AU2007240204A1 - Methods and compositions for treating oral and esophageal lesions - Google Patents
Methods and compositions for treating oral and esophageal lesions Download PDFInfo
- Publication number
- AU2007240204A1 AU2007240204A1 AU2007240204A AU2007240204A AU2007240204A1 AU 2007240204 A1 AU2007240204 A1 AU 2007240204A1 AU 2007240204 A AU2007240204 A AU 2007240204A AU 2007240204 A AU2007240204 A AU 2007240204A AU 2007240204 A1 AU2007240204 A1 AU 2007240204A1
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- Australia
- Prior art keywords
- agent
- intestinal trefoil
- composition
- mammal
- therapeutic agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Landscapes
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Description
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant(s): THE GENERAL HOSPITAL CORPORATION Invention Title: METHODS AND COMPOSITIONS FOR TREATING ORAL AND ESOPHAGEAL
LESIONS
The following statement is a full description of this invention, including the best method for performing it known to me/us: O METHODS AND COMPOSITIONS FOR TREATING ORAL SAND ESOPHAGEAL LESIONS Field of the Invention This invention provides methods and compositions for treating lesions of the upper alimentary canal including the oral cavity and esophagus.
Background of the Invention SOral mucositis is the destruction of the oral mucosal epithelium which results in erythema, ulcerations, and pain in the oral cavity. Mucositis often arises as a complication of antineoplastic therapy such as cancer chemotherapy or radiotherapy. The painful ulcerative lesions of mucositis can cause patients to restrict their oral intake of food and liquids; as a result, they lose weight and suffer from dehydration. Severe mucositis can necessitate the de-escalation or the complete interruption of anti-neoplastic therapy. Chemotherapy or radiotherapy can also disrupt mucosal epithelium more distally in the gastrointestinal tract including the esophagus, stomach, and small and large intestines, resulting in pain and organ dysfunction diarrhea).
The mucositis lesions are also sites of secondary infections, acting as portals of entry for endogenous oral microorganisms; a particularly serious concern in patients who are immunocompromised. Mucositis is therefore a significant risk factor for chronic debilitating local infections yeast (Candida) infections) as well as life-threatening systemic infection (septicemia).
Patients with mucositis and neutropenia have a relative risk of septicemia that is at least four times greater than that of individuals without mucositis.
Aphthous ulcers of the mouth (or aphthous stomatitis) are a common and painful problem; approximately 10% of the population suffers from these mouth sores at one time or another. The cause of outbreaks of aphthous sores are not well understood, although they tend to be associated with stress and minor injury to the inside of the mouth. No satisfactory treatments are available, although topical application of steroids provides relief for some patients.
O
0 Summary of the Invention SThis invention features a method for treating a lesion of the upper alimentary canal in a mammal by administering to the mammal a therapeutically effect amount of an intestinal trefoil peptide. Preferably, the mammal is a human.
1In preferred embodiments, the intestinal trefoil peptide is spasmolytic polypeptide 0 pS2, or intestinal trefoil factor (ITF). More preferably, the intestinal trefoil peptide is ITF.
SLesions of the upper alimentary canal such as mucositis, aphthous stomatitis, and gingivitis can be treated by the methods of this invention.
Additionally, lesions of the upper alimentary canal that result from antineoplastic therapy chemotherapy or radiotherapy), Behcet's Disease, biopsy, surgery, tumor resection, thermal or chemical bums, tooth extraction, trauma from any cause, or lesions caused by microbial bacterial, viral, or fungal) infection are also amenable to treatment.
In preferred embodiments, the patient is also administered a second therapeutic agent. Preferred second therapeutic agents include anti-inflammatory agents, antibacterial agents penicillins, cephalosporins, tetracyclines, or aminoglycosides), antifungal agents nystatin or amphotericin antiviral agents acyclovir), topical antiseptics povidone-iodine), analgesics lidocaine or benzocaine), or steroids triamcinolone or hydrocortisone).
Preferably, the second therapeutic agent is administered within 3 days, 1 day, 12 hours, 1 hour, or simultaneously with the intestinal trefoil peptide. The second therapeutic agent can be present in the same pharmaceutical composition as the intestinal trefoil peptide.
The invention also features pharmaceutical compositions suitable for 0 delivering an intestinal trefoil peptide to the upper alimentary canal. Preferably, Sthe pharmaceutical composition is an oral spray, an oral rinse (mouthwash), an Sointment, a paste, a cream, a gel, chewing gum, a chewable tablet, a lozenge, or a bioerodable film. In one embodiment, the pharmaceutical compositions use bioerodable microspheres to encapsulate one or more of the therapeutic agents.
0 In preferred embodiments of an oral spray, rinse, ointment, paste, gel, or 0 bioerodable film, a mucoadhesive or viscosity-enhancing agent is present.
In other preferred embodiments, the intestinal trefoil peptide of the 0pharmaceutical composition is SP, pS2, or ITF. More preferably, the intestinal trefoil peptide is ITF. In other preferred embodiments, the pharmaceutical composition further contains a second therapeutic. Preferred second therapeutic agents include anti-inflammatory agents, antibacterial agents penicillins, cephalosporins, tetracyclines, or aminoglycosides), antifungal agents nystatin or amphotericin antiviral agents acyclovir), topical antiseptics povidone-iodine), analgesics lidocaine or benzocaine), or steroids triamcinolone or hydrocortisone).
By "intestinal trefoil peptide" is meant all mammalian homologs of human spasmolytic polypeptide (SP; also known as TFF2), human pS2 (also known as TFFI) and human intestinal trefoil factor (ITF; also known as TFF3), and biologically active fragments thereof. Homologs of the trefoil peptides have, preferably, 70% amino acid identity to the human sequence, more preferably identity, most preferably 95%, or even 99% sequence identity. The length of comparison sequences will generally be at least about 10 amino acid residues, usually at least 20 amino acid residues, more usually at least 30 amino acid residues, typically at least 45 amino acid residues, and preferably more than amino acid residues.
The term "fragment" is meant to include polypeptides that are truncations or deletions of SP, pS2 and ITF. Preferably, the fragments have 70% amino acid identity to the corresponding regions of the human polypeptide sequence. More 4 preferably, the fragments are 85% identical, most preferably 95%, or even 99% Sidentical to the human polypeptide sequence to which they correspond. The Ulength of comparison sequences will generally be at least about 10 amino acid Sresidues, usually at least 20 amino acid residues, more usually at least 30 amino acid residues, typically at least 45 amino acid residues, and preferably more than amino acid residues.
0Preferable fragments contain four cysteine residues in any positions which
(N
0 correspond to the cysteines at positions 25, 35, 45, 50, 51, 62, or 71, of human ITF (Figure or positions 31, 41, 51, 56, 57, 68, and 82 of human pS2 (Figure 02). More preferably, fragments contain five cysteine residues at these positions.
Most preferably, six, or even all seven cysteines are present.
Fragments of SP are meant to include truncations or deletions and preferably have 70% sequence identity to the corresponding human SP polypeptide sequence (Figure More preferably, the fragments are identical, most preferably 95%, or even 99% identical to the human polypeptide sequence. Preferably, active fragments contain at least four cysteine residues which correspond to positions 6, 8, 19, 29, 34, 35, 46, 58, 68, 78, 83, 84, 95, and 104 in the human SP polypeptide. More preferably, fragments contain six cysteines which correspond to these positions. Even more preferable are fragments that contain eight cysteines. Most preferable are fragments that contain cysteines at ten, twelve, or even, all fourteen positions.
It is recognized in the art that one function of the identified cysteine residues is to impart the characteristic three-loop (trefoil) structure to the protein.
Accordingly, preferred fragments of ITF and pS2 have a least one loop structure, more preferably, the fragments have two loop structures, and most preferably, they have three loop structures. It is equally well recognized that the native SP polypeptide has a six loop confirmation. Preferable fragments contain at least two of these loop structures, more preferably, four loop structures are conserved, and most preferably, five, or even all six loop structures are present.
By "co-formulated" is meant any single pharmaceutical composition 0 which contains two or more therapeutic or biologically active agents.
UBy "pharmaceutical preparation" or "pharmaceutical composition" is Smeant any composition which contains at least one therapeutically or biologically active agent and is suitable for administration to a patient. For the purposes of this invention, pharmaceutical compositions suitable for delivering a therapeutic to the upper alimentary canal include, but are not limited to solutions and 0 suspensions delivered either as an oral spray or rinse, pastes, gels, chewable tablets, sublingual, gingival, or buccal wafers and films, chewing gum, lozenges, and other compositions designed to be retained in the mouth for an extended period of time. Any of these formulations can be prepared by well known and accepted methods of art. See, for example, Remingtion: The Science and Practice of Pharmacy, 19 th edition, (ed. AR Gennaro), Mack Publishing Co., Easton, PA, 1995.
By "microsphere" is meant a bioerodable polymeric pharmaceutical delivery device having a diameter of 5-100 im and a hollow central core suitable for encapsulation of the therapeutic agent. Typically, the therapeutic agent is encapsulated at the time of microsphere formulation.
By "therapeutically effective amount" is meant an amount sufficient to provide medical benefit. When administering trefoil peptides to a human patient according to the methods described herein, a therapeutically effective amount is usually about 0.1-1000 mg of intestinal trefoil peptide per day. Preferably, the patient receives, 10 mg, 100 mg, 250 mg, or 750 mg of intestinal trefoil peptide each day. The total daily does can be divided into multiple individual doses.
By "upper alimentary canal" is meant the portion of the digestive system proximal to the cardiac sphincter (cardioesophageal sphincter) of the stomach.
Specifically, the upper alimentary canal is meant to include the oral cavity and associated structures the tongue, gingival and sublingual tissues, and the hard and soft palates) and the esophagus.
6 By "biologically active," when referring to an intestinal trefoil peptide, fragment, or homolog is meant any polypeptide that exhibits an activity common to its related, naturally occurring family member, and that the activity is common Sto the family of naturally occurring intestinal trefoil peptides. An example of a biological activity common to the family of trefoil peptides is the ability to alter gastrointestinal motility in a mammal.
0By "isolated DNA" is meant DNA that is free of the genes which, in the 0 naturally-occurring genome of the organism from which the given DNA is derived, flank the DNA. Thus, the term "isolated DNA" encompasses, for example, cDNA, cloned genomic DNA, and synthetic DNA.
By "treating" is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. The active ingredients of the pharmaceutical composition can treat the primary indication epithelial lesion) or secondary symptoms concomitant infection, pain, or inflammation).
By "analgesic" is meant an agent which relieves pain by elevating the pain threshold without significantly disturbing the consciousness of the patient.
By "antimicrobial agent" is meant any compound that alters the growth of bacteria or fungi cells, or viruses whereby growth is prevented, stabilized, or inhibited, or wherein the microbes are killed. In other words, the antimicrobial agents can be microbiocidal or microbiostatic.
By "thermal burn" is meant injury to or destruction of at least the epithelial cell layer caused by exposure to excessive temperature. Thermal burns of the upper alimentary canal are usually caused by ingestion of overly-heated foods and liquids, or inhalation of super-heated air. Thermal burns are meant to include, but are not limited to, burns classified as first degree, second degree, and third degree burns.
By "chemical burn" is meant injury to or destruction of at least the epithelial cell layer caused by exposure to noxious chemicals. Typically, chemical exposures of the upper alimentary canal are caused by inhalation or ingestion.
S By "antineoplastic therapy" is meant any treatment regimen used to treat cancer. Typical antineoplastic therapies include chemotherapy and radiation Stherapy.
Brief Description of Drawings SFigure 1 is the amino acid sequence of a human intestinal trefoil factor 0 (ITF; Accession No. BAA95531; SEQ ID NO: 1).
Figure 2 is the amino acid sequence of a human pS2 protein (Accession 0 No. NP_003216; SEQ ID NO: 2).
Figure 3 is the amino acid sequence of human spasmolytic polypeptide (SP; Accession No. 1909187A; SEQ ID NO:3).
Figure 4 is a cDNA sequence encoding a human intestinal trefoil factor (SEQ ID NO: 4).
Figure 5 is a cDNA sequence encoding a human pS2 protein (SEQ ID NO: Figure 6 is a cDNA sequence encoding a human spasmolytic polypeptide (SEQ ID NO: 6).
Figure 7 is the nucleotide sequence of a gene encoding human intestinal trefoil factor (locus 10280533:52117-55412; SEQ ID NO: 7).
Figure 8 is the nucleotide sequence of a gene encoding human pS2 protein (locus 10280533:16511-21132; SEQ ID NO: 8).
Figure 9 is the nucleotide sequence of a gene encoding human spasmolytic polypeptide (locus 10280533:957-5208; SEQ ID NO: 9).
Detailed Description The invention provides methods and compositions useful for the treatment of a wide range of lesions of the upper alimentary canal. The intestinal trefoil peptide therapy of this invention is particularly useful for treating epithelial lesions of the oral and esophageal mucosa, tongue, and gingival tissue.
8 Mammalian trefoil peptides were discovered in 1982. One of the Smammalian trefoil peptides, human intestinal trefoil factor (ITF; TFF3), has been U characterized extensively, and is described in U.S. Patent Nos. 6,063,755, and S6,221,840, hereby incorporated by reference. The other two known human intestinal trefoil peptides are spasmolytic polypeptide (SP; TFF2) and pS2 (TFF Trefoil peptides, described extensively in the literature Sands et al., Annu. Rev. Physiol. 58: 253-273 (1996), hereby incorporated by reference), Sare expressed in the gastrointestinal tract and have a three-loop structure formed by intrachain disulfide bonds between conserved cysteine residues. These peptides protect the intestinal tract from injury and can be used to treat intestinal tract disorders such as peptic ulcers and inflammatory bowel disease. Homologs of these human peptides have been found in a number of non-human animal species. All members of this protein family, both human and non-human, are referred to herein as trefoil peptides. Human ITF will be referred to most extensively in this application; however, the activity of human ITF is common to each of the mammalian intestinal trefoil peptides.
We have discovered that epithelial lesions of the upper alimentary canal including the oral and esophageal mucosa, tongue, and gingival tissue can be treated by local administration of intestinal trefoil peptides. Thus, trefoil peptide therapy, according to the methods of this invention, can be delivered in any pharmaceutical composition which is useful for delivering therapeutics to the upper alimentary canal.
Pharmaceutical Preparations Oral Sprays, Rinses, and Emulsions Spray systems are particularly useful for delivering therapeutics to the upper alimentary canal. Suitable spray delivery systems include both pressurized and non-pressurized (pump actuated) delivery devices. The intestinal trefoil peptide-containing solution, delivered as an oral spray, is preferably an aqueous solution; however, organic and inorganic components, emulsifiers, excipients, and agents that enhance the organoleptic properties flavoring agents or odorants) 0may be included. Optionally, the solution may contain a preservative that prevents microbial growth methyl paraben). Although water itself may Smake up the entire carrier, typical liquid spray formulations contain a co-solvent, for example, propylene glycol, corn syrup, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients. In general, therefore, the compositions of this invention preferably contain from Sabout 1-95% v/v and, most preferably, about 5-50% v/v, of the co-solvent. When prepared as an spray, patients typically self-administer 1-5 times per day. The spray delivery system is normally designed to deliver 50-100 ll per actuation, and therapy may require 1-5 actuations per dose. The rheological properties of the spray formulation are optimized to allow shear and atomization for droplet formation. Additionally, the spray delivery device is designed to create a droplet size which promotes retention on mucosal surfaces of the upper alimentary canal and minimize respiratory exposure.
Compositions suitable for oral sprays can also be formulated as an oral rinse or mouthwash. Administration of trefoil peptides using these formulations is typically done by swishing, gargling, or rinsing the oral cavity with the formulation. Optionally, these formulations can be swallowed, providing trefoil peptide therapy to the esophagus, stomach, and/or intestines. This delivery method is particularly useful for treating patients suffering related disorders of the intestinal epithelium. For example, patients receiving antineoplastic chemotherapy, in addition to oral mucositis, frequently develop more distal lesions of the gastrointestinal tract such as lesions of the gastric and intestinal epithelium. It is well known that intestinal trefoil peptides, particularly ITF, are stable at stomach pH. Thus, swallowing an intestinal trefoil peptide-containing solution designed primarily for treating oral mucositis may also benefit lesions of the lower alimentary canal stomach and intestines).
In an alternative formulation, the intestinal trefoil peptides and/or other therapeutics can be encapsulated in bioerodable microspheres rather than being dissolved in the aqueous phase of the formulation. A wide variety of Smicroencapsulation drug delivery systems have been developed and many share similar polymeric compositions as used for bioerodable films (described below).
Polymers commonly used in the formation of microspheres include, for example, O poly-E-caprolactone, poly(e-caprolactone-Co-DL-lactic acid), poly(DL-lactic acid), poly(DL-lactic acid-Co-glycolic acid) and poly(e-caprolactone-Co-glycolic acid) (see, for example, Pitt et al., J. Pharm. Sci., 68:1534, 1979).
0Microspheres can be made by procedures well known in the art including spray drying, coacervation, and emulsification (see for example Davis et al.
Microsphere and Drug Therapy, Elsevier, 1984; Benoit et al. Biodegradable Microspheres: Advances in Production Technologies, Chapter 3, Ed. Benita, S, Dekker, New York, 1996; Microencapsulation and Related Drug Processes, Ed.
Deasy, Dekker, 1984, New York; U.S. Patent No. 6,365,187). Preferably, the microspheres are bioadhesive or are prepared in formulations containing a bioadhesive excipient.
Other technical features of the intestinal trefoil peptide-containing solutions are easily modified to suit the specific pharmaceutical formulation and the clinical indication being treated. For example, the pH and osmolality of the formulation may be adjusted to confer trefoil peptide stability, while minimizing oral irritancy and sensitivity.
Ointments, Pastes, and Gels Lesions of the oral and esophageal epithelium caused by trauma are amenable to trefoil peptide therapy delivered as an ointment, paste, or gel. The viscous nature of these types of preparations allows for direct application into the wound site. Optionally, the wound site can be covered with a dressing to retain the trefoil peptide-containing composition, protect the lesion from trauma, and/or absorb exudate. As discussed further below, these preparations are particularly useful to restore epithelial integrity following traumatic surgical procedures such as, for example, tooth extraction, tissue biopsy, or a tumor resection. Such Sviscous formulations may also have a local barrier effect thereby reducing Sirritation and pain.
Mucoadhesives SA mucoadhesive excipient can be added to any of the previously described C pharmaceutical compositions. The mucoadhesive formulations coat the upper alimentary canal providing protection, inhibiting irritation, and accelerating 0 healing of inflamed or damaged tissue. Mucoadhesive formulations also promote prolonged contact of the intestinal trefoil peptide with the mucosal epithelium.
Mucoadhesive formulations suitable for use in pharmaceutical preparations delivered by mouth are well known in the art U.S. Patent No. 5,458,879).
Particularly useful mucoadhesives are hydrogels composed of about 0.05-20% of a water-soluble polymer such as, for example, poly(ethylene oxide), poly(ethylene glycol), poly(vinyl alcohol), poly(vinyl pyrrolidine), poly(acrylic acid), poly(hydroxy ethyl methacrylate), hydroxyethyl ethyl cellulose, hydroxy ethyl cellulose, chitosan, and mixtures thereof. These polymeric formulations can also contain a dispersant such as sodium carboxymethyl cellulose Other preferred mucoadhesive excipients for liquid compositions are ones that allow the composition to be administered as a flowable liquid but will cause the composition to gel in the upper alimentary canal, thereby providing a bioadhesive effect which acts to hold the therapeutic agents at the lesion site for an extended period of time. The anionic polysaccharides pectin and gellan are examples of materials which when formulated into a suitable composition will gel in the upper alimentary canal, owing to the presence of cations in the mucosal and salivary fluids. The liquid compositions containing pectin or gellan will typically consist of 0.01-20% w/v of the pectin or gellan in water or an aqueous buffer system.
Other useful compositions which promote mucoadhesion and prolonged Ctherapeutic retention in the upper alimentary canal are colloidal dispersions Ucontaining 2-50% colloidal particles such as silica or titanium dioxide. Such Sformulations form as a flowable liquid with low viscosity suitable as a mouthwash or for generating a fine mist. However, the particles interact with glycoprotein, especially mucin, transforming the liquid into a viscous gel, providing effective mucoadhesion U.S. Patent Nos. 5,993,846 and S6,319,513).
Bioerodable Film Delivery Devices The most simple bioerodable devices contain the therapeutic agent(s) incorporated into a solid, usually lipid-containing, film or tablet. The device is formulated to remain solid at room temperature, but melt at body temperature, releasing the incorporated therapeutics. Suitable formulations of this type include, for example, cocoa butter.
Polymeric film devices provide several advantages for therapeutic delivery to the oral cavity. Unlike rinses, pastes, gels, and other flowable compositions, a film device can reside for prolonged periods of time hours to days) in the oral cavity and provide sustained release throughout its residency. Typically, the film is partially or completely bioerodable and contains a mucoadhesive layer to fasten the film to the oral mucosa. Film devices, in addition to its use for delivering therapeutics, can also provide protection against mechanical injury or microbial infection of a lesion site. This physical barrier function is particularly advantageous when treating conditions such as mucositis or aphthous stomatitis.
Additionally, as discussed further below, a film device can be used to release trefoil peptide therapy directly onto the underlying mucosa, into the lumen of the oral cavity, or a combination of both.
Film devices consist of at least two layers; a mucoadhesive layer suitable for attaching the film to the oral mucosa and a bulk layer which contains the active therapeutic(s). Many suitable mucoadhesives are known in the art and are discussed above. Optionally, one or more therapeutics can also be provided in the adhesive layer.
SThe bulk layer of the composite delivery device may be made of one or more bioerodable polymeric materials. Suitable polymers include, for example, starch, gelatin, polyethylene glycol, polypropylene glycol, polyethylene oxide, copolymers of ethylene oxide and propylene oxide, copolymers of polyethylene glycol and polypropylene glycol, polytetramethylene glycol, polyether urethane, Shydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, 0 hydroxypropylmethyl cellulose, alginate, collagen, polylactide, poly(lactide-coglycolide) (PLGA), calcium polycarbophil, polyethymethacrylate, cellulose 0 acetate, propylene glycol, polyacrylic acid, crosslinked polyacrylic acid, hydroxyethyl methacrylate/methyl methacrylate copolymer, silicon/ethyl cellulose/polyethylene glycol, urethane polyacrylate, polystyrene, polysulfone, polycarbonate, polyorthoesters, polyanhydrides, poly(amino acids), partially and completely hydrolyzed alkylene-vinyl acetate copolymers, polyvinyl chloride, polymers of polyvinyl acetate, polyvinyl alkyl ethers, styrene acrylonitrile copolymers, poly(ethylene terphthalate), polyalkylenes, poly(vinyl imidazole), polyesters and combinations of two or more of these polymers.
A particularly useful bulk layer polymer consists of PLGA and ethyl cellulose. PLGA is bioerodable and can be formulated to degrade over a wide range of conditions and rates. Ethyl cellulose is a water-insoluble polymer that can act as a plasticizer for the PLGA when a film is formed, but will be eroded in a bodily fluid. Due to its water-insolubility, it also has an effect on the degree and rate of swelling of the resultant film.
An optional third layer which is impermeable to the trefoil peptide can also be added to the wafer. Preferably, this barrier layer is also bioerodable. Suitable barrier layer polymers include ethyl cellulose, poly(acrylic acid), or other polyelectrolytes. In one configuration, the barrier layer is placed on the opposite side of the bulk layer relative to the adhesive layer, thereby directing the released therapeutic agent onto the contacted epithelium rather than being diluted in the lumenal fluid. This configuration is particularly useful for treating discrete lesions mucositis or aphthous stomatitis) of the tongue, sublingual tissue, or 0 buccal mucosa. In an alternative configuration of the film device, the barrier layer is placed between the bulk layer and the adhesive layer. This configuration Sdirects therapeutic release into the lumen of the oral cavity and is useful for treating more diffuse lesions of the tongue, oral cavity, and esophagus. The configuration is also useful for delivering therapeutics which are cytotoxic when administered at high concentrations because it has the effect of shielding the Sunderlying tissue from direct contact with the therapeutic-containing film.
Chewable Tablets, Lozenges, and Confectionaries Preparing a trefoil peptide-containing composition as a chewable tablet, lozenge, or a confectionary such as chewing gum provides several advantages to traditional drug delivery vehicles. First, prolonged contact and sustained release at the target site (mouth and esophagus) is achieved. Second, such formulations often results in higher patient compliance, especially when administering trefoil peptides to children.
Formulations for chewable tablets are well known and typically contain a base of sugar, starch, or lipid and a flavoring agent. An exemplary formulation for a chewable tablet is provided below.
Chewable ITF Tablet Formulation (per tablet) Intestinal trefoil factor 300 mg Mannitol 675 mg Microcrystalline cellulose Corn starch 30 mg Calcium sterate 22 mg Flavoring Agent sodium saccharin or peppermint oil) The incorporation of therapeutics into chewing gum and other confectionary style formulations is known in the art U.S. Patent No.
5,858,391).
Therapeutics Agents 0 Trefoil Peptides In preferred embodiments, the trefoil peptide is a human trefoil peptide.
SMore preferably, it is human intestinal trefoil factor (ITF), spasmolytic polypeptide or pS2. Most preferably, the trefoil peptide is human ITF.
The trefoil peptides are present in the compositions of the invention at a Sconcentration of between 0.1-1000 mg/ml, depending on the nature and condition O of the lesion being treated, the anticipated frequency and duration of therapy, and the type of pharmaceutical composition used to deliver the trefoil peptide.
0 Typically, therapy is designed to deliver 0.1-500 mg of trefoil peptide per day to the patient.
Anti-Inflammatory Agents Any suitable anti-inflammatory agent can be formulated in the compositions of the invention, at concentrations known for these agents. Many of the most useful anti-inflammatory agents also have analgesic and/or antipyretic properties. Anti-inflammatory agents suitable for co-formulation with a trefoil peptide include, for example, acetaminophen, aspirin (acetylsalicylic acid), ibuprofen, phenylbutazone, indomethacin, sulindac, diclofenac, and naproxen.
Antimicrobial Agents Any of the many known microbial agents can be used in the compositions of the invention at concentrations generally used for these agents. Antimicrobial agents include antibacterials, antifungals, antivirals, and other topical antiseptics.
Examples of antibacterial agents (antibiotics) include the penicillins penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), the cephalosporins cefadroxil, ceforanid, cefotaxime, and ceftriaxone), the tetracyclines doxycycline, minocycline, and tetracycline), the aminoglycosides amikacin, gentamycin, kanamycin, neomycin, streptomycin, and tobramycin), the macrolides azithromycin, clarithromycin, 16 and erythromycin), the fluoroquinolones ciprofloxacin, lomefloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, Scycloserine, isoniazid, rifampin, and vancomycin.
SAntiviral agents are substances capable of destroying or suppressing the replication of viruses. Examples of anti-viral agents include 1,-D-ribofuranosyl- 1,2,4-triazole-3 carboxamide, 9->2-hydroxy-ethoxy methylguanine, 0 adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, adenine o arabinoside, protease inhibitors, thymadine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, 0attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.
Antifungal agents include both fungicidal and fungistatic agents such as, for example, amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole.
Topical antiseptics include agents such as, for example, povidone-iodine and benzalkonium chloride.
Analgesics and Anesthetics Any of the commonly used topical analgesics can be used in the compositions of the invention. The analgesic is present in an amount such that there is provided to the oral lesion a topical concentration of between one-half and five percent concentration for lidocaine (5-50 mg/ml in 20-40 ml per dose of liquid). Examples of other useful anesthetics include procaine, lidocaine, tetracaine, dibucaine, benzocaine, p-buthylaminobenzoic acid 2-(diethylamino) ethyl ester HCI, mepivacaine, piperocaine, and dyclonine.
Other analgesics include opioids such as, for example, morphine, codeine, hydrocodone, and oxycodone. Any of these analgesics may also be coformulated with other compounds having analgesic or anti-inflammatory properties, such as acetaminophen, aspirin, and ibuprofen.
O Steroids SSteroids are commonly used to treat lesions of the upper alimentary canal.
SFor example, oral aphthous stomatitis is typically treated using a paste preparation of triamcinolone hydrocortisone, fluticasone, or beclomethasone.
SConditions of the Upper Alimentary Canal Treated Using Trefoil Peptides Mucositis 0 Mucositis is a common condition of the oral cavity which is characterized by inflammation of the mucous membranes. The condition is frequently caused by antineoplastic therapy, including chemotherapy and local radiation therapy.
Symptoms of mucositis include ulcerations, redness, and swelling, and is associated with epithelial cell injury and death. Patients suffering from severe mucositis are susceptible to dehydration and malnutrition because mucositis pain limits dietary intake. In severe cases, mucositis can be so debilitating that patients may require prolonged hospitalization, parenteral nutrition, and narcotic pain medication. Additionally, destruction of the mucosal epithelium increases a patient's susceptibility to local and systemic infection. Disruption of the barrier function permits entry of microorganisms and microbial products normally retained in the gut lumen. Thus, pharmaceutical preparations which reduce the adverse effects associated with chemotherapy will improve the patient's quality of life, compliance with self-medication, and may permit administration of higher chemotherapeutic doses. Typically, mucositis is treated using a trefoil peptidecontaining rinse or oral spray which the patient self-administers 1-5 times per day. The aqueous solution preferably contains a mucoadhesive and an antiinflammatory agent. Other therapeutics, such as an topical analgesic agent lidocaine) may also be present. Alternatively, if the lesions are few in number and spatially localized, an intestinal trefoil peptide-containing film device an be placed directly over the lesions.
Tooth Extraction 0 Intestinal trefoil peptide-containing compositions of the invention are used Uto lessen complications and speed healing of the wound created by the extraction of a tooth. An oral rinse, paste, ointment, or gel, as described above, is applied to the site of extraction immediately following the procedure and then 1-4 times per day, as needed, until epithelial regrowth is complete. Preferably, a topical 0analgesic is included in the formulation to relieve the temporary discomfort cause
(N
0 by the trauma of extraction. As a prophylactic measure, antibiotic agents may also be included in the formulation.
Gingivitis Gingivitis is most commonly a chronic disease requiring ongoing treatment, in some cases for months or even years. The trefoil peptide-containing compositions of the invention can be employed to treat gingivitis, alone or in conjunction with other treatments, particularly with an anti-microbial agent, and most commonly with an antibacterial agent. An oral intestinal trefoil peptidecontaining rinse is swished in the patient's mouth at least once every 2-3 days, but as often as thrice daily, over a 3-4 week period, and the regimen is repeated as needed. Alternatively, the trefoil peptide is formulated into a gel or toothpaste.
In severe cases, a viscous gel or ointment having a high intestinal trefoil peptide concentration is applied directly to the wound via a pledget with a stick applicator.
Intestinal trefoil peptide-containing compositions can also be delivered in biodegradable drug delivery systems capable of formation of films applied below the gum line (described in U.S. Patent Nos. 5,945,115 and 5,990,194. A biodegradable polymer, admixed with the intestinal trefoil peptide, is provided where the polymer can be injected in as a free-flowing solution below the gum line using a syringe. The polymer solution then, in situ, forms a solid biodegradable implant.
Aphthous Stomatitis 0 At the first indication of an outbreak of aphthous stomatitis (generally, the first twinge of pain), the patient swishes the mouth with an intestinal trefoil Speptide-containing rinse, 1-4 times per day until the ulcer heals (generally 5-10 days). An intestinal trefoil peptide-containing gel can also be applied to the ulcer, in the same manner that steroid-containing gels are currently used. In addition, a 0 gel can contain both an intestinal trefoil protein and a steroid known to be 0 effective for aphthous stomatitis treatment. A direct application of more concentrated material can be directly applied to the wound via a pledget with a stick applicator. Alternatively, the lesion can be treated directly by applying a bioerodable film device containing both a trefoil peptide and a steroid triamcinolone) directly to the lesion. Any formulation useful for treating aphthous stomatitis can also, optionally, contain a local anesthetic lidocaine or benzocaine).
Behcet's Disease Behcet's Disease is a rare, multi-system rheumatic disorder characterized by systemic vasculitis. One of the most frequent symptoms of Behcet's Disease is recurrent oral ulcerations which resemble aphthous lesions. Currently, treatment for Behcet's Disease is palliative, not curative. Thus, the intestinal trefoil peptides can be used to treat lesions of the upper alimentary canal in conjunction with currently available Behcet's Disease therapies including, for example, interferon alpha 2A and 2B, levamisole, cyclosporine, cyclophosphamide, and colchicine.
Oral Biopsy and Oral Surgery In cases in which an oral neoplasm is suspected or known to be malignant, a biopsy or a curative resection is performed using a needle or a scalpel, resulting in an open wound. The surgical area, susceptible to infection and inflammation, is treated by rinsing with a trefoil peptide-containing solution 1-4 times per day.
Preferably, an analgesic, an anti-inflammatory, and an antibiotic are included in Sthe formulation. Alternatively, a more concentrated gel, paste, or ointment may be directly applied to the lesion site. For post-operative treatment following Sresection of a malignancy, a topically active chemotherapeutic can be including in the trefoil peptide-containing composition.
Thermal and Chemical Burns STrauma to the upper alimentary canal is frequently caused by exposure to excessive heat or noxious chemicals. Thermal burns to the upper alimentary canal are frequently mild in nature first or second degree bums), resulting from the ingestion of overheated food or drink. More severe thermal burns of the oral mucosa and upper esophagus can be caused by inhalation of super heated air and are frequently observed in firefighters or victims of house or forest fires.
Chemical exposure can also damage the mucosa of the upper alimentary canal. Mild mucosal irritations and burns are often caused by ingestion of acidic food fruits). More severe chemical burns are usually associated with accidental industrial or occupational exposures.
The intestinal trefoil peptide-containing pharmaceutical formulations described herein are useful for treating thermal and chemical burns of the upper alimentary canal. Preferably, viscous liquid or gel formulation containing a mucoadhesive is used to prolong mucosal exposure to the trefoil peptide.
Alternatively, a sustained release formulation, such as a bioerodable film, is used.
Topical analgesics and antimicrobial agents are the most preferred secondary therapeutics to be co-administered.
Production of Intestinal Trefoil Peptides Intestinal trefoil peptides can be produced by any method known in the art for expression of recombinant proteins. Nucleic acids that encode trefoil peptides human intestinal trefoil factor (Figure 4 and human pS2 (Figure 5 and 8), and human spasmolytic polypeptide (Figure 6 and 9) or fragments thereof may be 21 introduced into various cell types or cell-free systems for expression thereby 0 allowing large-scale production, purification, and patient therapy.
Eukaryotic and prokaryotic trefoil peptide expression systems may be Sgenerated in which an intestinal trefoil peptide gene sequence is introduced into a plasmid or other vector, which is then used to transform living cells. Constructs in which the intestinal trefoil peptide cDNA contains the entire open reading 0frame inserted in the correct orientation into an expression plasmid may be used for protein expression. Prokaryotic and eukaryotic expression systems allow for the expression and recovery of intestinal trefoil peptide fusion proteins in which 0the trefoil peptide is covalently linked to a tag molecule which facilitates identification and/or purification. An enzymatic or chemical cleavage site can be engineered between the trefoil peptide and the tag molecule so that the tag can be removed following purification.
Typical expression vectors contain promoters that direct the synthesis of large amounts of mRNA corresponding to the inserted intestinal trefoil peptide nucleic acid in the plasmid-bearing cells. They may also include a eukaryotic or prokaryotic origin of replication sequence allowing for their autonomous replication within the host organism, sequences that encode genetic traits that allow vector-containing cells to be selected for in the presence of otherwise toxic drugs, and sequences that increase the efficiency with which the synthesized mRNA is translated. Stable long-term vectors may be maintained as freely replicating entities by using regulatory elements of, for example, viruses the OriP sequences from the Epstein Barr Virus genome). Cell lines may also be produced that have integrated the vector into the genomic DNA, and in this manner the gene product is produced on a continuous basis.
Expression of foreign sequences in bacteria, such as Escherichia co/i, requires the insertion of an intestinal trefoil peptide nucleic acid sequence into a bacterial expression vector. Such plasmid vectors contain several elements required for the propagation of the plasmid in bacteria, and for expression of the DNA inserted into the plasmid. Propagation of only plasmid-bearing bacteria is 22 achieved by introducing, into the plasmid, selectable marker-encoding sequences that allow plasmid-bearing bacteria to grow in the presence of otherwise toxic U drugs. The plasmid also contains a transcriptional promoter capable of producing Slarge amounts of mRNA from the cloned gene. Such promoters may be (but are not necessarily) inducible promoters that initiate transcription upon induction.
The plasmid also preferably contains a polylinker to simplify insertion of the gene Sin the correct orientation within the vector. Mammalian cells can also be used to 0 express a trefoil peptide. Stable or transient cell line clones can be made using intestinal trefoil peptide expression vectors to produce the trefoil peptides in a 0 soluble (truncated and tagged) form. Appropriate cell lines include, for example, COS, HEK293T, CHO, or NIH cell lines.
Once the appropriate expression vectors are constructed, they are introduced into an appropriate host cell by transformation techniques, such as, but not limited to, calcium phosphate transfection, DEAE-dextran transfection, electroporation, microinjection, protoplast fusion, or liposome-mediated transfection. The host cells that are transfected with the vectors of this invention may include (but are not limited to) E. coli or other bacteria, yeast, fungi, insect cells (using, for example, baculoviral vectors for expression in SF9 insect cells), or cells derived from mice, humans, or other animals. In vitro expression of trefoil peptides, fusions, or polypeptide fragments encoded by cloned DNA may also be used. Those skilled in the art of molecular biology will understand that a wide variety of expression systems and purification systems may be used to produce recombinant trefoil peptides and fragments thereof. Some of these systems are described, for example, in Ausubel et al. (Current Protocols in Molecular Biology, John Wiley Sons, New York, NY 2000, hereby incorporated by reference).
Transgenic plants, plant cells and algae are also particularly useful for generating recombinant intestinal trefoil peptides for use in the methods and compositions of the invention. For example, transgenic tobacco plants or cultured transgenic tobacco plant cells expressing an intestinal trefoil peptide can be created using techniques known in the art (see, for example, U.S. Patent Nos.
S5,202,422 and 6,140,075). Transgenic algae expression systems can also be used Sto produce recombinant intestinal trefoil peptides (see, for example, Chen et al., Curr. Genet. 39:365-370, 2001).
Once a recombinant protein is expressed, it can be isolated from cell lysates using protein purification techniques such as affinity chromatography.
SOnce isolated, the recombinant protein can, if desired, be purified further by e.g., 0 high performance liquid chromatography (HPLC; see Fisher, Laboratory Techniques In Biochemistry And Molecular Biology, Work and Burdon, Eds., SElsevier, 1980).
Polypeptides of the invention, particularly short intestinal trefoil peptide fragments can also be produced by chemical synthesis using, for example, Merrifield solid phase synthesis, solution phase synthesis, or a combination of both (see, for example, the methods described in Solid Phase Peptide Synthesis, 2nd ed., 1984, The Pierce Chemical Co., Rockford, IL). Optionally, peptide fragments are then be condensed by standard peptide assembly chemistry.
Example 1: Mucositis Treatment for Patients Receiving Antineoplastic Therapy Trefoil peptide therapy is initiated prior to antineoplastic therapy chemotherapy or radiation therapy), as a prophylactic to delay or prevent the onset of mucositis. Preferably, the patient begins intestinal trefoil peptide therapy three days prior to the first dose of antineoplastic therapy. During the prophylactic stage, the patient rinses the oral cavity with an intestinal trefoil peptide-containing solution. Alternatively, for convenience, the trefoil peptide is provided as a concentrated oral spray. Preferably, the patient swallows the solution, providing protection for the epithelial cells of the esophagus and lower gastrointestinal tract. Rinsing with and swallowing the intestinal trefoil peptidecontaining solution continues at least twice daily until oral or esophageal mucositis is detected.
In patients with existing mucositis, epithelial healing is promoted using Sintestinal trefoil peptide therapy as described above. Palliative therapy is U provided using benzocaine (a local anesthetic), and nystatin (an antifungal). The Sintestinal trefoil peptide can be co-formulated with the benzocaine and nystatin.
For example, the patient swishes an oral rinse solution (mouthwash), containing all therapeutic agents, 1-5 times each day. Alternatively, the trefoil peptide can 0 be provided in a concentrated oral spray, with or without benzocaine and the 0 nystatin is administered in an oral rinse.
The oral rinse solutions can either be swallowed or spit out. If swallowed, C an antacid may also be included in the formulation. Other useful therapeutics which provide palliative therapy include anti-inflammatories ibuprofen) and other anti-microbial agents. Exemplary oral rinses useful for treating chemotherapy-induced mucositis are provided below, but are not intended to be limiting. A skilled physician or pharmacist will immediately recognize appropriate substitutions, additions, and deletions that can be made to these formulations.
Rinse# 1: Mix equal parts of: diphenhydramine elixir (Benadryl®) (ii) kaolin-pectin suspension (Kaopectate®) (iii) viscous lidocaine HC1 (iv) nystatin (oral suspension; 100,000 iu/ml) ITF (2.5 mg/ml) preferably swallowed after swishing Rinse#2: Mix equal parts of: diphenhydramine elixir (Benadryl®) (ii) Maalox® (MgOH AlOH; 40 mg/ml) (iii) viscous lidocaine HCI (iv) ITF (2.5 mg/ml) preferably swallowed after swishing Other Embodiments All publications and patent applications cited in this specification are Sherein incorporated by reference as if each individual publication or patent I application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of' this invention that certain changes and modifications may be made thereto without N, departing from the spirit or scope of the appended claims.
SThe entire disclosure in the complete specification of our Australian cl Patent Application No. 2002307512 is by this cross-reference incorporated into the present specification.
What is claimed is:
Claims (47)
1. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of oral mucositis in a mammal. S2. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of aphthous stomatitis in a mammal. S3. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of a lesion of the upper alimentary canal of a mammal, said lesion caused by antineoplastic therapy.
4. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of gingivitis in a mammal. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of a thermal or chemical burn in the upper alimentary canal of a mammal.
6. The use of an intestinal trefoil peptide in the manufacture of a medicament for the treatment of Behcet's disease in a mammal.
7. The use of any of claims 1-6, wherein said intestinal trefoil peptide is spasmolytic polypeptide, pS2, intestinal trefoil factor, or biologically active fragment thereof.
8. The use of claim 1-6, wherein said intestinal trefoil peptide is intestinal trefoil factor, or biologically active fragment thereof. 27
9. The use of claims 1-6, wherein said intestinal trefoil peptide is a biologically active fragment of intestinal trefoil factor, wherein said fragment comprises a trefoil structure. The use of any of claims 1-9, wherein said mammal is a human.
11. The use of any of claims 1-10, wherein said medicament further comprises a second therapeutic.
12. The use of claim 11, wherein said second therapeutic agent is an anti- inflammatory agent.
13. The use of claim 11, wherein said second therapeutic agent is an antibacterial agent.
14. The use of claim 13, wherein said antibacterial agent is a penicillin, a cephalosporin, a tetracycline, or an aminoglycoside. The use of claim 13, wherein said antibacterial agent is povidone-iodine.
16. The use of claim 11, wherein said second therapeutic agent is an anti-fungal agent.
17. The use of claim 16, wherein said anti-fungal agent is nystatin or Amphotericin B.
18. The use of claim 11, wherein said second therapeutic agent is an anti-viral agent. 28 C 19. The use of claim 18, wherein said anti-viral agent is acyclovir. The use of claim 11, wherein said second therapeutic agent is an analgesic.
21. The use of claim 20, wherein said analgesic is lidocaine or benzocaine.
22. The use of claim 11, wherein said second therapeutic agent is a steroid. S23. The use of claim 22, wherein said steroid is triamcinolone or hydrocortisone.
24. A composition suitable for therapeutic delivery to the upper alimentary canal of a mammal, wherein said composition is an oral spray, oral rinse, bioerodable film, or chewing gum comprising an intestinal trefoil peptide. The composition of claim 24, wherein said intestinal trefoil peptide is spasmolytic polypeptide, pS2, or intestinal trefoil factor.
26. The composition of claim 24, wherein said intestinal trefoil peptide is intestinal trefoil factor.
27. The composition of claim 24, wherein said intestinal trefoil peptide is a biologically active fragment of intestinal trefoil factor, wherein said fragment comprises a trefoil structure.
28. The composition of any of claims 24-27, wherein said composition further comprises a mucoadhesive agent.
29. The composition of any of claims 24-27, wherein said composition further comprises a second therapeutic agent. 29 The composition of claim 29, wherein said second therapeutic agent is an anti- inflammatory agent.
31. The composition of claim 29, wherein said second therapeutic agent is an antibacterial agent.
32. The composition of claim 31, wherein said antibacterial agent is a penicillin, a cephalosporin, a tetracycline, or an aminoglycoside.
33. The composition of claim 31, wherein said antibacterial agent is povidone- iodine.
34. The composition of claim 29, wherein said second therapeutic agent is an anti- fungal agent. The composition of claim 34, wherein said anti-fungal agent is nystatin or Amphotericin B.
36. The composition of claim 29, wherein said second therapeutic agent is an anti- viral agent.
37. The composition of claim 36, wherein said anti-viral agent is acyclovir.
38. The composition of claim 29, wherein said second therapeutic agent is an analgesic.
39. The composition of claim 38, wherein said analgesic is lidocaine or benzocaine. 30 The composition of claim 29, wherein said second therapeutic agent is a steroid. S41. The composition of claim 40, wherein said steroid is triamcinolone or hydrocortisone.
42. A method of treating oral mucositis in a mammal, comprising administering to said mammal a therapeutically C effective amount an intestinal trefoil peptide.
43. A method of treating aphthous stomatitis in a Smammal, comprising administering to the mammal a C-i therapeutically effective amount of an intestinal trefoil peptide.
44. A method of treating a lesion of the upper alimentary canal of a mammal, said lesion caused by antineoplastic therapy, comprising administering to the mammal a therapeutically effective amount of an intestinal trefoil peptide. A method of treating gingivitis in a mammal, comprising administering to the mammal a therapeutically effective amount of an intestinal trefoil peptide.
46. A method of treating a thermal or chemical burn in the upper alimentary canal of a mammal, comprising administering to the mammal a therapeutically effective amount of an intestinal trefoil peptide.
47. A method of treating Behcet's disease in a mammal, comprising administering to the mammal a therapeutically effective amount of an intestinal trefoil peptide.
48. The method of any one of claims 42 to 47, wherein the intestinal trefoil peptide is spasmolytic polypeptide, pS2, intestinal trefoil factor, or biologically active fragment thereof. 31 C 49. The method of any one of claims 42 to 47, O wherein the intestinal trefoil peptide is intestinal trefoil factor, or biologically active fragment thereof. The method of any one of claims 42 to 47, wherein the intestinal trefoil peptide is a biologically active fragment of intestinal trefoil factor, wherein said Ci fragment comprises a trefoil structure. N ~51. The method of any one of claims 42 to wherein said mammal is a human.
52. The method of any one of claims 42 to 51, wherein the method further comprises administering a second therapeutic agent.
53. The method of claim 52, wherein the second therapeutic agent is an anti-inflammatory agent.
54. The method of claim 52, wherein the second therapeutic agent is an antibacterial agent. The method of claim 54, wherein said antibacterial agent is a penicillin, a cephalosporin, a tetracycline, or an aminoglycoside.
56. The method of claim 54, wherein said antibacterial agent is povidone-iodine.
57. The method of claim 52, wherein said therapeutic agent is an anti-fungal agent.
58. The method of claim 57, wherein the anti-fungal agent is nystatin or Amphotericin B.
59. The method of claim 52, wherein said second therapeutic agent is an anti-viral agent. 32 U The method of claim 59, wherein agent is acyclovir.
61. The method of claim 52, wherein therapeutic agent is an analgesic.
62. The method of claim 61, wherein is lidocaine or benzocaine.
63. The method of claim 52, wherein therapeutic agent is a steroid.
64. The method of claim 63, wherein triamcinolone or hydrocortisone. A use of any one of claims 1 to as herein described with reference to any detailed description or the figures. said anti-viral said second said analgesic the second the steroid is 6, substantially one of the
66. A composition of claim 24, substantially as herein described with reference to any one of the detailed description or the figures.
67. A method of claim 42 to 47, substantially as herein described with reference to any one of the detailed description or the figures.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/286,240 | 2001-04-24 | ||
AU2002307512A AU2002307512A1 (en) | 2001-04-24 | 2002-04-24 | Methods and compositions for treating oral and eosophageal Lesions |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2002307512A Division AU2002307512A1 (en) | 2001-04-24 | 2002-04-24 | Methods and compositions for treating oral and eosophageal Lesions |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2007240204A1 true AU2007240204A1 (en) | 2008-01-03 |
Family
ID=38903089
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2007240204A Abandoned AU2007240204A1 (en) | 2001-04-24 | 2007-12-10 | Methods and compositions for treating oral and esophageal lesions |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2007240204A1 (en) |
-
2007
- 2007-12-10 AU AU2007240204A patent/AU2007240204A1/en not_active Abandoned
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