy the epithelial cells lining the gastrointestinal (GI) tract, exposing mucosal tissue to ulceration and infection. Amifostine is a known cytoprotectant that has the potential to protect certain tissues from radiation damage. It may help prevent and / or treat mucositis. However, efforts to use it have not been clinically successful due to challenges associated with its administration.

[0107] Only WR-2721 has commercial potential due to the instability of WR-1065. WR-1065 was used in clinical studies to examine the rate of absorption through mucous membranes. However, clinical studies on animals have demonstrated that there are inherent problems with this approach. Successful use of WR-2721 in animal studies requires sedation of the animals and high concentrations of WR-2721 applied to mucosal surfaces for extended periods of time. These conditions make it impractical (if not impossible) for therapeutic use.

[0108] The same problem was encountered in clinical trials in humans. Conventional formulations of amifostine require it to remain in contact with the mucosa for extended periods of time. This is not practical as patients generally find it difficult to rinse for more than one minute. Such rinsing / contact times do not allow for adequate absorption. Both WR-2721 and WR-1065 remain in the liquid, with the result that a large proportion remains in the rinse liquid after it is expelled.

[0109] Furthermore, given the location of the major salivary glands outside the accessible oral cavity, safe swallowing of high-concentration amifostine formulations would allow amifostine products to treat these hard-to-reach areas. Given the labeled intravenous amifostine dose of 500 mg, there are negligible potential toxicity or safety concerns for swallowing up to 500 mg of amifostine, and swallowed doses in excess of 500 mg may be tolerated.

[0110] Thus, embodiments include improved formulations for administering amifostine. The applicant recognizes that the oral mucosa has a thin epithelium and a rich vasculature, both favorable for absorption. However, contact is usually too short for substantial absorption. Drugs placed between the gums and cheek (buccal administration) or under the tongue (sublingual administration) are retained longer, facilitating absorption. The intended absorption is not limited to the oral cavity, but may be directed to the pharynx, larynx and / or esophagus, rectal cavity or vaginal cavity.

[0111] A particular embodiment of the invention is an amifostine composition that has a foaming action (i.e., foaming) in the mouth / oral cavity, which allows for the delivery of a therapeutic amount of amifostine across the oral mucosa. In a preferred embodiment, amifostine is delivered as part of a non-aqueous composition without the administration of additional liquid.

[0112] In embodiments, the formulations described herein are not administered with water to maximize the concentration of amifostine in the oral cavity and upon swallowing. Amifostine, which is highly water soluble, tends to solubilize in the saliva of the oral cavity.

[0113] The embodiments also included immediate release formulations. Thus, typically, amifostine (or other drugs or active agents) are not coated. However, coated amifostine particles can be used to manipulate the release pattern.

[0114] Dispersing agents such as crospavidone, Pharmasperse 416 (available from SPI Pharma™ containing 49.3-69.3% polyol and 30.4-50.4% calcium carbonate), isomaltodextrin, mannitol, maltose, sorbital, etc. are combined with a bicarbonate foaming agent. This combination leaves a film on the oral cavity including the teeth, tongue and gums. The continued presence of WR-2721 / WR-1065 as a film allows the larger composition to be swallowed and absorbed for an extended period of time after.

[0115] Bicarbonate is necessary for the foaming properties of the product, but has the effect of raising the pH of the environment outside the optimal range for WR-2721 conversion and absorption to WR-1065, where the pKa of WR-2721 is much lower. Sodium bicarbonate appears as an odorless, white crystalline powder with a slightly alkaline (bitter) taste. The pH of a freshly prepared 0.1 molar aqueous solution of sodium bicarbonate is 8.3 at 77°F, and the pH of a saturated solution is 8-9.

[0116] Applicants propose an amifostine formulation for oral mucosal delivery that also includes sodium bicarbonate, succinic acid, a surfactant, a polyol, a negatively charged product (chitosan or gelatin) and sucralose at a pH of about 4.5. Upon administration, the resulting solution has a consistency that allows it to coat the oral mucosa with a thin film for gradual absorption of the active agent (i.e., amifostine). In one embodiment, the amifostine solution includes the ingredients in Table 1. [Table 1]

[0117] Succinate is administered (in molar excess) as a counterion to amifostine. Other counterions that can be used for ion pairing include phthalate and benzoate. Ion pairing can improve absorption and subsequently increase local drug availability.

[0118] When placed in a patient's mouth, the amifostine is solubilized in the patient's saliva within the oral cavity.

[0119] In one embodiment, the concentration of amifostine in the oral mucosal delivery formulation is at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50% or more. In one embodiment, the concentration of amifostine in the oral mucosal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 50% or less or less. In one embodiment, the concentration of amifostine in the oral mucosal delivery formulation is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50% or more. In one embodiment, the concentration of amifostine in the oral mucosal delivery formulation is 10%-40%, 15%-35%, 20%-30%, 25%-30%, 30%-40%, or 40%-50%.

[0120] In one embodiment, the concentration of polyol (xylitol) in the oral mucosal (or other delivery site) delivery formulation is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or more. In one embodiment, the concentration of polyol (xylitol) in the oral mucosal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less or less. In one embodiment, the concentration of polyol (xylitol) in the oral mucosal delivery formulation is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or more. In one aspect, the concentration of polyol (xylitol) in the oral mucosal delivery formulation is 5%-10%, 10%-15%, 15%-25%, 20%-30%, 25%-30%, 30%-40%, or 40%-50%.

[0121] In one embodiment, the concentration of sodium bicarbonate in the oral mucosal (or other delivery site) delivery formulation is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or more. In one embodiment, the concentration of sodium bicarbonate in the oral mucosal (or other delivery site) delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less or less. In one embodiment, the concentration of sodium bicarbonate in the oral mucosal (or other delivery site) delivery formulation is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40% or more. In one embodiment, the concentration of sodium bicarbonate in the oral mucosal (or other delivery site) delivery formulation is 5%-10%, 10%-15%, 15%-25%, 20%-30%, 25%-30%, 30%-40%, or 40%-50%.

[0122] In one embodiment, the concentration of succinic acid in the oral mucosal (or other delivery site) delivery formulation is at least 0.5%, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 5% or more. In one embodiment, the concentration of succinic acid in the oral mucosal (or other delivery site) delivery formulation is 1% or less, 1.5% or less, 2% or less, 2.5% or less, 3% or less, 3.5% or less, 4% or less, 5% or less or less. In one embodiment, the concentration of succinic acid in the oral mucosal (or other delivery site) delivery formulation is about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 5% or more. In one embodiment, the concentration of succinic acid in the oral mucosal (or other delivery site) delivery formulation is 1%-4%, 1.5%-3.5%, 2%-3%, 2.5%-3%, 3%-4%, or 4%-5%.

[0123] In one embodiment, one or more surfactants (e.g., lecithin) are included in the effervescent formulation with a view to achieving an effervescent formulation. By expanding the formulation, the gas released from the effervescence (typically carbon dioxide) is trapped in bubbles, where the "bubbles" now contain the solubilized amifostine.

[0124] In this embodiment, the effervescent formulation comes into contact with saliva, amifostine solubilizes in the saliva, and the formulation releases CO2 trapped in the amifostine-containing saliva, which rapidly forms gas bubbles (due to the presence of surfactants). The result is a volumetrically expanded amifostine-containing liquid that can rapidly coat the oral cavity due to its volume.

[0125] The compositions of the present invention include drugs that are not soluble or are only partially soluble.

[0126] In embodiments, when swallowed, the expanded formulation also tends to be effective in coating the pharynx, larynx and / or esophagus.

[0127] In one embodiment, the concentration of sucralose in the oral mucosal delivery formulation is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40% or more. In one embodiment, the concentration of sucralose in the oral mucosal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less or less. In one embodiment, the concentration of sucralose in the oral mucosal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40% or more. In one embodiment, the concentration of sucralose in the oral mucosal delivery formulation is 5%-10%, 10%-15%, 15%-25%, 20%-30%, 25%-30%, 30%-40%, or 40%-50%.

[0128] How to use Methods for treating, preventing or ameliorating a disease, disorder, condition, or symptom thereof (e.g., mucositis or eosinophilic esophagitis) or a condition associated therewith are provided herein using the mucosal delivery formulations described herein for delivery to mucosal cavities, including, but not limited to, the pharynx, larynx, esophagus, nasal cavity, paranasal sinuses, rectal cavity and vaginal cavity.

[0129] The methods provided herein may include administering one or more of the mucosal delivery formulations described herein to a mucosal cavity (i.e., to the mouth as a mouthwash) of a subject in need of administration.Preferred, but non-limiting, embodiments relate to methods of treating, preventing, inhibiting, or ameliorating diseases, disorders, conditions, or symptoms associated with radiation exposure or chemotherapy.For example, amifostine may be administered as a mouthwash using the formulations described herein to allow absorption through the oral mucosa.

[0130] Pharmaceutical compositions containing amifostine or other small molecule drug products according to the present disclosure can be formulated in any pharma- ceutically acceptable carrier or excipient. As used herein, the term "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity and absorption delaying agents, and the like. Pharmaceutical compositions can include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Exemplary pharma- ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it is preferred to include an isotonicity agent, for example, a sugar, a polyalcohol, such as mannitol, sorbitol, or sodium chloride, in the composition. Pharmaceutically acceptable carriers can further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.

[0131] Amifostine or other small molecule drug products can be incorporated into pharmaceutical compositions suitable for mucosal administration. Suitable buffers include, for example, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate. Cryoprotectants can be included in the lyophilized dosage form, primarily 0-10% sucrose (optimally 0.5-1.0%). Other suitable cryoprotectants include trehalose and lactose. Bulking agents can be included in the lyophilized dosage form, primarily 1-10% mannitol (optimally 2-4%). ​​Stabilizers can be used in both liquid and lyophilized dosage forms, primarily L-methionine at 1-50 mM. Other suitable bulking agents include glycine and arginine, which can be included at 0-0.05%. Additional surfactants include, for example, polysorbate 20 and BRIJ surfactants.

[0132] Examples of finishing agents that may be used in some embodiments include β- and γ-cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalenediamide diimides, and naphthalenediester diimides. One or more antioxidants, such as vitamin C, vitamin E, proanthocyanidins, and α-lipoic acid, typically at concentrations of 0.1% to 2.5% (w / w), may also be included.

[0133] Amifostine or other small molecule drug products are suitably administered to the patient at one time or over a series of treatments and may be administered to the patient at any time following diagnosis. Amifostine or other small molecule drug products may be administered as the sole treatment or in combination with other drugs or therapeutic agents useful for treating the symptoms in question.

[0134] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to use such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, any combination of all possible variations of the above-described embodiments is encompassed by the present invention, unless otherwise indicated herein or clearly contradicted by context.

[0135] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfill all Markush group descriptions used in the appended claims.

[0136] Administration The compositions may be self-administered or administered by a caregiver. The product may simply be placed in the oral cavity and spread, or the composition may be delivered to various locations in the mouth when administered.

[0137] In some embodiments, the patient may be instructed to help spread the composition into the mucosal cavity ("patient-assisted expansion"). Patient-assisted expansion has a duration of 10 seconds to 120 seconds, preferably 20 seconds to 60 seconds. For oral administration, preferably during this period, the patient is instructed to lead his head back to help coat the posterior and upper reaches of the oral cavity. The patient may be instructed to move his head from side to side. For rectal administration, the patient may be instructed to lie supine and move or roll his body from side to side for a longer duration, including a longer duration of 15 minutes or more.

[0138] For buccal administration, after administration, and typically after a period of intraoral administration that includes "patient-assisted expansion," the patient is generally instructed to swallow the composition in the mouth. Similarly, the composition may be delivered to other delivery sites by the patient themselves or a caregiver.

[0139] For oral administration, swallowing preferably occurs while the composition is still expanding and foaming. Typically, the patient is instructed to swallow within 180 seconds after administration. In an embodiment, the patient is instructed to swallow within 60 to 180 seconds.

[0140] Pharmaceutical compositions containing amifostine or other small molecule drug products according to the present disclosure can be formulated in any pharma- ceutically acceptable carrier or excipient. As used herein, the term "pharma-ceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutical compositions can include suitable solid or gel phase carriers or excipients. Exemplary carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Exemplary pharma-ceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases, it is preferred to include an isotonic agent, such as a sugar, a polyalcohol, such as mannitol, sorbitol, or sodium chloride, in the composition. Pharmaceutically acceptable carriers may further contain minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life and / or effectiveness of the therapeutic agent.

[0141] As a general proposition, a therapeutically or prophylactically effective amount of amifostine or other drug product is administered in the range of about 1 ng / kg body weight to about 100 mg / kg body weight, whether in one or more doses. In certain embodiments, amifostine is administered in the range of about 1 ng / kg body weight to about 10 mg / kg body weight, about 1 ng / kg body weight to about 1 mg / kg body weight, about 1 ng / kg body weight to about 100 g / kg body weight, about 1 ng / kg body weight to about 10 g / kg body weight, about 1 ng / kg body weight / day to about 1 g / kg body weight, about 1 ng / kg body weight to about 100 ng / kg body weight, about 1 ng / kg body weight to about 10 ng / kg body weight, about 10 ng / kg body weight to about 100 mg / kg body weight, about 10 ng / kg body weight to about 1 0mg / kg body weight, approximately 10ng / kg body weight ~ approximately 1mg / kg body weight, approximately 10ng / kg body weight ~ approximately 100g / kg body weight, approximately 10ng / kg body weight ~ approximately 10mg / kg body weight, approximately 10ng / kg body weight ~ approximately 1mg / kg body weight, 10ng / k g body weight ~ approx. 100 ng / kg body weight, approx. 100 ng / kg body weight ~ approx. 100 mg / kg body weight, approx. 100 ng / kg body weight ~ approx. 10 mg / kg body weight, approx. 100 ng / kg body weight ~ approx. 1 mg / kg body weight, approx. mg / kg body weight, about 100 ng / kg body weight to about 10 mg / kg body weight, about 100 ng / kg body weight to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight / day, about 1m g / kg body weight ~ approx. 1 mg / kg body weight, approx. 1 mg / kg body weight ~ approx. 100 mg / kg body weight, approx. 1 mg / kg body weight ~ approx. 10 mg / kg body weight, approx. 10 mg / kg body weight ~ approx. 100 mg / kg body weight, approx. 10 mg / kg body weight ~ approx. 10 mg / k g body weight, about 10 mg / kg body weight to about 1 mg / kg body weight / day, about 10 mg / kg body weight to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 100 mg / kg body weight, about 100 mg / kg body weight / day to about 10 mg / kg body weight, about 100 mg / kg body weight / day to about 1 mg / kg body weight, about 1 mg / kg body weight to about 100 mg / kg body weight, about 1 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 100 mg / kg body weight / day.

[0142] In other embodiments, amifostine or other medicinal products are administered at a dose of about 10 ng to about 1 g per individual dose, about 10 ng to about 10 g per individual dose, about 10 ng to about 100 mg per individual dose, about 10 ng to about 1 mg per individual dose, about 10 ng to about 10 mg per individual dose, about 10 ng to about 100 mg per individual dose, about 10 ng to about 1000 mg per injection, about 10 ng to about 10,000 mg per individual dose, about 100 ng to about 1 mg per individual dose, about 100 ng to about 10 mg per individual dose, about 100 ng to about 100mg / individual administration, about 100ng to about 1mg / individual administration, about 100ng to about 10mg / individual administration, about 100ng to about 100mg / individual administration, about 100ng to about 1000mg / injection, about 100ng to about 10,000mg / individual administration, about 1mg to about 10mg / individual administration, about 1mg to about 100mg / individual administration, about 1mg to about 1mg / individual administration, about 1mg to about 10mg / individual administration, about 1mg to about 100mg / individual administration, about 1mg to about 100mg / individual administration, about 1mg to about 1000mg / injection, about 1mg to about 10,000 mg / individual administration, about 10 mg to about 100 mg / individual administration, about 10 mg to about 1 mg / individual administration, about 10 mg to about 10 mg / individual administration, about 10 mg to about 100 mg / individual administration, about 10 mg to about 1000 mg / injection, about 10 mg to about 10,000 mg / individual administration, about 100 mg to about 1 mg / individual administration, about 100 mg to about 10 mg / individual administration, about 100 mg to about 100 mg / individual administration, about 100 mg to about 1000 mg / injection, about 100 mg to about 10,00 Amifostine is administered in the range of about 0 mg / individual administration, about 1 mg to about 10 mg / individual administration, about 1 mg to about 100 mg / individual administration, about 1 mg to about 1000 mg / injection, about 1 mg to about 10,000 mg / individual administration, about 10 mg to about 100 mg / individual administration, about 10 mg to about 1000 mg / injection, about 10 mg to about 10,000 mg / individual administration, about 100 mg to about 1000 mg / injection, about 100 mg to about 10,000 mg / individual administration, and about 1000 mg to about 10,000 mg / individual administration. Amifostine may be administered according to chemotherapy treatment. Alternatively, it may be administered daily, BID, TID, QID, every 2, 3, 4, 5, 6 or 7 days, or every 1, 2, 3 or 4 weeks.

[0143] In other specific embodiments, the amount of amifostine or other drug product may be administered in a dose of about 0.0006 mg, 0.001 mg, 0.003 mg, 0.006 mg, 0.01 mg, 0.03 mg, 0.06 mg, 0.1 mg, 0.3 mg, 0.6 mg, 1 mg, 3 mg, 6 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg, 5000 mg or 10,000 mg. As expected, dosage will depend on the symptoms, size and age of the patient.

[0144] In other aspects, the pharmaceutical composition compounds disclosed herein reduce the incidence of mucositis (e.g., signs and symptoms) by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein reduce the incidence of viral infection by, for example, about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about Reduce by 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0145] The pharmaceutical composition disclosed herein is sufficient to allow conventional administration to individual.In this embodiment, the pharmaceutical composition disclosed herein can be, for example, at least 5mg, at least 10mg, at least 15mg, at least 20mg, at least 25mg, at least 30mg, at least 35mg, at least 40mg, at least 45mg, at least 50mg, at least 55mg, at least 60mg, at least 65mg, at least 70mg, at least 75mg, at least 80mg, at least 85mg, at least 90mg, at least 95mg, or at least 100mg pharmaceutical composition. In other aspects of this embodiment, a pharmaceutical composition disclosed herein can be, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a pharmaceutical composition. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein can be in the range of, for example, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg.In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein may be administered in an amount of, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 10 ... The amount of the active ingredient may be in the range of about 5 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0146] The pharmaceutical compositions disclosed herein may include a solvent, emulsion, or other diluent in an amount sufficient to dissolve the pharmaceutical compositions disclosed herein. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may include, for example, less than about 90% (v / v), less than about 80% (v / v), less than about 70% (v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), less than about 45% (v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), less than about 20% (v / v), less than about 15% (v / v), less than about 10% (v / v), less than about 5% (v / v), or less than about 1% (v / v) of the solvent, emulsion, or diluent.

[0147] In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may be, for example, from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 80% (v / v), from about 1% (v / v) to 90% (v / v), from about 1% (v / v) to 100% (v / v), from about 1% (v / v) to 150% (v / v), from about 1% (v / v) to 20% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to 30% (v / v), from about 1% (v / v) to 40% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 50% (v / v), from about 1% (v / v) to 60% (v / v), from about 1% (v / v) to 70% (v / v), from about 1% (v / v) to 80% (v / v), from about 1% (v / v) to 15% (v / v), from about 1% (v / v) to 25% (v / v), from about 1% (v / v) to v / v)~20%(v / v), approx. 1%(v / v)~10%(v / v), approx. 2%(v / v)~50%(v / v), approx. 2%(v / v)~40%(v / v), approx. 2%(v) / v)~30%(v / v), approx. 2%(v / v)~20%(v / v), approx. 2%(v / v)~10%(v / v), approx. 4%(v / v)~50%(v / v), approx. 4%(v / v) )~40%(v / v), approx. 4%(v / v)~30%(v / v), approx. 4%(v / v)~20%(v / v), approx. 4%(v / v)~10%(v / v), approx. 6%(v / v) ~50%(v / v), approx. 6%(v / v)~40%(v / v), approx. 6%(v / v)~30%(v / v), approx. 6%(v / v)~20%(v / v), approx. 6%(v / v)~1 The composition may contain a solvent, emulsion or diluent in the range of 0% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% (v / v) to 30% (v / v), about 8% (v / v) to 20% (v / v), about 8% (v / v) to 15% (v / v), or about 8% (v / v) to 12% (v / v).

[0148] The final concentration of the pharmaceutical composition disclosed herein can be any desired concentration. In one aspect of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be, for example, at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL, at least 0.1 mg / mL, at least 1 mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL, or at least 500 mg / mL. In other aspects of this embodiment, the final concentration of the pharmaceutical composition in the pharmaceutical composition can be, for example, about 0.00001 mg / mL to about 3,000 mg / mL, about 0.0001 mg / mL to about 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1mg / mL to approx. 3,000mg / mL, approx. 1mg / mL to approx. 3,000mg / mL, approx. 250mg / mL to approx. 3,000mg / mL, approx. 500mg / mL to approx. 3,000mg / mL, approx. 750mg / mL to approx. 3,000mg / mL, approx. 1,000m g / mL ~ approx. 3,000 mg / mL, approx. 100 mg / mL ~ approx. 2,000 mg / mL, approx. 250 mg / mL ~ approx. 2,000 mg / mL, approx. 500 mg / mL ~ approx. 2,000 mg / mL, approx. 750 mg / mL ~ approx. 2,000 mg / mL, approx. 1,000 m g / mL~about 2,000mg / mL, about 100mg / mL~about 1,500mg / mL, about 250mg / mL~about 1,500mg / mL, about 500mg / mL~about 1,500mg / mL, about 750mg / mL~about 1,500mg / mL, about 1,000m g / mL ~ approx. 1,500 mg / mL, approx. 100 mg / mL ~ approx. 1,200 mg / mL, approx. 250 mg / mL ~ approx. 1,200 mg / mL, approx. 500 mg / mL ~ approx. 1,200 mg / mL, approx. 750 mg / mL ~ approx. 1,200 mg / mL, approx. 1,000 m g / mL~about 1,200mg / mL, about 100mg / mL~about 1,000mg / mL, about 250mg / mL~about 1,000mg / mL, about 500mg / mL~about 1,000mg / mL, about 750mg / mL~about 1,000mg / mL, about 100mg / mL mL~about 750mg / mL, about 250mg / mL~about 750mg / mL, about 500mg / mL~about 750mg / mL, about 100mg / mL~about 500mg / mL, about 250mg / mL~about 500mg / mL, about 0.00001mg / mL~about 0.00 The concentration of the glycerol in the solution may range from about 0.01 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL.

[0149] Aspects of the present specification disclose, in part, treating individuals susceptible to or suffering from mucositis. As used herein, the term "treating" refers to reducing or eliminating the incidence of mucositis, or alleviating signs and symptoms. For example, the term "treating" can mean alleviating symptoms of a condition characterized by mucositis, including, but not limited to, reducing inflammation by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. Those skilled in the art will know the appropriate symptoms or indicators associated with a particular type of disease and know how to determine whether an individual is a candidate for the treatment disclosed herein.

[0150] In aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of mucositis (e.g., inflammation) by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of mucositis, e.g., by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%.

[0151] In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces signs / symptoms of mucositis by about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0152] In yet another aspect of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein generally ranges from about 0.001 mg / kg to about 100 mg / kg, e.g., administered every 3, 5, 7, 10, or 14 days. In aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be, e.g., at least 0.001 mg / kg, at least 0.01 mg / kg, at least 0.1 mg / kg, at least 1.0 mg / kg, at least 5.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, or at least 50 mg / kg, e.g., administered every 3, 5, 7, 10, or 14 days.

[0153] In other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.001 mg / kg to about 10 mg / kg, about 0.001 mg / kg / day to about 15 mg / kg, about 0.001 mg / kg to about 20 mg / kg, about 0.001 mg / kg to about 25 mg / kg, about 0.001 mg / kg to about 30 mg / kg, about 0.001 mg / kg to about 35 mg / kg, about 0.001 mg / kg to about 40 mg / kg, about 0.001 mg / kg to about 45 mg / kg, about 0.001 mg / kg to about 50 mg / kg, about 0.001 mg / kg to about 75 mg / kg, or about 0.001 mg / kg to about 100 mg / kg, and can be administered, for example, every 3, 5, 7, 10, or 14 days.

[0154] In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 75 mg / kg, or about 0.01 mg / kg to about 100 mg / kg, and can be administered, for example, every 3, 5, 7, 10, or 14 days.

[0155] In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein can be in the range of, for example, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 35 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to about 45 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 75 mg / kg, or about 0.1 mg / kg to about 100 mg / kg, and can be administered, for example, every 3, 5, 7, 10, or 14 days.

[0156] Administration may be single or cumulative (continuous administration), and can be easily determined by one skilled in the art. For example, treatment of mucositis may include a single administration of an effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment of mucositis may include multiple administrations of an effective dose of the pharmaceutical composition administered over a range of time periods, such as, for example, once a day, twice a day, three times a day, once every few days, or once a week. The timing of administration may vary from individual to individual, depending on factors such as the severity of the individual's symptoms and / or chemotherapy treatment regimen. For example, an effective amount of the pharmaceutical composition disclosed herein may be administered once to an individual immediately after a single chemotherapy treatment. Alternatively, it may be administered daily for an indefinite period of time, or until the individual no longer requires treatment. One skilled in the art will recognize that an individual's symptoms can be monitored throughout the course of treatment, and the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0157] In further embodiments, amifostine and its derivatives have a half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months or more.

[0158] packaging If the formulation is a powder, a stick pack or sachet is a preferred embodiment. Flexible packaging is preferred, although other embodiments use non-flexible packaging - harder plastics, glass and other non-flexible materials.

[0159] Although unit dose packaging is preferred, multi-dose packaging is possible, particularly for institutional use.

[0160] In certain embodiments, it may be desirable to package the product using a gas blanket, including, but not limited to, nitrogen. The package may be vacuum sealed.

[0161] Barrier packaging may be preferred. The packaging may be packaged with the device.

[0162] In certain embodiments, the powder composition is in a soluble sachet, which dissolves on contact with bodily fluid, thereby exposing the powder composition to the bodily fluid.

[0163] device A variety of devices can be used to administer the powder in or to the desired delivery site: dry powder syringes, powder syringes, powder applicators, pessaries, tampons and other devices can be used.

[0164] The device may be configured for nasal delivery. The device may be delivered and is capable of oral, vaginal; and rectal delivery.

[0165] In certain embodiments, the applicator may be used to stir or agitate the foam either before or after administration. EXAMPLES

[0166] The following non-limiting examples are provided for illustrative purposes only, to facilitate a more complete understanding of the representative embodiments currently contemplated.These examples are intended to be merely a subset of all possible situations in which the components of the formulation can be combined.Therefore, these examples should not be interpreted as limiting any of the embodiments described herein, including those related to the type and amount of components of the formulation and / or its method and use. EXAMPLES

[0167] Formulations for oral mucosal administration of amifostine Conventional methods of administering amifostine are generally ineffective. Most of the amifostine is not effectively converted to its active form (i.e., WR-1065). In addition, WR-1065 is poorly absorbed through mucous membranes. The formulations described herein can increase the concentration, permeability and residence time at the target site.

[0168] Amifostine can be prepared as a dry powder composition for oromucosal administration. The components can be added in any order, but the process is detailed in Figure 2. In the first step 105, amifostine is combined with Pharmasperse 416 (or other dispersing agent). Sodium bicarbonate is then added to induce foaming 110. Succinic acid is added for ion pairing 115. Sucralose 120 can be added in an amount sufficient to improve taste.

[0169] In another example (summarized in Table 2), 200 mg of amifostine is combined with 200 mg of sodium bicarbonate, 250 mg of succinic acid, 100 mg of chitosan, 100 mg of lecithin, and 100 mg of xylitol. The ingredients are gently mixed or milled to create a homogenous formulation with the ingredients evenly dispersed. The product is a dry powder (i.e., non-aqueous) with a consistency that allows it to flow and foam in the oral cavity when exposed to saliva or other mucosal fluids. The resulting foam coats the oral mucosa with a thin film for gradual absorption of the active agent (i.e., amifostine). [Table 2]

[0170] Upon administration, the resulting solution has a consistency that allows it to coat the oral mucosa with a thin film for gradual absorption of the active agent (i.e., amifostine). The resulting foam expands to a volume of 32.5 mL and has a pH of 4.61. The foam has excellent adhesive properties and the foam has a solid consistency that maintains its shape for more than 1 minute.

[0171] Amifostine formulations can be prepared in variations as shown in the table below (weights listed do not include the weight of amifostine). The contents of each vial were ground prior to the experimental conditions to ensure uniformity of contents. The succinic acid, xylitol and agar controls were selected to provide base levels for the increase in saliva production that occurs with the change in pH and addition of sweeteners, which provides a baseline volume. All weights are in milligrams (mg). [Table 3]

[0172] The properties of the above formulations are listed in Figure 3. Each formulation was studied to determine volume (after whipping), pellet depth, adhesion and pH. All experimental conditions were completed in triplicate. Data was generated as follows:

[0173] As a general observation, it would be desirable to have a large capacity (for dispensing the drug), a "sticky" or adhesive foam to maintain contact between the drug and the mucosal surface (or other bodily surface), and a "stable" foam that may also serve to prolong the contact between the drug and the mucosal surface (or other bodily surface).

[0174] The experimental formulations (vials no. 1-13) were dissolved in 15 mL of water and the pH was determined with a calibrated digital pH meter.

[0175] The dry powder was placed into a conical 50 mL graduated tube containing 10 mL of BZ108 artificial saliva formulation (5 mL for control due to the lower corresponding mass) followed by gentle swirling and inversion three times for 10 seconds. The contents were measured after 30 seconds.

[0176] Following the volume measurement, a 6 mm 0.12 g standard airsoft pellet was placed in the conical tube and allowed to settle into the resulting foam for 30 seconds, and the depth was measured by the volume marker. This test was intended to measure the stiffness of the foam.

[0177] After measuring the depth, the 50 mL conical tube was fully inverted for 5 seconds and the remaining volume was measured to determine adhesion.

[0178] Using the tests described herein, a "voluminous foam" refers to a foam that reaches a volume of more than 30 mL. A "very voluminous foam" is one that reaches a volume of more than 40 ml. A "stable foam" refers to a foam that reaches a pellet depth of 70% (or more). A "very stiff" foam is one that reaches a pellet depot depth of 80% or more. Similarly, a "sticky foam" refers to a foam that is 60% or more attached to a surface. A "very sticky" foam refers to a foam that is 80% or more attached to a surface.

[0179] For additional experiments, artificial saliva for pharmaceutical research (BZ108) was obtained from BioChema Zone™ (Edmonton, Alberta). Artificial Saliva for Pharmaceutical Research Artificial saliva is formulated according to the literature for pharmaceutical research such as the study of drug dissolution and drug delivery through the oral mucosa. This is a ready-to-use formulation. The pH of the solution was 6.8.

[0180] Artificial saliva formulations have similar compositions and ingredients that simulate the mineral composition, enzymes, and pH of natural saliva. Artificial saliva is used to study and treat dry mouth and other conditions. This ready-to-use formulation contains viscosity enhancers that mimic real human saliva.

[0181] Although the studies conducted are directed to oromucosal products, the uses are expressly contemplated for vaginal and related site delivery, wound care and rectal administration.

[0182] In an embodiment, the dry formulation comprises the ingredients identified in Table 4 (also listed as Vial No. 11 above). The formulation had desirable qualities of volume, pellet depth, adhesion and pH (see FIG. 3). [Table 4]

[0183] In an embodiment, the dry formulation comprises the ingredients identified in Table 5 (also listed as Vial No. 13 above). The formulation also had desirable qualities of volume, pellet depth, adhesion and pH (see FIG. 3). [Table 5]

[0184] In embodiments, the concentration of the active ingredient (e.g., amifostine) can be determined from the literature (i.e., published recommended doses) and methods known to those of skill in the art. Other active agents include, for example, antibiotics, antifungals, nonsteroidal anti-inflammatory drugs, and steroidal anti-inflammatory drugs. EXAMPLES

[0185] Formulation of budesonide for rectal administration Budesonide is a corticosteroid drug that reduces inflammation. Budesonide rectal can be used to treat distal ulcerative colitis flare-ups (spreading from the part of the large intestine closest to the rectum). This drug is used to treat the symptoms of a certain bowel disease (ulcerative colitis). It works by reducing swelling (inflammation). Budesonide rectal is generally used once in the morning and once in the evening for two weeks. Then, only once a day (at bedtime) for another four weeks.

[0186] In this example, budesonide is formulated as a foam formulation as detailed in Table 6. The foam formulation can be administered rectally to increase the concentration, permeability and residence time at the target site. By administering it as a foam, it can act directly on the affected tissues of the intestine and rectum. [Table 6] EXAMPLES

[0187] Preventing / treating mucositis in combination with chemotherapy In this example, a patient undergoes chemotherapy as part of a treatment plan for head and neck cancer. The patient presents with multiple squamous cell carcinoma tumors in the throat and larynx. The patient is administered amifostine for use after each chemotherapy session (e.g., as a mouthwash within 15 minutes to 2 hours after chemotherapy).

[0188] Amifostine is administered to the patient in the formulation described above (Table 2). Specifically, 125 mg of amifostine is provided as a mouthwash. The patient rinses for approximately 1 minute, after which the rinse is drained / discarded. The rinsing process can be repeated. Radioprotection is evident as the patient does not show signs / symptoms of mucositis during the course of chemotherapy treatment.

[0189] This study demonstrated high cellular uptake of the drug by oral mucosal epithelial cells. Furthermore, no systemic side effects were observed and WR-1065 was well tolerated. In this study, WR-1065 was administered at approximately 3.7–19.9 ng / 10 ng / mL in washed, isolated, and live oral mucosal cells. 5 These findings suggest that 200 mg of WR-2721 (10 ml, 0.09 M) or 125 mg of WR-1065 (10 ml, 0.09 M) can be safely administered and the cytoprotective concentrations achieved may be effective in preventing / treating mucositis.

[0190] The surprising effects achieved by the formulations and methods of the present invention can be attributed, in part, to improved oral mucosal delivery formulations that enhance the delivery of amifostine through the skin. Applicants have found that by using the formulations described in Tables 1 and 2, the delivery levels of amifostine to oral epithelial cells are significantly improved. EXAMPLES

[0191] Physical Observation with a Microscope A flexible nasopharyngoscope (Olympus) attached to a Storz Telepack video system was utilized for each evaluation. Topical decongestants and local anesthetics (oxymetolazone and 4% lidocaine spray in a 1:1 mixture) were used in standard fashion (i.e., two sprays in each nostril). The nasopharynx was accessed via the right nasal cavity to visualize an initial assessment of the upper airway anatomy. Once complete, subjects were administered 500 grams of carrier compound (composition of vial 11) mixed with 10 mg of green food coloring (Wilton powdered food coloring) to view the extent of dispersion in the oral cavity and upper airway. Similar to the control compound, the upper airway was accessed via the nasal cavity. The nasopharynx, oropharynx, hypopharynx, and laryngopharynx were all evaluated. Additionally, the oral cavity was also evaluated using a video laryngoscope to ascertain the extent to which the compound was dispersed as it first moved from the oral anatomy and then into the upper airway via deglutination (first swallow). The widespread application or dispersion of carrier compound throughout the upper airway was assessed by video documentation using an Olympus laryngoscope.

[0192] Control samples were administered orally, after which the mouth was closed for 40 seconds before deglutenization. The oral cavity was evaluated, showing minimal exposure to the video, represented by uptake of the green dye, which was seen in the oral tongue, but not in the hard or soft palate. A nasopharyngoscope was then passed through the right nostril to evaluate the upper airway, which revealed that the entire nasopharynx was spared. There was minimal or no uptake at the nares (the area between the epiglottis and the base of the tongue), only mild uptake along the nasoepiglottic folds (the tissue connecting the epiglottis to the larynx), and limited exposure or dispersion at the pyriform sinuses (the area just lateral to the vocal cords). Additionally, the posterior pharyngeal wall was not stained, and the laryngeal vestibule, subglottis, and true vocal cords also did not appear to have any staining or exposure to the mixture.

[0193] After administration of the test compound product into the oral cavity without deglutenization for 40 seconds with the mouth closed, the oral cavity was first evaluated and the mixture was moderately present on the oral tongue, roof of the mouth / hard palate, with delayed dispersion but moderate staining of the soft palate. Moderate dispersion / dye uptake was seen along the floor of the mouth and lingual side of the gingiva. A nasopharyngoscope was then passed through the right nostril to evaluate the upper airway and the entire nasopharynx was found to be spared. The mixture with an early coordinated swallow showed moderate evidence of green dye staining (dispersion) into the oropharynx (tonsils and base of tongue), oviduct, and postcricoid. The pyriform sinuses were stained with green dye, as were areas along the arytenoid-epiglottic folds. The laryngeal opening did not have any green exposure or staining based on administration of this mixture. Finally, there was no dye staining in the subglottic region (area below the vocal cords).

[0194] As described above, the oral mucosal amifostine formulations may be administered as a single, single mouthwash at the time of or shortly after chemotherapy or radiation exposure. Alternatively, they may be administered once a week, once every two weeks, once a month, or once to twelve times a day for a period sufficient to alleviate symptoms or symptoms, such as 1 week, 1 week to 12 weeks or more, 1 week to 6 weeks, 2 weeks to 12 weeks, 2 weeks to 8 weeks, 2 weeks to 6 weeks, 2 weeks to 4 weeks, 4 weeks to 12 weeks, 4 weeks to 8 weeks, or 4 weeks to 6 weeks. The compositions may be administered, for example, as frequently as once a day to hourly as needed. The formulations described herein may be administered once or more a day for a period of 1 week to 4 weeks, 1 week to 2 weeks, 1 week, 2 weeks, 3 weeks, or 4 weeks or more. In some cases, it may be desirable to continue treatment indefinitely, for example to suppress recurrent inflammation. Suitable administration of oral mucosal delivery formulations, including mouthwashes, is, for example, once, twice, three times, four times a day, or hourly as needed.

[0195] If desired, other therapeutic agents can be used in conjunction with those provided in the above compositions. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated, the nature of the disease, disorder, or condition, and the nature of the active ingredient.

[0196] In embodiments, the dry powder compositions described herein expand upon combination with bodily fluid (e.g., saliva). In aspects, the volume of the dry powder composition expands by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 8 times, or at least 10 times its original (i.e., dry) volume.

[0197] In embodiments, the expanded composition maintains its expanded volume (or at least 80% of its volume) for at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 1 minute, at least 2 minutes, at least 3 minutes, at least 5 minutes, at least 7 minutes, at least 8 minutes, at least 10 minutes, at least 12 minutes, or at least 15 minutes.

[0198] In embodiments, the expanded composition has improved adhesion to the target site (e.g., mucosa). In embodiments, the expanded composition has greater homogeneity (i.e., more uniform distribution of the active agent). In embodiments, the expanded composition provides higher permeability and / or penetration into and / or through the mucosa. In embodiments, the methods described herein allow for smaller doses of the agent due to improved administration to the target tissue.

[0199] In embodiments, active agents are used with the compositions described herein. The active agents may be anesthetics, antiallergics, dermatological agents, chemotherapeutic agents, quinines, antifungals, antibiotics, thalidomide, serotonin, eicosanoids, analgesics, anticonvulsants, nonsteroidal antirheumatic drugs, leukotrienes, leukotriene inhibitors, androgens, antiandrogens, corticoids, opiates, receptor antagonists, blood clotting inhibitors, platelet aggregation inhibitors, histamine antagonists, peptides / proteins, nucleic acids, antipruritics, antidiabetic agents, prostaglandins, prostaglandin synthesis inhibitors, antiviral or virostatic agents. In one embodiment, the therapeutic agent is one or more of: antimicrobial agents, immunosuppressants, hormones, wart or wound treatment agents, vitamins, plant extracts or essences of plant extracts, psychotropic agents, analgesics, muscle relaxants, antiepileptics, antiparkinsonian agents, antiemetics, antiparasitic agents, ganglion active agents, sympathetic active agents, parasympathetic active agents, antibacterial agents, calcium antagonists, cardiovascular agents, antiasthmatic agents, antitussives, expectorants, hepatic agents, diuretics, choleretic agents, disinfectants, trace elements, anti-infective agents, cytostatic agents, metabolic antagonists, hormone antagonists, antifungal agents or immunomodulatory agents.

[0200] It is understood that the specific dose level for any particular patient will vary depending on a variety of factors, including the activity of the particular active agent: the age, weight, general health, sex and diet of the patient; administration time; excretion rate; possible drug combinations; the severity of the particular condition being treated; the area being treated and the form of administration. Those skilled in the art will understand the variability of such factors and will be able to establish a specific dose level using only routine experimentation.

[0201] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, excretion rate constant, half-life, and mean residence time can be determined by methods well known in the art.

[0202] The disclosed compositions can be combined with the above-mentioned pharmaceutically acceptable carrier and formulated into various dosage forms.For example, for oral administration, pharmaceutical compositions can be formulated into tablets, troches, capsules, elixirs, suspensions, syrups or wafers.Pharmaceutical compositions can also be formulated into liquids, suspensions, tablets, pills, capsules and long-acting preparations.

[0203] Meanwhile, suitable carriers, excipients and diluents for pharmaceutical preparations include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.In addition, pharmaceutical preparations may further include fillers, anticoagulants, lubricants, moisturizers, flavorings and preservatives.

[0204] The composition can be used by blending with various pharma- ceutically acceptable carriers such as physiological saline or organic solvents. To enhance stability or absorption, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers can be used.

[0205] The dosage and frequency of administration of the pharmaceutical compositions disclosed herein will be determined by the type of active ingredient, as well as by various factors such as the disease being treated, the route of administration, the patient's age, sex, weight, and disease severity.

[0206] The total effective dose of the compositions disclosed herein may be administered to the patient in a single dose or may be administered over an extended period of time in multiple doses according to a divided treatment protocol. In the pharmaceutical compositions disclosed herein, the content of the active ingredient may vary depending on the severity of the disease. Preferably, the total daily dose of the drug disclosed herein may be about 0.0001 μg to 500 mg per kg of the patient's body weight. However, the effective amount of the drug is determined by taking into consideration various factors including the age, body weight, health condition, sex, disease severity, diet, and secretion rate of the patient, in addition to the administration route and treatment frequency of the pharmaceutical composition. In consideration of this, a person skilled in the art can easily determine an effective dose suitable for a particular use of the pharmaceutical composition disclosed herein. The pharmaceutical composition disclosed herein is not particularly limited in formulation, administration route, and administration form, as long as it shows an appropriate effect.

[0207] In addition, the pharmaceutical compositions may be administered alone or in combination or concurrently with other pharmaceutical agents that exhibit prophylactic or therapeutic efficacy.

[0208] Given the teachings and guidance provided herein, one skilled in the art will understand that the formulations described herein may be equally applicable to many types of biopharmaceuticals, including those exemplified, as well as others known in the art. Given the teachings and guidance provided herein, one skilled in the art will also understand that, for example, the selection of the type or and / or amount of one or more excipients, surfactants, and / or optional ingredients may be based on chemical and functional compatibility with the formulated biopharmaceutical and / or mode of administration, as well as other chemical, functional, physiological, and / or medical factors known in the art. For example, non-reducing sugars exhibit favorable excipient properties compared to reducing sugars when used with polypeptide biopharmaceuticals. Thus, exemplary formulations are further exemplified herein with reference to polypeptide biopharmaceuticals. However, the scope of applicability, chemical and physical properties, considerations, and methodologies that apply to polypeptide biopharmaceuticals may be equally applicable to biopharmaceuticals other than polypeptide biopharmaceuticals.

[0209] In various embodiments, the formulation may include one or more preservatives and / or additives known in the art. Similarly, the formulation may be further formulated into any of a variety of known delivery formulations, including, but not limited to, in one embodiment. For example, in one embodiment, the formulation may include surfactants, adjuvants, biodegradable polymers, hydrogels, and the like, such optional components, their chemical and functional properties being known in the art. Also known in the art are formulations that promote immediate, sustained or delayed release of bioactive agents after administration. The formulations described may be manufactured to include these or other formulation components known in the art.

[0210] In certain embodiments, the kit can include, but is not limited to, one or more single-chamber or dispersing syringes (e.g., liquid syringes and lyosyringes) for administering one or more formulations described herein. In various embodiments, the kit can include formulation components for parenteral, subcutaneous, intramuscular or IV administration, sealed in a vial under partial vacuum, in a form ready to be loaded into a syringe and administered to a subject. In this regard, the composition can be placed therein under partial vacuum. In all of these and other embodiments, the kit can include one or more vials according to any of the above, each vial containing a single unit dose for administration to a subject.

[0211] The kits can include a lyophilisate disposed as described herein that, when reconstituted, provides a composition accordingly, in various embodiments, the kits can include a lyophilisate and a sterile diluent for reconstituting the lyophilisate.

[0212] Also described herein is a method for treating a subject in need of treatment, comprising administering to the subject an effective amount of the formulation described herein. The therapeutically effective amount or dose of the formulation depends on the disease or condition of the subject and the actual clinical situation.

[0213] In one embodiment, the formulation as described herein can be administered by any suitable route, specifically by parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will also be understood that the preferred route will vary according to the condition and age of the recipient and the disease being treated. The method of determining the most effective administration means and dosage is known to those skilled in the art and will vary according to, but not limited to, the composition used in the treatment, the purpose of the treatment, and the subject being treated. Single or multiple administrations can be performed, and the dose level and pattern are selected by, but not limited to, the treating physician. Appropriate dosage formulations and methods of administering drugs are known in the art.

[0214] The formulations described herein can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0215] Also provided herein are combinatorial methods for developing suitable virus formulations using combinations of amino acids. These methods are useful for developing stable liquid or lyophilized formulations, particularly pharmaceutical virus formulations.

[0216] Compositions according to embodiments described herein have desirable properties such as desirable solubility, viscosity, syringeability and stability. Lyophilizates according to embodiments described herein also have desirable properties such as desirable recovery, stability and reconstitution.

[0217] In one embodiment, the pH of the pharmaceutical formulation is at least about 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, or 9.

[0218] In one embodiment, the pH of the pharmaceutical formulation is about 3 to about 9, about 4 to about 19, about 5 to about 9, about 6 to about 8, about 6 to about 7, about 6 to about 9, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 7 to about 8, about 7 to about 9, or about 7 to about 10.

[0219] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to use such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, any combination of all possible variations of the above-described embodiments is encompassed by the present invention, unless otherwise indicated herein or clearly contradicted by context.

[0220] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfill all Markush group descriptions used in the appended claims.

[0221] Unless otherwise indicated, all numbers expressing properties, items, amounts, parameters, properties, terms, etc. used in the specification and claims should be understood to be modified in all instances by the term "about". As used herein, the term "about" means that the property, item, amount, parameter, property, or term so modified encompasses a range of 10% above and below the value of the stated property, item, amount, parameter, property, or term. Thus, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, Unless otherwise stated herein, each individual value of the numerical range is incorporated herein as if it were individually recited herein.

[0222] Specific embodiments disclosed herein may be further limited in the claims using the phrase "consisting of" or "consisting essentially of." When used in a claim, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim, whether added at the time of filing or by amendment. The transitional term "consisting essentially of" limits the scope of the claim to the particular materials or steps, as well as those that do not materially affect the basic and novel characteristics. The embodiments of the invention so claimed are essentially or explicitly described and enabled herein.

[0223] Grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfill all Markush group descriptions used in the appended claims.

[0224] All patents, patent publications, and other publications referenced and identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the accuracy of the dates or contents of these documents.

[0225] Finally, although aspects of the present specification have been emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Thus, it should be understood that the disclosed subject matter is in no way limited to the specific methods, protocols, and / or reagents, etc., described herein. Thus, various modifications or variations of the disclosed subject matter or alternative configurations can be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Thus, the present invention is not limited to what has been precisely shown and described.

Claims

1. An oral mucosal preparation for use in the prevention or treatment of mucositis in a subject, said preparation comprising: a) amifostine trihydrate (5% to 40% w / w); b) polyols (5% to 30% w / w); c) a base (10% to 40% w / w), and d) Acids (15% to 50% w / w) It consists of the base induces foaming of the formulation, increasing at least one of the surface area and volume of the amifostine trihydrate at or near epithelial cells of the oral cavity and gastrointestinal tract; Oral mucosal preparations.

2. The oral mucosal preparation described in claim 1, wherein the mucositis is associated with radiation exposure or chemotherapy.

3. An oral mucosal preparation as described in claim 1, wherein the volume of the preparation increases upon exposure to saliva.

4. An oral mucosal preparation as described in claim 3, wherein the preparation maintains its increased volume for at least 30 seconds.

5. An oral mucosal formulation as described in claim 3, wherein the formulation forms a foam upon exposure to saliva or other mucosal-derived fluid, the foam having a volume greater than 30 mL, and the volume remains greater than 30 mL within the mucosal cavity for at least 30 seconds.

6. The oral mucosal preparation of claim 1 , wherein the acid is succinic acid.

7. 10. The oral mucosal formulation of claim 1, further comprising a penetration enhancer.

8. The oral mucosal preparation of claim 1 , further comprising a film-forming agent.

9. A formulation for use in administering a drug to mucosal epithelial cells, said formulation comprising: a) a drug (1% to 40% w / w); b) polyols (5% to 30% w / w); c) a base (5% to 30% w / w), and d) Acids (15% to 50% w / w) It consists of Upon contact with bodily fluids, the formulation foams, increasing one or more of the surface area, volume, and viscosity of the agent at the target site. formulation.

10. 10. The formulation of claim 9, wherein the agent is amifostine, budesonide, an antibiotic, an antifungal, or a corticosteroid.

11. 10. The formulation of claim 9, wherein the target site is the oral or rectal cavity.

12. The formulation of claim 9, wherein the volume of the formulation increases upon exposure to bodily fluids, and the formulation maintains the increased volume for at least 30 seconds.

13. An oral mucosal preparation as described in claim 3, wherein the preparation forms a foam upon exposure to saliva, the foam having a volume of more than 30 mL, and the volume remains greater than 30 mL in the oral cavity for at least 30 seconds.

14. A formulation for use in preventing or treating mucositis in a subject, comprising: a) the formulation is orally administered to the subject as a dry powder; b) the formulation comprises a base to induce foaming of the formulation upon contact with saliva; c) the formulation comprises a polyol to increase the viscosity and / or consistency of the formulation upon aeration; and d) the formulation contains an acid as a counterion to increase foaming and / or control pH; formulation.

15. The formulation of claim 14, further comprising a negatively charged excipient for improving mucosal binding, wherein the negatively charged excipient is selected from one or more of chitosan, chitan, and gelatin.

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