TWI810656B - Eflornithine and sulindac, fixed dose combination formulation - Google Patents

Abstract

Provided herein are fixed-dose combination formulations of a pharmaceutically effective amount of eflornithine together with a pharmaceutically effective amount of sulindac. Also provided are methods of use and of methods of manufacture of these formulations.

Description

Difluoromethylornithine and sulindac (SULINDAC), fixed-dose combination formulation

The present invention relates generally to the fields of cancer biology and medicine. More specifically, it relates to compositions for the prevention and treatment of cancer.

Cancer cells have the ability to recruit multiple pathways to meet their increased need for specific metabolites (Vander Heiden, 2011). Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, piroxicam (Reddy et al., 1990; Singh et al., 1994), indomethacin (Narisawa, 1981) and sulindac (Piazza et al., 1997; Rao et al., 1995) effectively inhibited colon carcinogenesis in AOM-treated rat models. Sulindac, a metabolite of the NSAID sulindac, lacks COX-inhibitory activity, induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b), and is active in several rodent models of carcinogenesis. Inhibition of tumor development (Thompson et al., 1995; Piazza et al., 1995, 1997a). α-Difluoromethylornithine (DFMO) is an enzyme-activating, irreversible inhibitor of ornithine decarboxylase (ODC) and causes depletion of intracellular concentrations of putrescine and its derivatives, spermidine (Pegg , 1988). In experimental animal models, DFMO is a potent inhibitor of carcinogenesis, and it is particularly active in preventing carcinogen-induced epithelial cancers of many organs, including those of the colon (Weeks et al., 1982; Thompson et al. , 1985; Nowels et al., 1986; Nigro et al., 1987). The major barriers to translating cancer chemoprevention research into clinical practice are marginal agent efficacy and toxicity that outweigh the benefits (Psaty and Potter, 2006; Lippman, 2006). For example, long-term daily oral administration of D,L -α-difluoromethylornithine (DFMO, difluoromethylornithine) and a polyamine-inhibiting combination of sulindac has been shown to be effective in colorectal adenomas (CRA). ) in patients with significant efficacy (Meyskens et al., 2008), however, treatment was associated with modest subclinical ototoxicity (McLaren et al., 2008) and a greater number of cardiovascular events in patients with high baseline cardiovascular risk (Zell et al., 2009) are related. It is recognized in the field of medicine and described in U.S. Pat. Nos. 6,428,809 and 6,702,683 that co-administering two or more drugs in unit dosage form, as opposed to administering multiple separate doses at regular intervals, or the convenience of more active pharmaceutical ingredients. Potential advantages to patients and clinicians include (1) minimization or elimination of local and/or systemic side effects; (2) more effective treatment of complications; (3) improved polypharmacy; Better patient compliance for overall disease management, which in turn can lead to lower costs due to fewer visits to physicians, fewer hospitalizations, and improved patient health. Fixed dose combinations of two or more formulations combined or co-formulated in a single dosage form may be suitable for use in multiple drug regimens where improved clinical effectiveness, enhanced patient comfort, and simplified dosing are desired. However, drug product development for solid oral dosage forms remains complex at the level of research and development and commercial manufacturing even for single active pharmaceutical ingredient (API) formulations. For more than one API, additional concomitant factors are expected, including (1) drug-drug interactions, (2) drug-excipient interactions, (3) simultaneous release profiles, (4) differential release profiles, and (5) ) Blending uniformity of each drug component. Given these hurdles, developing fixed-dose combinations with identical or similar release profiles as single-entity drug products often represents a considerable challenge. A fixed dose combination of difluoromethylornithine and sulindac that overcomes some or all of these challenges would have considerable potential for the effective treatment and/or prevention of a wide range of diseases or disorders, including familial adenomatous polyposis (FAP). potential impact.

In one aspect, the present invention provides a composition comprising a fixed dose combination of a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) or a metabolite thereof. In some embodiments, the fixed dose combination is a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of sulindac. In some embodiments, the difluoromethylornithine is difluoromethylornithine hydrochloride monohydrate. In some embodiments, difluoromethylornithine is difluoromethylornithine hydrochloride monohydrate racemate. In some embodiments, difluoromethylornithine hydrochloride monohydrate is a racemic mixture of its two enantiomers. In some embodiments, difluoromethylornithine hydrochloride monohydrate is a substantially optically pure preparation. In some embodiments, difluoromethylornithine hydrochloride monohydrate is L-difluoromethylornithine hydrochloride monohydrate or D-difluoromethylornithine hydrochloride monohydrate things. In some embodiments, the difluoromethylornithine is the anhydrous free base difluoromethylornithine. In some embodiments, difluoromethylornithine is present in an amount from about 10 mg to about 1000 mg. In some embodiments, difluoromethylornithine is present in an amount from about 250 mg to about 500 mg. In some embodiments, difluoromethylornithine is present in an amount from about 300 mg to about 450 mg. In some embodiments, difluoromethylornithine is present in an amount from about 350 mg to about 400 mg. In some embodiments, difluoromethylornithine is present in an amount from about 35% to about 60% by weight. In some embodiments, difluoromethylornithine is present in an amount from about 40% to about 55% by weight. In some embodiments, difluoromethylornithine is present in an amount from about 50% to about 55% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 52% to about 54% by weight. In some embodiments, the amount of difluoromethylornithine hydrochloride monohydrate racemate is 52% to 54% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 375 mg. In some embodiments, the amount of difluoromethylornithine hydrochloride monohydrate racemate is 375 mg. In some embodiments, the sulindac is present in an amount from about 10 mg to about 1500 mg. In some embodiments, the sulindac is present in an amount from about 50 mg to about 100 mg. In some embodiments, the sulindac is present in an amount from about 70 mg to about 80 mg. In some embodiments, the sulindac is present in an amount of about 75 mg. In some embodiments, the amount of sulindac is 75 mg. In some embodiments, sulindac is present in an amount from about 5% to about 20% by weight. In some embodiments, sulindac is present in an amount from about 8% to about 15% by weight. In some embodiments, sulindac is present in an amount from about 10% to about 12% by weight. In some embodiments, the amount of sulindac is 10% to 11% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 375 mg and sulindac is present in an amount of about 75 mg. In some embodiments, the formulations further comprise excipients. In some embodiments, the excipient is starch, colloidal silicon dioxide, or silicified microcrystalline cellulose. In some embodiments, the excipient is colloidal silicon dioxide. In some embodiments, the formulation further comprises a second excipient. In some embodiments, the second excipient is silicified microcrystalline cellulose. In some embodiments, the formulation further comprises a lubricant. In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, aluminum stearate, polyethylene glycol, boric acid, or sodium benzoate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, magnesium stearate is present in an amount from about 0.25% to about 2% by weight. In some embodiments, the amount of magnesium stearate is from about 0.75% to about 2% by weight. In some embodiments, the amount of magnesium stearate is from about 1% to about 1.5% by weight. In some embodiments, the amount of magnesium stearate is about 1.1% by weight. In some embodiments, magnesium stearate is present in an amount of about 1.5% by weight. In some embodiments, the compositions are in the form of capsules, lozenges, mini-tablets, granules, pellets, solutions, gels, creams, foams or patches. In some embodiments, the composition is in the form of a lozenge, such as a single-layer lozenge. In some embodiments, the lozenge weighs from about 10 mg to about 2,500 mg. In some embodiments, the lozenge weighs from about 250 mg to about 1,500 mg. In some embodiments, the lozenge weighs from about 650 mg to about 1,000 mg. In some embodiments, the lozenge weighs from about 675 mg to about 725 mg. In some embodiments, the lozenge weighs about 700 mg. In some embodiments, the capsules, mini-tablets, granules or pellets weigh from about 10 mg to about 2,500 mg. In some embodiments, the capsules, mini-tablets, granules or pellets weigh from about 250 mg to about 1,500 mg. In some embodiments, the capsules, mini-tablets, granules or pellets weigh from about 650 mg to about 1,000 mg. In some embodiments, the capsules, mini-tablets, granules or pellets weigh from about 675 mg to about 725 mg. In some embodiments, the weight of the capsule, mini-tablet, granule or pellet is about 700 mg. In some embodiments, the lozenge further comprises a coating. In some embodiments, the coating is a modified release coating or an enteric coating. In some embodiments, the coating is a pH responsive coating. In some embodiments, the coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP), phthalate Hydroxypropyl methylcellulose formate (HP), poly(methacrylate ethyl acrylate) (1:1) copolymer (MA-EA), poly(methacrylate methyl methacrylate) (1:1) 1) Copolymer (MA MMA), poly(methacrylate methyl methacrylate) (1:2) copolymer or hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the coating masks the taste of difluoromethylornithine. In some embodiments, the coating comprises hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. In some embodiments, the amount of coating is from about 1% to about 5% by weight. In some embodiments, the amount of coating is about 2% to about 4% by weight. In some embodiments, the amount of coating is about 3% by weight. In some embodiments, the amount of coating is from about 5 mg to about 30 mg. In some embodiments, the amount of coating is from about 15 mg to about 25 mg. In some embodiments, the coating amount is about 21 mg. In some embodiments, the weight of the tablet comprising the coating is from about 675 mg to about 750 mg. In some embodiments, the weight of the tablet comprising the coating is from about 700 mg to about 725 mg. In some embodiments, the weight of the tablet comprising the coating is about 721 mg. In one aspect, there is provided a method of preventing and/or treating a disease or condition in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of difluoromethylornithine provided herein and a pharmaceutical A fixed dose combination of an effective amount of sulindac. In some embodiments, the method further comprises administering to the patient a second combination comprising a fixed dose combination of a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of sulindac provided herein things. In some embodiments, the first and second compositions comprise the same fixed dose combination. In some embodiments, the first and second administrations are performed simultaneously. In some embodiments, the second administration follows the first administration at an interval of between 1 second and 1 hour. In some embodiments, both the first and second compositions are formulated as lozenges and contain the same amount of difluoromethylornithine and sulindac. In some embodiments, the disease is cancer. In some embodiments, the cancer is colon cancer, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer, or esophageal cancer. In some embodiments, the colon cancer is familial adenomatous polyposis. In some embodiments, the cancer is a neuroendocrine tumor. In some embodiments, the neuroendocrine tumor is neuroblastoma. In some embodiments, the condition is a skin condition. In some embodiments, the skin condition is facial hirsutism. In some embodiments, the composition is administered orally, intraarterially, intravenously or topically. In some embodiments, the compositions are administered orally. In some embodiments, the compositions are administered orally. In some embodiments, the composition is administered every 12 hours. In some embodiments, the composition is administered every 24 hours. In some embodiments, the composition is administered at least a second time. In another aspect, there is provided a method of preparing a lozenge comprising about 375 mg difluoromethylornithine hydrochloride and about 75 mg sulindac, comprising: (a) premixing sulindac and excipients excipient to form a first mixture; (b) mixing the first mixture with a second mixture comprising difluoromethylornithine and excipients to form a blend; (c) sieving the blend to form granules (d) adding a lubricant to the granular blend to obtain the final blend; and (e) applying a compressive force to the final blend to form lozenges. In some embodiments, the method further comprises mixing the granular blend prior to step (d) and mixing the final blend prior to step (e). In some embodiments, two excipients are present in the first mixture, wherein the first excipient is colloidal silicon dioxide and the second excipient is silicified microcrystalline cellulose. In some embodiments, the excipient of the second mixture is silicified microcrystalline cellulose. In some embodiments, premixing is performed in polyethylene coated containers. In some embodiments, mixing is performed in a diffusion blender. In some embodiments, the lubricant is magnesium stearate. In some embodiments, prior to step (d), the magnesium stearate is sieved through a screen. In some embodiments, the screen is a 500 µm screen. In some embodiments, sieving comprises applying the blend to a rotation corrector. In some embodiments, the rotation corrector comprises a 1.0 mm screen. In some embodiments, the method further comprises a pre-compression step after step (d) and before step (e), wherein the blend is compressed with a force lower than that of step (e) to pre-compress the blend , further wherein the compressive force of step (e) is subsequently applied to pre-compress the blend to form a lozenge. In some embodiments, the pre-compression step prevents tablet capping. In some embodiments, the compressive force of the pre-compressing step is applied at about 5% to about 15% of the compressive force applied in step (e). In some embodiments, the compression force of the pre-compression step is 2.5 kN to 3.5 kN. In some embodiments, the compression force of the pre-compression step is about 3 kN. In some embodiments, the compressive force of step (e) is 20 kN to 35 kN. In some embodiments, the compressive force of step (e) is about 25 kN. In some embodiments, the method further comprises coating the lozenge. In some embodiments, the coating comprises hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. Other objects, features and advantages of the present invention will become apparent from the following embodiments. It should be understood, however, that the embodiments and specific examples which are preferred embodiments of the invention will become apparent to those of ordinary skill in the art from this description, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. Given by way of illustration only.

This application claims the rights of U.S. Provisional Application No. 62/248,810, filed October 30, 2015, and U.S. Provisional Application No. 62/358,698, filed July 6, 2016, the entire contents of which are incorporated by reference way incorporated into this article. In several aspects, compositions are provided for a fixed dose combination (FDC) of difluoromethylornithine and sulindac. Also provided are methods of making the fixed dose combinations of the invention that overcome problems associated with current methods. Manufacturing methods have been designed to address issues including drug-drug interactions, drug-excipient interactions, and uniformity of blending of individual drug components. Thus, the fixed dose combinations of the present invention can be used to minimize local and/or systemic side effects, provide more effective therapy, improve polypharmacy and provide better patient compliance.I. familial adenomatous polyposis Excessive polyamine formation has been implicated in epithelial carcinogenesis, especially colorectal carcinogenesis. Polyamines are small ubiquitous molecules involved in a variety of processes including, for example, transcription, RNA stabilization, and ion channel gating (Wallace, 2000). Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is critical for normal development and tissue repair in mammals, but is downregulated in most adult tissues (Gerner and Meyskens, 2004) . Multiple abnormalities in the control of polyamine metabolism and transport lead to increased polyamine levels, which can promote tumorigenesis in several tissues (Thomas and Thomas, 2003). Familial adenomatous polyposis (FAP) is a syndrome associated with a high risk of colon and other cancers. FAP is caused by adenomatous polyposis of the colon (APCs ) tumor suppressor gene and APC signaling has been shown to regulate ODC expression in human cells (Fultz and Gerner, 2002) and in a mouse model of FAP (Erdman et al., 1999). Polyamine metabolism is upregulated in the intestinal epithelium of humans with FAP (Giardiello et al., 1997). Wild typeAPCs expression results in a decrease in ODC expression, while mutant APC results in an increase in ODC expression. The mechanism of APC-dependent regulation of ODC involves E-box transcription factors, including transcriptional activatorsc-MYC and transcription repressorMAD1 (Fultz and Gerner, 2002; Martinez et al., 2003).c-MYC ODC transcription is regulated by other displays (Bellofernandez et al., 1993). Several genes involved in polyamine metabolism are essential for optimal growth in most organisms and are downregulated in non-proliferating and/or adult cells and tissues (Gerner and Meyskens, 2004). As reviewed elsewhere, polyamines affect specific cellular phenotypes by, in part, affecting patterns of gene expression (Childs et al., 2003). Familial adenomatous polyposis (FAP), an inherited polyposis syndrome, is the result of germline mutations in the adenomatous polyposis of the colon (APC) tumor suppressor gene (Su et al., 1992). This autosomal dominant condition with variable presentation is associated with the development of hundreds of colonic adenomas, all of which developed into adenocarcinomas by age forty, twenty years earlier than the mean age of diagnosis for sporadic colon cancer (Bussey, 1990). In a previous study of presymptomatic individuals with FAP, the polyamines spermidine and spermine and their diamines were detected in normal-appearing colorectal biopsies when compared to normal family member controls Levels of the precursor putrescine increased (Giardiello et al., 1997). The activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in mammalian polyamine synthesis, was also elevated in apparently normal colonic mucosal biopsies from FAP patients (Giardiello et al., 1997; Luk and Baylin, 1984). These findings were highlighted as polyamines are essential for optimal cell proliferation (Pegg, 1986). In addition, suppression of ODC activity using the enzyme-activating irreversible inhibitor DFMO inhibited colon carcinogenesis in carcinogen-treated rodents (Kingsnorth et al., 1983; Tempero et al., 1989). Shared mutants with FAPAPCs /apc The genotyped Min (multiple intestinal neoplasia) mouse serves as a useful experimental animal model for human FAP patients (Lipkin, 1997). Min mice can develop >100 gastrointestinal adenomas/adenocarcinomas throughout the GI tract at 120 days of life, resulting in GI bleeding, obstruction and death. Combination therapy of DFMO and sulindac was shown to effectively reduce adenomas in these mice. See US Patent No. 6,258,845 and Gerner and Meyskens, 2004, which are incorporated herein by reference.II. Difluoromethylornithine When used by itself and without context, the term "difluoromethylornithine" refers to 2,5-diamino-2-(difluoromethyl)pentanoic acid in any of its forms, including non-salt and salt forms (such as difluoromethylornithine HCl), non-salt and salt forms of anhydrous and hydrated forms (such as difluoromethylornithine hydrochloride monohydrate), non-salt and salt forms of solvates, Its enantiomers (R andS form, which can also be identified asd andl form) and mixtures of such enantiomers (eg racemic mixtures). "Essentially optically pure preparation" means a preparation that contains about 5% by weight or less of the first enantiomer of the opposite enantiomer. Specific forms of difluoromethylornithine include difluoromethylornithine hydrochloride monohydrate (aka CAS ID: 96020-91-6; MW: 236.65), difluoromethylornithine hydrochloride salt (ie CAS ID: 68278-23-9; MW: 218.63) and the anhydrous free base difluoromethylornithine (ie CAS ID: 70052-12-9; MW: 182.17). Specific forms of difluoromethylornithine are further specified if necessary. In some embodiments, the difluoromethylornithine of the present invention is difluoromethylornithine hydrochloride monohydrate (ie CAS ID: 96020-91-6). The terms "difluoromethylornithine" and "DFMO" are used interchangeably herein. DFMO is an abbreviation for difluoromethylornithine. Other synonyms for difluoromethylornithine and DFMO include: α-Difluoromethylornithine, 2-(difluoromethyl)-DL-ornithine, 2-(difluoromethyl)-dl -ornithine, 2-(difluoromethyl)ornithine, DL-α-difluoromethylornithine,N- Difluoromethylornithine, αδ-diamine-α-(difluoromethyl)valeric acid and 2,5-diamino-2-(difluoromethyl)valeric acid. Difluoromethylornithine is an irreversible inhibitor of the enzymatic activation of ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway. Due to this polyamine synthesis inhibition, the compounds are effective in preventing cancer formation, inhibiting cancer growth and reducing tumor size in many organ systems. It also has a synergistic effect with other antineoplastic agents. Difluoromethylornithine was shown to reduce APC-dependent intestinal tumorigenesis in mice (Erdman et al., 1999). Daily oral administration of difluoromethylornithine to humans inhibits ODC enzyme activity and polyamine content in multiple epithelial tissues (Love et al., 1993; Gerner et al., 1994; Meyskens et al., 1994; Meyskens et al. , 1998; Simoneau et al., 2001; Simoneau et al., 2008). Difluoromethylornithine and the nonsteroidal anti-inflammatory drug (NSAID) sulindac were reported to significantly reduce the rate of adenoma recurrence in individuals with colon adenomas when compared to placebo in a randomized clinical trial (Meyskens et al., 2008). Difluoromethylornithine was initially synthesized by the Center de Recherche Merrell, Strasbourg. Current U.S. Food and Drug Administration (FDA) approvals include: ˙African sleep disorders. High-dose systemic IV dosage form, not for sale (Sanofi/WHO) ˙ Hirsutism (androgen-induced excessive hair growth) topical formulations Although the FDA has not approved oral formulations of difluoromethylornithine, topical and injectable forms have been approved. Vaniqa® is a cream containing 15% w/w difluoromethylornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous difluoromethylornithine in cream for topical administration Ornithine (EU), 13.9% w/w Anhydrous Difluoromethylornithine Hydrochloride (U.S.). Ornidyl® is a solution of difluoromethylornithine HCl suitable for injection or infusion. It is supplied in a strength of 200 mg per mL of difluoromethylornithine hydrochloride monohydrate (20 g/100 mL). Difluoromethylornithine and its use in the treatment of benign prostatic hypertrophy are described in US Patents 4,413,141 and 4,330,559. The '141 patent describes difluoromethylornithine as a potent inhibitor of ODC in vitro and in vivo. Administration of difluoromethylornithine was reported to reduce putrescine and spermidine concentrations in cells where these polyamines are normally actively produced. In addition, difluoromethylornithine was shown to slow neoplastic cell proliferation when tested in standard tumor models. The '559 patent describes difluoromethylornithine and difluoromethylornithine derivatives for the treatment of benign prostatic hypertrophy. Benign prostatic hypertrophy, like many disease states characterized by rapid cell proliferation, is accompanied by abnormally elevated concentrations of polyamines. Difluoromethylornithine can potentially be administered continuously with significant antitumor effects. This drug is given at 0.4 g/m per day² The low dose is relatively non-toxic to humans, and at the same time inhibits the synthesis of putrescine in tumors. Studies in a rat tumor model have shown that difluoromethylornithine infusion can produce a 90% reduction in tumor putrescine levels without suppressing peripheral platelet counts. Adverse effects observed with difluoromethylornithine include² The effect of high doses on hearing disappeared when difluoromethylornithine was interrupted. At 0.4 g/m per day when administered for up to one year² Such effects on hearing were not observed at lower doses of β-(Meyskens et al., 1994). Additionally, several instances of vertigo/dizziness were found to disappear when the drug was stopped. Thrombocytopenia was treated with high "therapeutic" doses of difluoromethylornithine (>1.0 g/m² ) and was reported for the first time in cancer patients who had previously undergone chemotherapy or in patients with impaired bone marrow. Although the toxicity associated with difluoromethylornithine therapy is generally not as severe as with other types of chemotherapy, it was found to promote dose-related thrombocytopenia in limited clinical trials. In addition, studies in rats demonstrated that continuous infusion of difluoromethylornithine for 12 days significantly reduced platelet counts compared to controls. Similar observations were made by other studies in which thrombocytopenia was the main toxicity of continuous intravenous difluoromethylornithine therapy. The results of these studies indicated that difluoromethylornithine can significantly inhibit the ODC activity of the bone marrow precursors of megakaryocytes. Difluoromethylornithine inhibits proliferative repair processes such as epithelial wound healing. The phase III clinical trial assessed adenomatous polyp recurrence after 36 months of treatment with DFMO plus sulindac or matching placebo. Transient hearing loss is a known toxicity of treatment with DFMO, so a comprehensive approach was developed to analyze continuous airborne sonograms. The general estimating equation approach assessed the mean difference between treatment groups for change in air-conducted pure tone threshold, while calculating intrasubject correlations due to repeated measurements at frequency. Based on 290 individuals, adjusted for baseline, age, and frequency, compared with individuals treated with placebo (95% confidence interval, -0.64 to 1.63 dB; P=0.39), in individuals treated with DFMO plus sulindac There was a mean cut-off value of <2 dB in patients treated with DFMO plus sulindac compared to patients treated with placebo, with a mean difference of 0.50 dB. The results of this study are discussed in more detail in McLaren et al., 2008, which is incorporated herein by reference in its entirety.III.NSAIDs NSAIDs are non-steroidal anti-inflammatory agents. In addition to anti-inflammatory effects, it is also reported to have analgesic, antipyretic and platelet inhibitory effects. It is used, for example, to treat chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. It is reported to act by blocking prostaglandin synthesis by inhibiting the cyclooxygenase enzyme that converts eicosadonic acid to cyclic endoperoxide, a prostaglandin precursor. Inhibition of prostaglandin synthesis explains its analgesic, antipyretic, and platelet inhibitory effects; other mechanisms may contribute to its anti-inflammatory effects. Certain NSAIDs can also inhibit lipoxygenase or phospholipase C, or modulate T cell function. See AMA Drug Evaluations Annual, 1814-5, 1994. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, piroxicam (Reddy et al., 1990; Singh et al., 1994), indomethacin (Narisawa, 1981), and sulindac (Piazza et al. People, 1997; Rao et al., 1995) effectively inhibited colon carcinogenesis in AOM-treated rat models. NSAIDs also inhibit tumor development with activated Ki-ras (Singh and Reddy, 1995). NSAIDs appear to inhibit carcinogenesis by inducing apoptosis in tumor cells (Bedi et al., 1995; Lupulescu, 1996; Piazza et al., 1995; Piazza et al., 1997b). Several studies suggest that the chemopreventive properties of NSAIDs, including induction of apoptosis, are a function of their ability to inhibit prostaglandin synthesis (reviewed in DuBois et al., 1996; Lupulescu, 1996; Vane and Botting, 1997). However, studies indicate that NSAIDs can act through prostaglandin-dependent and -independent mechanisms (Alberts et al., 1995; Piazza et al., 1997a; Thompson et al., 1995; Hanif, 1996). Sulindac, a metabolite of the NSAID sulindac, lacks COX-inhibitory activity, induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b), and is active in several rodent models of carcinogenesis. Inhibition of tumor development (Thompson et al., 1995; Piazza et al., 1995, 1997a). The effects of several NSAIDs have been tested in human clinical trials. Completed a Phase IIa trial (one month) of ibuprofen and found that even at a dose of 300 mg/day, prostaglandin E₂ (PGE₂ ) levels were significantly lowered. The dose of 300 mg ibuprofen is extremely low (therapeutic doses range from 1200-3000 mg/day or more) and toxicity is unlikely to be observed even over the long term. However, ibuprofen was less effective than other NSAIDs in animal chemoprevention models.a. aspirin Aspirin, also known as acetylsalicylic acid, is a salicylate drug that is often used as an analgesic to relieve minor pain and suffering, as an antipyretic to reduce fever, and as an anti-inflammatory drug therapy. Aspirin was first isolated in 1897 by Felix Hoffmann, a chemist at the German company Bayer. Salicylic acid, the major metabolite of aspirin, is an integral part of human and animal metabolism. Although much is attributable to diet in humans, a substantial portion is synthesized endogenously. Today, aspirin is one of the most widely used pharmaceuticals worldwide, with an estimated 40,000 tons consumed annually. In countries where aspirin is a registered trademark owned by Bayer, the generic term is acetylsalicylic acid (ASA). Aspirin also has antiplatelet effects by inhibiting the production of thromboxane, which normally binds platelet molecules together to create patches on damaged walls of blood vessels. Because platelet patches can become oversized locally and downstream and also block blood flow, aspirin is also used chronically in low doses to help prevent heart attack, stroke, and blood clot formation in humans at high risk of developing blood clots. It also established that low-dose aspirin can be given immediately after a heart attack to reduce the risk of another heart attack or death of heart tissue. Aspirin is effective in preventing certain types of cancer, especially colorectal cancer. Adverse side effects of oral aspirin include gastrointestinal ulcers, stomach bleeding, and tinnitus, especially at higher doses. In children and adolescents, aspirin is no longer prescribed to control flu-like symptoms or symptoms of chickenpox or other viral diseases because of the risk of Reye's syndrome. Aspirin is part of a group of agents known as nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from most other NSAIDs in its mechanism of action. Although aspirin and other drugs in its group called salicylates have similar effects (antipyretic, anti-inflammatory, analgesic) to other NSAIDs and inhibit the same enzyme cyclooxygenase, aspirin (but not other Salicylates) do so in an irreversible manner, and unlike other drugs, affect the COX-1 variant of the enzyme but not the COX-2 variant.b. Sulindac and its major metabolites , Sulindac and Sulindac Sulphide Sulindac is a nonsteroidal, anti-inflammatory derivative of indene with the following chemical name: (Z)-5-fluoro-2-methyl-1-((4-(methylsulfinyl)phenyl)methylene yl)-1H-indene-3-acetic acid (Physician's Desk Reference, 1999). Without being bound by theory, the sulfide moiety is converted in vivo by reversible reduction to the sulfide metabolite and by irreversible oxidation to the sulfide metabolite (exisulind). See US Patent 6,258,845, which is incorporated herein by reference. Sulindac, which also inhibits Ki-ras activation, is metabolized into two different molecules that differ in their ability to inhibit COX, but both are capable of exerting a chemopreventive effect by inducing apoptosis. Sulindac lacks COX inhibitory activity and most likely contributes to the induction of apoptosis in a manner independent of prostaglandin synthesis. Available indications indicate that the sulfide derivative is at least one of the biologically active compounds. Based on this, sulindac can be regarded as a prodrug. Sulindac (Clinoril®) is available, for example, in the form of 150 mg and 200 mg lozenges. The most common dose for adults is 150 to 200 mg twice daily, with a maximum daily dose of 400 mg. Following oral administration, about 90% of the drug is absorbed. Peak plasma levels are reached within about 2 hours in fasted patients and 3 to 4 hours when administered with food. The average half-life of sulindac was 7.8 hours: the average half-life of the sulfide metabolite was 16.4 hours. US Patent Nos. 3,647,858 and 3,654,349 cover formulations of sulindac; both patents are incorporated herein by reference in their entirety. Sulindac is indicated for the acute and long-term relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gout, and acute painful shoulder. The analgesic and anti-inflammatory effects exerted by sulindac (400 mg per day) were comparable to those exerted by aspirin (4 g per day), ibuprofen (1200 mg per day), indomethacin (125 mg per day) and benzene Similar effects were achieved with methazone (400 to 600 mg per day). Side effects of sulindac include mild gastrointestinal effects in almost 20% of patients, with abdominal pain and nausea being the most frequent complaints. CNS side effects were found in up to 10% of patients, with somnolence, headache, and nervousness most commonly reported. Rash and scrapie occurred in 5% of patients. Chronic treatment with sulindac can lead to severe gastrointestinal toxicities such as bleeding, ulceration and perforation. The potential use of sulindac for chemoprevention of cancer and especially colorectal polyps has been well studied. For example, US Patent Nos. 5,814,625 and 5,843,929, both incorporated herein by reference, report on the potential chemopreventive use of sulindac in humans. Although at least one study in incidental adenomas showed no such effect (Ladenheim et al., 1995), sulindac was shown to produce adenoma regression in patients with familial adenomatous polyposis (FAP) (Muscat et al., 1994) . Sulindac and its metabolite exixulin were tested and continue to be tested clinically for the prevention and treatment of several cancer types.c. piroxicam Piroxicam is a non-steroidal anti-inflammatory agent well established in the treatment of rheumatoid arthritis and osteoarthritis under the following chemical name: 1,1-dioxide 4-hydroxy-2-methyl-N -2-pyridyl-2h -1,2-Benzothiazine-3-carboxamide. It has also demonstrated usefulness in the treatment of musculoskeletal disorders, dysmenorrhea, and post-surgical pain. Its long half-life enables it to be administered once daily. Drugs were shown to be effective if administered rectally. Gastrointestinal upset was the most commonly reported side effect. Although piroxicam exhibited side effects in recent lib trials, piroxicam was shown to be an effective chemopreventive agent in animal models (Pollard and Luckert, 1989; Reddy et al., 1987). A large meta-analysis of side effects of NSAIDs also indicated that piroxicam has more side effects than other NSAIDs (Lanza et al., 1995). Although DFMO exerted a greater inhibitory effect on Ki-ras mutation and tumorigenesis than piroxicam when the agents were administered separately (Reddy et al., 1990), the combination of DFMO and piroxicam was A synergistic chemopreventive effect was demonstrated in an AOM-treated rat model of carcinogenesis (Reddy et al., 1990). In one study, administration of DFMO or piroxicam to AOM-treated rats reduced the number of tumors with Ki-ras mutations from 90% to 36% and 25%, respectively (Singh et al., 1994). The agent also reduces the amount of biochemically active p21 ras in existing tumors.d. celecoxib (Celecoxib) Celecoxib is a non-steroidal anti-inflammatory agent which is well established under the following chemical name in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, ankylosing spondylitis and in reducing the number of colon and rectal polyps in patients with FAP : 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide. Celecoxib is sold by Pfizer under the brand names Celebrex, Celebra and Onsenal. Celecoxib is a selective COX-2 inhibitor. Side effects of celecoxib include a 30% increase in heart and vascular disease rates. In addition, the risk of gastrointestinal side effects was greater than 80%.E. NSAIDs combination of In some embodiments, combinations of various NSAIDs may also be used. By using lower doses of two or more NSAIDs, it is possible in some embodiments to reduce side effects or toxicity associated with higher doses of individual NSAIDs. For example, in some embodiments, sulindac may be used with celecoxib. Examples of NSAIDs that may be used in combination with each other include, but are not limited to: ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen , oxaprozin, indomethacin, sulindac, etodolac, diclofenac, piroxicam, meloxicam, for Tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic, meclofenamic, flufen Flufenamic, tolfenamic, rofecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and etoricoxib.IV. Difluoromethylornithine / Sulindac combination therapy In some embodiments, the compositions provided herein can be used to reduce the number of cancer cells in a patient, inhibit the growth of cancer cells in a patient, and/or prevent the development of cancer cells in a patient. Target cancer cells include lung cancer, brain cancer, prostate cancer, kidney cancer, liver cancer, ovarian cancer, breast cancer, skin cancer, stomach cancer, esophagus cancer, head and neck cancer, testicular cancer, colon cancer, cervical cancer, lymphatic system cancer and blood cancer . In some embodiments, the compositions are useful for treating and/or preventing colon cancer, familial adenomatous polyposis (FAP), pancreatic cancer, and/or neuroblastoma. In some embodiments, the compositions provided herein can be used to treat patients exhibiting precancerous symptoms, and thus prevent the onset of cancer. Target cells and tissues for such prophylactic treatment include polyps and other premalignant, premalignant, preneoplastic or other abnormal phenotypes indicative of a state likely to progress to cancer. For example, the compositions provided herein can be used to prevent adenomas with little additional toxicity. Shared mutants with FAPAPC/apc The genotyped Min (multiple intestinal neoplasia) mouse serves as a useful experimental animal model for human FAP patients (Lipkin, 1997). Min mice can develop >100 gastrointestinal adenomas/adenocarcinomas throughout the GI tract at 120 days of life, resulting in GI bleeding, obstruction and death. Combination therapy of DFMO and sulindac was shown to effectively reduce adenomas in these mice. See US Patent 6,258,845, which is incorporated herein by reference in its entirety.V. Fixed Dose Combinations and Routes of Administration In one aspect, the invention provides a composition comprising a fixed dose combination of a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) or a metabolite thereof. In some embodiments, the fixed dose combination is a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of sulindac. In some embodiments, the difluoromethylornithine is difluoromethylornithine hydrochloride monohydrate. In some embodiments, difluoromethylornithine is difluoromethylornithine hydrochloride monohydrate racemate. In some embodiments, difluoromethylornithine hydrochloride monohydrate is a racemic mixture of its two enantiomers. In some embodiments, difluoromethylornithine is present in an amount from about 10 mg to about 1000 mg. In some embodiments, difluoromethylornithine is present in an amount from about 250 mg to about 500 mg. In some embodiments, difluoromethylornithine is present in an amount from about 300 mg to about 450 mg. In some embodiments, difluoromethylornithine is present in an amount from about 350 mg to about 400 mg. In some embodiments, difluoromethylornithine is present in an amount from about 35% to about 60% by weight. In some embodiments, difluoromethylornithine is present in an amount from about 40% to about 55% by weight. In some embodiments, difluoromethylornithine is present in an amount from about 50% to about 55% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 52% to about 54% by weight. In some embodiments, the amount of difluoromethylornithine hydrochloride monohydrate racemate is 52% to 54% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 375 mg. In some embodiments, the amount of difluoromethylornithine hydrochloride monohydrate racemate is 375 mg. In some embodiments, the sulindac is present in an amount from about 10 mg to about 1500 mg. In some embodiments, the sulindac is present in an amount from about 50 mg to about 100 mg. In some embodiments, the sulindac is present in an amount from about 70 mg to about 80 mg. In some embodiments, the sulindac is present in an amount of about 75 mg. In some embodiments, the amount of sulindac is 75 mg. In some embodiments, sulindac is present in an amount from about 5% to about 20% by weight. In some embodiments, sulindac is present in an amount from about 8% to about 15% by weight. In some embodiments, sulindac is present in an amount from about 10% to about 12% by weight. In some embodiments, the amount of sulindac is 10% to 11% by weight. In some embodiments, difluoromethylornithine is present in an amount of about 375 mg and sulindac is present in an amount of about 75 mg. In some embodiments, the formulations further comprise excipients. In some embodiments, the excipient is starch, colloidal silicon dioxide, or silicified microcrystalline cellulose. In some embodiments, the excipient is colloidal silicon dioxide. In some embodiments, the formulation further comprises a second excipient. In some embodiments, the second excipient is silicified microcrystalline cellulose. In some embodiments, the formulation further comprises a lubricant. In some embodiments, the lubricant is magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, aluminum stearate, polyethylene glycol, boric acid, or sodium benzoate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, magnesium stearate is present in an amount from about 0.25% to about 2% by weight. In some embodiments, the amount of magnesium stearate is from about 0.75% to about 2% by weight. In some embodiments, the amount of magnesium stearate is from about 1% to about 1.5% by weight. In some embodiments, the amount of magnesium stearate is about 1.1% by weight. In some embodiments, magnesium stearate is present in an amount of about 1.5% by weight. In some embodiments, the compositions are in the form of capsules, lozenges, mini-tablets, granules, pellets, solutions, gels, creams, foams or patches. In some embodiments, the composition is in the form of a lozenge, such as a single-layer lozenge. In some embodiments, the lozenge weighs from about 650 mg to about 1,000 mg. In some embodiments, the lozenge weighs from about 675 mg to about 725 mg. In some embodiments, the lozenge weighs about 700 mg. In some embodiments, the lozenge further comprises a coating. In some embodiments, the coating is a modified release coating or an enteric coating. In some embodiments, the coating is a pH responsive coating. In some embodiments, the coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP), phthalate Hydroxypropyl methylcellulose formate (HP), poly(methacrylate ethyl acrylate) (1:1) copolymer (MA-EA), poly(methacrylate methyl methacrylate) (1:1) 1) Copolymer (MA MMA), poly(methacrylate methyl methacrylate) (1:2) copolymer or hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the coating masks the taste of difluoromethylornithine. In some embodiments, the coating comprises hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. In some embodiments, the amount of coating is from about 1% to about 5% by weight. In some embodiments, the amount of coating is about 2% to about 4% by weight. In some embodiments, the amount of coating is about 3% by weight. In some embodiments, the amount of coating is from about 5 mg to about 30 mg. In some embodiments, the amount of coating is from about 15 mg to about 25 mg. In some embodiments, the coating amount is about 21 mg. In some embodiments, the weight of the tablet comprising the coating is from about 675 mg to about 750 mg. In some embodiments, the weight of the tablet comprising the coating is from about 700 mg to about 725 mg. In some embodiments, the weight of the tablet comprising the coating is about 721 mg. In one aspect, the invention provides a composition comprising a fixed dose combination of a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of sulindac. In some embodiments, the compositions are in the form of capsules, lozenges, mini-tablets, granules, pellets, solutions, gels, creams, foams or patches. In some embodiments, the composition is a solid and takes the form of a lozenge, eg, a single-layer lozenge. In some embodiments, the lozenge is film coated. In some aspects, the invention provides oral fixed dose combination formulations of difluoromethylornithine and an NSAID. In some embodiments, a pharmaceutical composition comprising a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of an NSAID is provided. In some embodiments, the NSAID is sulindac, aspirin, piroxicam, or celecoxib. In some preferred embodiments, the NSAID is sulindac. In some embodiments, the pharmaceutical compositions and formulations of the invention are used enterally, such as orally, and also rectally or parenterally, wherein the compositions comprise pharmaceutically active compounds. Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dosage forms such as coated tablets, lozenges, capsules or suppositories, and ampoules. They are prepared in a manner known per se, for example using customary mixing, granulating, coating, dissolving or lyophilization methods. Thus, pharmaceutical preparations for oral use can be prepared by combining the active compound with a solid excipient, granulating the resulting mixture, if desired, and processing the mixture or granules, after adding suitable auxiliary substances, if desired or necessary, into tablets. Available as tablets or coated lozenge cores. In a preferred embodiment, the mixture of active ingredients and excipients is formulated in the form of lozenges. Appropriate coatings may be applied to enhance palatability or delay absorption. For example, coatings can be applied to lozenges to mask the objectionable taste of active compounds such as DFMO, or to maintain and/or delay the release of active molecules to specific regions in the gastrointestinal tract. Therapeutic compounds can be administered orally, for example, with an inert diluent or an assimilable edible carrier. Therapeutic compounds and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into lozenges, or incorporated directly into the individual's diet. For oral therapeutic administration, the therapeutic compounds can be combined with excipients and used in the form of ingestible lozenges, buccal lozenges, dragees, capsules, elixirs, suspensions, syrups, or powdered tablets. In certain embodiments, tablets and/or capsules provided herein comprise the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents can be used in the preparation of compressed lozenges. In other embodiments, tablets and capsules can be manufactured for immediate or modified release. In some embodiments, tablets and/or capsules are manufactured as sustained release products to provide sustained release of the drug over a period of hours. In some embodiments, compressed lozenges are sugar coated and/or film coated to mask an unpleasant taste and/or protect the lozenge from exposure to the atmosphere. In some embodiments, lozenges are provided with an enteric coating for selective disintegration in the gastrointestinal tract. In some embodiments, the tablet or capsule is capable of disintegrating or dissolving to release a multiparticulate comprising varying amounts of particles of the first component and the second component, eg, coated with a release-modifying coating. In some of these embodiments, the lozenge or capsule may disintegrate or dissolve in the mouth, stomach, small intestine, terminal ileum, or colon. In some of these embodiments, the tablet or capsule may release multiparticulates with a modified release profile. In some embodiments, the present invention provides a pharmaceutical oral fixed dose combination in the form of a multi-layer lozenge. Multilayer tablets have at least two layers (bilayer tablets) or may have three, four, five or more layers. In some embodiments, each of the layers contains no more than one active pharmaceutical ingredient (API). For example, in some embodiments, the tablet has two layers, with one of the APIs in each of the two layers. In some embodiments, besides these two layers, the tablet also contains other layers containing only the carrier, and which can function, for example, as a separating layer or as an outer coating layer. In some embodiments, if more than two layers are present, components may be present in more than one layer, as long as they are not present together in the same layer. In certain embodiments, single-layer lozenges are preferred, but all information detailed below applies equally to multi-layer lozenges. In some embodiments, the fixed dose combination may be formulated to provide an overall dose in the range of about 0.1 μM to about 1000 μM, preferably in the range of about 1 μM to 100 μM, and more preferably in the range of about 1 μM to about 50 μM. Mean steady-state plasma concentrations of difluoromethylornithine and/or sulindac.a. Pharmaceutically acceptable excipients In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some of these embodiments, a pharmaceutically acceptable excipient may include a pharmaceutically acceptable diluent, a pharmaceutically acceptable disintegrant, a pharmaceutically acceptable binder, a pharmaceutically acceptable An acceptable stabilizer, a pharmaceutically acceptable lubricant, a pharmaceutically acceptable pigment, or a pharmaceutically acceptable slip agent. In the fixed dose combination formulation of the present invention, the active ingredient can be mixed with a pharmaceutically acceptable excipient in a weight ratio of 1:0.25 to 1:20. Diluents that can be used in the pharmaceutical formulations of the invention include, but are not limited to, microcrystalline cellulose ("MCC"), siliconized MCC (e.g., PROSOLV™ HD 90), microfine cellulose, lactose, starch, pregelatinized starch, Sugar, mannitol, sorbitol, dextrose, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, magnesium carbonate, magnesium oxide, and any mixture. Preferably, the diluent is siliconized MCC. The diluent is used in an amount of about 5% to about 95% by weight, and preferably in an amount of about 25% to about 40% by weight, such as about 30% to about 35% by weight, based on the total weight of the formulation The amount used. In certain aspects, the diluent can be a soluble diluent. When a diluent is used, its ratio to the active ingredient in each discrete layer is of utmost importance. The term "soluble diluent" means a diluent dissolved in: water, lactose, Ludipress (BASF, lactose, crospovidone, and povidone (93:3.5:3.5, a mixture of w/w (%)), mannitol and sorbitol. Disintegrants are used to facilitate swelling and disintegration of the lozenge after exposure to fluids in the oral cavity and/or gastrointestinal tract. Examples of disintegrants suitable for use in fixed dose combination formulations of the invention include crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt and mixtures thereof. Other disintegrants that may be used in the pharmaceutical formulations of the invention include, but are not limited to, methylcellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL™ , PRIMELLOSE™), povidone, guar gum, magnesium aluminum silicate, colloidal silicon dioxide (such as AEROSIL™, CARBOSIL^tm ), polacrilin potassium (polacrilin potassium), starch, pregelatinized starch, sodium starch glycolate, (such as EXPLOTAB™), sodium alginate, and any mixture thereof. Preferably, the disintegrant is colloidal silicon dioxide. Disintegrants may be used in an amount of about 0.1% to about 30% by weight, and preferably in an amount of about 0.2% to about 5% by weight, based on the total weight of the formulation. The compositions of the present invention may contain lubricants. Sticking can occur when the pellets attach themselves to the pellet press punch face. Lubricants are used to facilitate powder flow and reduce friction between the tablet punch face and the tablet punch and between the tablet surface and the die wall. Lubricants include, for example, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate and sodium benzoate. Preferably, the lubricant is magnesium stearate. In the present invention, the lubricant is preferably contained in an amount of 0.25% to 2% by weight of the solid dosage form, and preferably about 1.5% by weight. In an exemplary formulation, the lubricant is magnesium stearate present in an amount of about 1.5% by weight to prevent sticking. Binders may be used in the pharmaceutical compositions of the present invention to help hold tablets together after compression. Examples of binders suitable for use in the present invention are gum arabic, guar gum, alginic acid, carbomers (such as Carbopol™ products), dextrin, maltodextrin, methylcellulose, ethylcellulose Hydroxyethyl Cellulose, Hydroxypropyl Cellulose (e.g. KLUCEL™), Hydroxypropyl Methyl Cellulose (e.g. METHOCEL™), Sodium Carboxymethyl Cellulose, Liquid Dextrose, Magnesium Aluminum Silicate, Polymethyl Acrylates, polyvinylpyrrolidone (eg povidone K-90 D, KOLLIDON™), copovidone (PLASDONE™), gelatin, starch and any mixture thereof. Preferably, the binder is starch. In the present invention, the binder preferably comprises about 1% to about 15% by weight of the solid dosage form. In other embodiments, the solid dosage form does not contain a binder. In certain embodiments, stabilizers useful in the fixed dose combination formulations of the invention may be antioxidants. The use of antioxidants promotes the stability of active ingredients against adverse reactions with other pharmaceutically acceptable additives and against changes over time caused by heat or moisture. Antioxidants are, for example, ascorbic acid and its esters, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha-tocopherol, cysteine, citric acid, propyl gallate esters, sodium bisulfate, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) and any mixture thereof.b. Tablet manufacturing method Another aspect of the present invention is to provide methods of making the lozenges disclosed herein, including lozenges comprising difluoromethylornithine and sulindac. In some embodiments, the active agent is prepared by sieving at least one active agent and one or more excipients through a sieve of desired mesh size, and then using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor or any other suitable device for mixing. The blend can be granulated or granulated such as by adding an alcoholic or hydroalcoholic or aqueous solution or suspension with or without a binder in a low or high shear mixer, fluidized bed granulator, and the like. Granulation was performed by dry granulation. Granules can be dried using tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like. The granules can be sized using an oscillating granulator or pulverizer mill or any other known device equipped with a suitable screen. Alternatively, granules are prepared by extrusion and spheronization or rolling. Alternatively, manufacturing granules containing the active agent may involve mixing or rolling with directly compressible excipients. In other embodiments of the invention, small tablets (microtablets) can be made by compressing the granules using dies and punches of various sizes and shapes (as desired). Coatings may, if desired, be applied to the tablets by techniques known to those skilled in the art, such as spray coating, dip coating, fluidized bed coating, and the like. In certain embodiments of the invention, suitable solvent systems, such as alcoholic, hydroalcoholic, aqueous or organic solvent systems, may be used to facilitate processing.1. granulation Granulation is a process in which powder particles are produced that adhere to each other, thereby producing larger, multi-particle entities or granules. In an embodiment of the invention, granules obtained by dry or wet techniques can be blended with one or more lubricants and/or anti-adhesive agents and then filled into a single capsule or into different capsules of different sizes. capsules so that a smaller capsule can be filled into another larger capsule. In a certain embodiment, dry granulation by compression is used to prepare solid dosage compositions. In dry granulation, powder blends are compacted by applying conventional forces to the powders, thereby resulting in considerable size increase. In some aspects, pellets are used in the dry granulation process, where a pelletizer is used in the compression process. In other aspects, a roller compactor is used for dry granulation including a feed system, a compression unit, and a size reduction unit. In this method, the powder is compacted between two rollers by applying a force, which is the most important parameter in the dry granulation method. The applied force is expressed in kN/cm, which is force per centimeter of roll width. Compression pressure is also occasionally indicated in bar. However, this only represents the pressure in the hydraulic system and is not actually a suitable measure of the force applied to the powder. With an imparted force that depends on the amount of powder delivered to the rollers, the powder will be compressed to a predefined strip thickness. In other embodiments, wet granulation is used to prepare solid dosage compositions. Wet granulated powders improve the flowability and compression plasticity of compressed mixtures. In wet granulation, granules are formed by adding the granulation liquid to a powder bed which is controlled by an impeller (in a high shear granulator), a screw (in a twin-screw granulator), or air (in a twin-screw granulator). in a fluidized bed granulator). Creating agitation in the system and wetting the components within the formulation causes primary powder particles to agglomerate to produce wet granules. The granulation liquid (fluid) contains solvents which must be volatile so that they can be removed by drying, and non-toxic. Typical liquids include water, ethanol and isopropanol alone or in combination. Liquid solutions can be aqueous or solvent based. Aqueous solutions have the advantage of being safer to handle than organic solvents. Tablets can also be formed by tumbling melt granulation (TMG) essentially as described in Maejima et al., 1997 (which is incorporated herein by reference). Tumbling melt granulation can be used to prepare fused granules. It can be done in a tumbling mixer. The molten low melting point compound is sprayed onto the crystallized and powdered sugar in the blender and mixed until granules form. In this case, the low melting point component is the binder and the crystalline sugar is the seed. An alternative is to combine the unmelted low melting point ingredients, crystalline sugar such as sucrose or maltose, and water soluble ingredients in powder form such as mannitol or lactose in a tumbling mixer and mix while heating to the low melting point binder melting point or higher. The seeds should be crystalline or granular water-soluble ingredients (sugars), such as granulated mannitol, crystalline maltose, crystalline sucrose, or any other sugar. Examples of tumbling mixers are double shell blenders (V-blenders) or any other shape of tumbling mixers. Hot air can be circulated through the granulator chamber and heating is achieved by heating the bottom surface of the chamber. As the seed material and powder pastille ingredients circulate in the heated chamber, the low melting point compound melts and adheres to the seed crystals. The unmelted powder material adheres to the seed-bonded, molten low-melting material. The spherical beads formed by this method were then cooled and sieved through a screen to remove non-adhered powder. Spray coagulation or granulation can also be used to form the tablet compositions of the present invention. Spray condensation involves atomizing molten droplets of a composition including low melting compounds or preferably other tablet ingredients on the surface. Equipment that can be used for spray condensation includes spray dryers (eg Nero spray dryers) and fluid bed coaters/granulators with top spray (eg Glatt fluid bed coaters/granulators). In a preferred embodiment, the preferably water soluble excipient, more preferably sugar, is suspended in the molten low melting point ingredient and spray condensed to form instant granules. After spray condensation, the resulting composition is allowed to cool and condense. After coagulating the mixture, it is screened or sifted and mixed with the remaining lozenge ingredients. It is within the scope of the invention to melt and spray-condense instant granules comprising any combination of low-melting compounds and other tablet ingredients and spray congeal them onto the other tablet ingredients. It is also within the scope of the present invention to mix all the tablet ingredients including the low melting compound, melt the low melting compound and spray congeal the mixture onto a surface.2. blend In certain embodiments, the mixture is blended after granulation. Blending in solid dose manufacturing achieves blend uniformity and distributes lubricants. In certain aspects, the blending step is designed to achieve homogeneity of all components prior to the final blend of the lubricant. However, blending powders presents challenges due to particle size, moisture content, structure, bulk density, and flow characteristics. The key to a successful recipe is the order of addition. Typically the components and pharmaceutically acceptable additives are dispensed into suitable containers such as diffusion blenders or diffusion mixers. Examples of tumbling mixers are double shell blenders (V-blenders) or any other shape of tumbling mixers.3. compression When preparing lozenge compositions, they can be formed into a variety of shapes. In preferred embodiments, the lozenge composition is compressed into shapes. The method may comprise placing the lozenge composition into the form, and applying pressure to the composition so that the composition assumes the shape of the surface of the form that the composition contacts. Compression into tablet form can be accomplished by a tablet press. The ingot press consists of a lower punch that fits into the bottom die and an upper punch of corresponding shape and size that enters the top die cavity after the ingot material falls into the die cavity. Tablets are formed by the pressure applied to the lower and upper punches. The lozenges of the present invention generally have a hardness of about 20 kP or less; preferably the lozenges have a hardness of about 15 kP or less. Typical compression pressures are from about 5 kN to about 40 kN and will vary based on desired size and tablet hardness. In some aspects, the compression pressure is from about 25 kN to about 35 kN. In certain aspects, the compression pressure is less than about 37 kN, such as less than about 30 kN, such as less than about 25 kN. A hydraulic press (such as a Carver Press) or a rotary tablet press (such as a Stokes Versa Press) are suitable means of compressing the tablet compositions of the present invention. Exemplary compressive force parameters are shown in Table 3. In certain embodiments, the lubricating blend can be compressed using a suitable device, such as a rotary machine, to form ingots, which are passed through a mill equipped with a suitable screen, or a fluid energy mill, or a ball mill, or a colloid mill, or roller mill. mill or hammer mill and similar devices to obtain ground active agent ingots. A pre-compression step may be used in order to prevent tablet capping. Capping means a break or fissure in the cap or top of the tablet from the main body of the tablet. Capping can be caused by incompressible fine particles migrating as the air is pushed out during compression. For example, the pre-compression can be about 5%, 10% or 15% of the main compression force. In a preferred embodiment, the lozenge is pre-compressed into form with a compression force of no more than about 10 kN, preferably less than 5 kN. For example, at less than 1 kN, 1.5 kN, 2 kN, 2.1 kN, 2.2 kN, 2.5 kN, 3 kN, 3.5 kN, 4 kN, 4.5 kN, 5 kN, 6 kN, 7 kN, 8 kN, 9 kN or 10 kN compressed lozenges are within the scope of the present invention. In certain aspects, the pre-compression force is from about 2.5 kN to about 3.5 kN. Exemplary pre-compression force parameters are shown in Table 3.4. Film coating The compositions or solid dosage forms according to the invention may also be coated with film coatings, enteric coatings, release-modifying coatings, protective coatings or anti-adhesive coatings. The composition of the present invention may be coated with an enteric coating. By enteric coating or coating is meant a pharmaceutically acceptable coating that prevents the release of the active agent in the stomach and allows release in the upper intestinal tract. In other embodiments, an enteric coating is applied to delay the release of the active agent to the terminal ileum or to the colon. Enteric coatings can be added as topcoats when modifying release coatings. Enteric coating polymers may be used alone or in combination in the enteric coating formulation. The enteric coating can be designed as a single layer or as a multi-layer coating embodiment. Preferred enteric coatings for use in the compositions of the present invention comprise a film former selected from the group consisting of: cellulose acetate phthalate; cellulose acetate trimellitate; methacrylic acid copolymers, methacrylic acid-derived Copolymers of their esters containing at least 40% methacrylic acid; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate or polyvinyl acetate phthalate. Examples of polymers suitable for enteric coatings include, for example, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP) , hydroxypropylmethylcellulose phthalate (HP), poly(methacrylate ethyl acrylate) (1:1) copolymer (MA-EA), poly(methacrylate methyl methacrylate ) (1:1) copolymer (MA MMA), poly(methacrylate methyl methacrylate) (1:2) copolymer, EUDRAGIT™ L 30D (MA-EA, 1:1), EUDRAGIT™ 100 55 (MA-EA, 3:1), Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS), SURETERIC (PVAP), AQUATERIC™ (CAP), Shellac or AQOAT™ (HPMCAS). Colon-targeted delivery systems that can be used with the present invention are known and use materials such as: hydroxypropyl cellulose; microcrystalline cellulose (MCE, AVICEL™ from FMC Corp.); poly(ethylene-vinyl acetate ester) (60:40) copolymer (EVAC from Aldrich Chemical Co.); 2-hydroxyethyl methacrylate (HEMA); MMA; in N,N'-bis(methacryloxyethyl HEMA:MMA:MA terpolymer synthesized in the presence of oxycarbonylamino)-azobenzene; azo polymer; coated enteric coating time release system (TIME CLOCK from Pharmaceutical Profiles, Ltd., UK ®) and calcium pectinate and osmotic mini pump system (ALZA corp.). In some embodiments, the film coat comprises polymers such as: Hydroxypropylcellulose (HPC), Ethylcellulose (EC), Hydroxypropylmethylcellulose (HMPC), Hydroxyethylcellulose (HEC) , sodium carboxymethylcellulose (CMC), poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), dimethylaminoethyl methacrylate-methacrylate copolymer, or acrylic acid Ethyl ester-methyl methacrylate copolymer (EA-MMA). In some embodiments, the composition has a release modifying coating. The modified release coating may be a pH responsive coating that will deliver the active agent (eg, to the colorectal tract) when exposed to a specific pH. In some embodiments, the pH-responsive coating is a pH-responsive polymer that dissolves when exposed to a pH of greater than or equal to about 6; although a pH-responsive polymer may dissolve at a pH of greater than or equal to about 5 . The pH-responsive polymers can be, for example, polymeric compounds such as EUDRAGIT™ RS and EUDRAGIT™ RL. EUDRAGIT™ products form latex dispersions with a weight of about 30D. EUDRAGIT™ RS 30D is designed for slow release as it is not very water permeable as a coating and it is designed for rapid release as it is relatively water permeable as a coating. These two polymers are generally used in combination. As contemplated herein, the allowable ratio of EUDRAGIT™ RS 30D/EUDRAGIT™ RL 30D is from about 10:0 to about 8:2. Ethylcellulose or S100 or other equivalent polymers designed for enteric or colorectal release can also be used in place of the above EUDRAGIT™ RS/EUDRAGIT™ RL combinations. Optionally, the method comprises the step of film coating the tablet. Film coating can be accomplished using any suitable means. Suitable film coatings are known and are commercially available or can be produced according to known methods. Typically film coating materials are polymeric film coating materials comprising materials such as polyethylene glycol, talc and colorants. Suitable coating materials are methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate Esters, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, gelatin, methacrylic acid copolymer, polyethylene glycol, Shellac, sucrose, titanium dioxide, camauba wax, microcrystalline wax and zein. In some aspects, the film coating is hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and yellow iron oxide. An example of a film coat is OPADRY® Yellow (Colorcon). Typically, the film coating material is applied in such an amount as to provide a film coating in the range of 1% to 6% by weight of the coated film-coated tablet, such as 2% to 4% by weight, such as about 3% by weight. Plasticizers and other ingredients can be added to the coating material. The same or different active substances can also be added to the coating material. In some embodiments, the coating of the tablet can improve palatability to mask the unpleasant taste of active ingredients such as DFMO. For example, tablet coating compositions may include cellulosic polymers, plasticizers, sweeteners, or powder flavor compositions including flavoring agents in association with a solid carrier.c. Investment schedule and plan In some embodiments, agents can be administered on a regular schedule. As used herein, regular schedule refers to a predetermined specified time period. Regular schedules may cover periods of equal or different duration, as long as the schedule is scheduled. For example, a regular schedule may involve dosing twice a day, dosing daily, dosing every two days, dosing every three days, dosing every four days, dosing every five days, dosing every six days , weekly delivery, monthly delivery or any set number of days or weeks between delivery. Alternatively, a predetermined routine schedule may involve twice daily administration for a first week, followed by daily administration for several months, and so on. In other embodiments, the present invention provides orally administrable agents with or without timing of food intake. Thus, for example, the medicament can be taken every morning and/or every evening, regardless of whether the individual has eaten or not.VI. Diagnosis and treatment of patients In some embodiments, methods of treatment can be supplemented with diagnostic methods to improve efficacy and/or minimize toxicity of anticancer therapies, including administration of compositions provided herein. Such methods are described, for example, in US Patents 8,329,636 and 9,121,852, US Patent Publications US2013/0217743 and US2015/0301060, and PCT Patent Publications WO2014/070767 and WO2015/195120, all of which are incorporated herein by reference. In some embodiments, the compositions and formulations of the invention can be administered to an individual wherein the genotype at position +316 of at least one allele of the ODCl gene promoter is G. In some embodiments, the patient's genotype at position +316 of the two alleles of the ODCl gene promoter can be GG. In some embodiments, the patient's genotype at position +316 of the two alleles of the ODCl gene promoter can be GA. In the complete model for adenoma recurrence detected aboutODC1 Statistically significant interaction of genotype and treatment resulted in adenoma recurrence pattern in placebo patients: GG 50%, GA 35%, AA 29% vs. difluoromethylornithine/sulindac patients: GG 11% , GA 14%, AA 57%. In contrast to a previous report showing a reduced risk of recurrent adenomas receiving aspirin in CRA patients with at least one A allele, the adenoma-suppressive effect of difluoromethylornithine and sulindac in patients with predominantly G homozygousODC1 The genotype was greater in these patients (Martinez et al., 2003; Barry et al., 2006; Hubner et al., 2008). These results show that compared with GG genotype patients, theODC1 A allele carriers differ in response to chronic exposure to difluoromethylornithine and sulindac, with A allele carriers having less beneficial effects on adenoma recurrence, and especially in AA homozygotes, likely Increased risk of ototoxicity. In some embodiments, the invention provides a method for the prophylactic or curative treatment of colorectal cancer in a patient comprising: (a) obtaining a result from a test that determines at least oneODC1 Patient genotype at position +316 of the promoter gene allele; and (b) if the results indicateODC1 If the genotype of the patient at position +316 of at least one allele of the promoter gene is G, the composition provided herein is administered to the patient. In some embodiments, the invention provides methods for treating colorectal cancer risk factors in a patient comprising: (a) obtaining a result from a test that determines at least oneODC1 Patient genotype at position +316 of the promoter gene allele; and (b) if the results indicateODC1 If the genotype of the patient at position +316 of at least one allele of the promoter gene is G, the composition provided herein is administered to the patient, wherein the methods prevent the formation of new abnormal glandular lesions, new glandular foci, in the patient. Neoplastic polyps or new dysplastic adenomas. See US Patent 8,329,636, incorporated herein by reference. In some embodiments, the invention provides a method for the prophylactic or curative treatment of familial adenomatous polyposis (FAP) or neuroblastoma in a patient, comprising: (a) obtaining a result from a test that determines at least oneODC1 Patient genotype at position +316 of the promoter gene allele; and (b) if the results indicateODC1 If the genotype of the patient at position +316 of at least one allele of the promoter gene is G, the composition provided herein is administered to the patient. In some embodiments, the invention provides methods for treating familial adenomatous polyposis or neuroblastoma risk factors in a patient comprising: (a) obtaining a result from a test that determines at least oneODC1 Patient genotype at position +316 of the promoter gene allele; and (b) if the results indicateODC1 If the genotype of the patient at position +316 of at least one allele of the promoter gene is G, the composition provided herein is administered to the patient, wherein the methods prevent the formation of new abnormal glandular lesions, new glandular foci, in the patient. Neoplastic polyps or new dysplastic adenomas. See US Patent 9,121,852, which is incorporated herein by reference. In some embodiments, the present invention provides methods for treating a patient with cancer comprising administering to the patient a composition provided herein, wherein the patient has been determined to have a low dietary polyamine intake and/or Tissue polyamine level and/or tissue polyamine flux. In some of these embodiments, the low dietary polyamine intake is 300 μM polyamine per day or less. In some of these embodiments the cancer is colorectal cancer. See US Patent Publication US2013/0217743, which is incorporated herein by reference. In some embodiments, the present invention provides methods for the prophylactic or curative treatment of cancer in a patient comprising: (a) obtaining a result from a test that determineslet-7 Expression levels of non-coding RNA, HMGA2 protein, and/or LIN28 protein; and (b) if the results indicate that the patient's cancer presents with referencelet-7 Non-coding RNA performance levels compared tolet-7 Decreased expression levels of non-coding RNA, increased HMGA2 protein expression levels compared to reference HMGA2 protein expression levels, and/or increased LIN28 protein expression levels compared to reference LIN28 protein expression levels, then administering a composition provided herein to the patient . In some of these embodiments, the reference level is the level observed in a non-diseased individual or the level observed in a non-cancerous cell from a patient. In some of these embodiments, "obtaining" comprises providing a cancer sample from a patient and assessing the presence of cancer cells in the samplelet-7 Expression levels of noncoding RNA, HMGA2 protein, or LIN28 protein. In some of these embodiments, "Assessinglet -7 Expression level of non-coding RNA" includes quantitative PCR or Northern blotting. In some of these embodiments, "assessing the expression level of HMGA2 protein or LIN28 protein" comprises immunohistochemistry or ELISA. In some of these embodiments, the sample is blood or tissue, such as tumor tissue. In some of these embodiments, the patient is human. In some of these embodiments, the cancer is colorectal cancer, neuroblastoma, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer, esophageal cancer cancer, cervical cancer, head and neck cancer, non-melanoma skin cancer, or glioblastoma. In some of these embodiments, the method further comprises (c) obtaining a result from a test that measures, at a second time point, in a second cancer cell from the patientlet-7 Expression of non-coding RNA followed by administration of at least one dose of an ODC inhibitor. In some of these embodiments, the method further comprises if it is observed thatlet-7 With no or less increase in non-coding RNA, the amount of ODC inhibitor administered to the patient is increased. In some of these embodiments, the method further comprises obtaining results from a test measuring expression of HMGA2 protein or LIN28 protein at a second time point in a second cancer cell from the patient, followed by administering at least one dose of ODC Inhibitors. In some of these embodiments, the method further comprises increasing the amount of the ODC inhibitor administered to the patient if no or less decrease in HMGA2 protein or LIN28 protein is observed. In some such embodiments, the method further comprises (i) obtaining a result from a test that determinesODC1 Patient genotype at position +316 of at least one allele of the gene promoter; and (ii) if the results indicateODC1 If the genotype of the patient at position +316 of at least one allele of the gene promoter is G, the composition provided herein is administered to the patient. In some embodiments, the method comprises diagnosing a cancer or precancerous condition in a patient comprising obtaining a sample from the patient and (b) determining a value selected from the samplelet-7 The expression level of at least two markers of the group consisting of non-coding RNA, LIN28 protein and HMGA2 protein, wherein if relative to the reference level, in the samplelet-7 A decrease in the expression level of non-coding RNA or an increase in LIN28 protein or HMGA2 protein is diagnosed as having cancer or a precancerous condition. In some embodiments, the fixed dose combinations of the invention are directed toward having low cellular or tissuelet-7 level of patient input. In other aspects, compositions of the invention are administered to patients with high cellular or tissue HMGA2 levels. In other aspects, compositions of the invention are administered to patients with high cellular or tissue LIN28 levels. See US Patent Publication US2015/0301060, which is incorporated herein by reference. In some embodiments, there is provided a method for prophylactically or curatively treating a cancer in a patient comprising: (a) obtaining a result from a test that determines at least oneODC1 the patient's genotype at the position of the allele + 263; and (b) if the results indicateODC1 A patient whose genotype is T at position +263 of at least one allele of the gene is administered a composition provided herein. In some of these embodiments, the test can determine in patientsODC1 The nucleotide base at position +263 of an allele of the gene. In some embodiments, the test can determine theODC1 The nucleotide base at position +263 of the two alleles of the gene. In some embodiments, the results may indicateODC1 The patient's genotype at position +263 of the two alleles of the gene is TT. In some embodiments, the results may indicateODC1 The genotype of the patient at position +263 of the two alleles of the gene is TG. In some such embodiments, the method may further comprise obtaining a result from a test that determines at least oneODC1 Patient genotype at position +316 of the allele, and if the result indicatesODC1 For patients whose genotype is G at position +316 of at least one allele of the gene, only a composition provided herein is administered to the patient. In another aspect, there is provided a method for treating a risk factor for colorectal cancer in a patient comprising: (a) obtaining a result from a test that determines at least oneODC1 the patient's genotype at the position of the allele + 263; and (b) if the results indicateODC1 If the patient's genotype at position +263 of at least one allele of the gene is T, a composition provided herein is administered to the patient, wherein the method prevents the formation of new abnormal glandular lesions, new adenomatous polyps, or New dysplastic adenoma. In another aspect, there is provided a method for preventing the development or recurrence of cancer in a patient at risk thereof comprising: (a) obtaining a result from a test that determines at least oneODC1 the patient's genotype at the position of the allele + 263; and (b) if the results indicateODC1 A patient whose genotype is T at position +263 of at least one allele of the gene is administered a composition provided herein. See PCT Patent Publication WO2015/195120, which is incorporated herein by reference. In variations of any of the above embodiments, the cancer may be colorectal cancer, neuroblastoma, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer , liver, esophagus, cervix, head and neck, non-melanoma skin cancer, or glioblastoma. In some embodiments, the cancer may be colorectal cancer. In some embodiments, colorectal cancer may be stage I. In some embodiments, the colorectal cancer may be stage II. In some embodiments, colorectal cancer may be stage III. In some embodiments, the colorectal cancer may be stage IV. In variations of any of the above embodiments, the method prevents the formation of new advanced colorectal neoplasia in the patient. In some embodiments, the method prevents the formation of new right-sided advanced colorectal neoplasia. In some embodiments, the method prevents the formation of new left advanced colorectal neoplasia. In variations of any of the above embodiments, a patient may be identified as having one or more adenomatous polyps in the colon, rectum, or appendix. In some embodiments, a patient can be identified as having one or more advanced colorectal neoplasms. In some embodiments, a patient can be identified as having one or more left-sided advanced colorectal neoplasms. In some embodiments, a patient can be identified as having one or more right-sided advanced colorectal neoplasms. In some embodiments, the patient is diagnosed with familial adenomatous polyposis. In some embodiments, the patient is diagnosed with Lynch syndrome. In some embodiments, the patient is diagnosed with familial type X colorectal cancer. In some embodiments, the patient may meet the Amsterdam Criteria or Amsterdam Criteria II. In some embodiments, the patient may have a history of resection of one or more colorectal adenomas. In some embodiments, the patient may have ODC hyperactivity associated with intraepithelial neoplasia or precancerous lesions. In some embodiments, the patient may have intraepithelial neoplasia or precancerous lesions and elevated cellular polyamine levels. In variations of any of the above embodiments, the patient is a human.VII. definition As used in this specification, "a (a/an)" may mean one or more. As used in this patent claim, the word "a/an" when used in conjunction with the word "comprises" can mean one or more than one. Throughout this application, the term "about" is used to indicate that a value includes the inherent variation in error of the device, the method used to determine the value, or the variation that exists among individuals studied. As used herein, the term "bioavailability" means the degree to which a drug or other substance is available to a target tissue after administration. In this context, the term "suitable bioavailability" is intended to mean that the administration of the composition according to the invention will result in an improved bioavailability compared to that obtained after administration of the active substance in conventional lozenges; or The bioavailability is at least the same or improved compared to the bioavailability obtained after administration of a commercially available product containing the same active substance in the same amount. In particular, there is a need to obtain faster and greater and/or more thorough capture of active compounds, and thereby provide for a reduced dose of administration or a reduction in the number of administrations per day. The terms "composition", "pharmaceutical composition", "formulation" and "preparation" are used synonymously and interchangeably herein. The terms "comprises", "has" and "includes" are open linking verbs. Any form or tense of one or more of these verbs, such as "comprises", "comprising", "has", "having", "includes" " and "including" are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to having only those one or more steps and also encompasses other unlisted steps. The term "derivatives thereof" refers to any chemically modified polysaccharide in which at least one of the monomeric sugar units is modified by substituting atoms or molecular groups or bonds. In one embodiment, derivatives thereof are salts thereof. Salts are, for example, salts with suitable inorganic acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochloride, hydrobromide, sulfate, hydrogensulfate or hydrogenphosphate; salts with suitable carboxylic acids, Such as optionally hydroxylated lower alkanoic acids such as acetic acid, glycolic acid, propionic acid, lactic acid or pivalic acid, optionally hydroxylated and/or pendant substituted lower alkane dicarboxylic acids such as oxalic acid, succinic acid , fumaric acid, maleic acid, tartaric acid, citric acid, pyruvic acid, malic acid, ascorbic acid, and salts with the following aromatic, heteroaromatic or araliphatic carboxylic acids, such as benzoic acid, nicotine acid or mandelic acid; and salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate orN- Cyclamate (cyclamate). The term "disintegration" as used herein refers to the process by which a pharmaceutical oral fixed dose combination is broken down into individual particles and dispersed, usually by means of a fluid. When the solid oral dosage form is in a state in which any solid oral dosage form residue other than insoluble coating or capsule shell fragments (if present) remaining on the test equipment sieve is free of perceivable hard cores according to USP <701> Disintegration is achieved when there is a soft block. The fluid used to determine the disintegration properties is water, such as tap water or deionized water. Disintegration times are measured using standard methods known to those skilled in the art, see Pharmacopoeia USP <701> and harmonized procedures set forth in EP 2.9.1 and JP. The term "dissolved" as used herein refers to a solid substance, here the means by which the active ingredient is dispersed in molecular form in a medium. The dissolution rate of the active ingredients of the pharmaceutical oral fixed dose combination of the present invention is defined by the amount of the drug substance going into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Dissolution rates are measured using standard methods known to those skilled in the art, see Pharmacopeia USP <711> and harmonized procedures set forth in EP 2.9.3 and JP. For the purposes of the present invention, the tests used to measure the dissolution of the individual active ingredients are carried out according to the Pharmacopoeia USP <711> at the pH as described herein for the different examples. Specifically, the test was performed using a paddle stirring element at 75 rpm (rotations per minute). The dissolution medium is preferably a buffer, usually a phosphate buffer (eg at pH 7.2). The molar concentration of the buffer is preferably 0.1 M. An "active ingredient" (Al) (also known as an active compound, active substance, active agent, pharmaceutical agent, medicament, biologically active molecule or therapeutic compound) is an ingredient in a biologically active drug or pesticide. The similar terms active pharmaceutical ingredient (API) and bulk active are also used for pharmaceutical products, and the term active substance can be used for pesticide formulations. "Pharmaceutical drug" (also known as medicine, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, medicinal product, medicinal product, medicine, medication, medicament or simply drug )) are drugs used to diagnose, cure, treat or prevent disease. An active ingredient (Al) (as defined above) is an ingredient in a biologically active drug or pesticide. The similar terms active pharmaceutical ingredient (API) and bulk active are also used for pharmaceutical products, and the term active substance can be used for pesticide formulations. Certain pharmaceutical and insecticide products may contain more than one active ingredient. Compared to active ingredients, inert ingredients are often referred to as excipients in a pharmaceutical context. As used in this specification and/or claims, the term "effective" means sufficient to achieve a desired, desired or anticipated result. "Effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" when used in the context of treating a patient or subject with a compound means sufficient to affect the Amount of compound for such treatment or prevention of disease. "Prevention/preventing" includes: (1) inhibiting the onset of a disease in an individual or patient who may be at risk and/or susceptible to the disease but has not experienced or exhibited any or all of the pathology of the disease or symptomology, and/or (2) slow down the onset of pathology or symptoms of a disease in an individual or patient who may be at risk and/or susceptible to the disease but has not experienced or demonstrated any or All pathologies or syndromes. "Treatment/treating" includes (1) inhibiting the disease in an individual or patient experiencing or exhibiting the pathology or symptoms of the disease (e.g. arresting further development of the pathology and/or symptoms), (2) ameliorating the experience or symptoms of the disease Disease in an individual or patient exhibiting the pathology or symptoms of the disease (e.g. reversing the pathology and/or symptoms) and/or (3) causing disease in an individual or patient experiencing or exhibiting the pathology or symptoms of the disease Any measurable weakening occurs. "Prodrug" means a compound which is metabolically convertible in vivo into an inhibitor according to the invention. Prodrugs themselves may or may not also have activity relative to the protein of interest to which they are administered. For example, a compound containing a hydroxy group can be administered as an ester that is converted to the hydroxy compound by in vivo hydrolysis. Suitable esters that can be converted to hydroxy compounds in vivo include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, butanes Ester, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluene Acyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclamate, quinate, esters of amino acids and the like ester. Similarly, compounds containing amine groups can be administered as amides that are converted to amine compounds by in vivo hydrolysis. An "excipient" is a pharmaceutically acceptable substance formulated with an active ingredient of a drug, a pharmaceutical composition, formulation or drug delivery system. Excipients may be used, for example, to stabilize the composition, to swell the composition (thus often referred to as "bulking agents", "fillers" or "diluents" when used for this purpose), or to allow the active ingredient in the final dosage form. Efficacy enhancement, such as enhancing drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavoring agents, slip agents, lubricants, preservatives, adsorbents, sweeteners, and vehicles. The primary excipient, which serves as a medium for the delivery of the active ingredient, is commonly referred to as a vehicle. Excipients may also be used in the manufacturing process eg to aid active substance handling such as by promoting powder flowability or non-adherence, in addition to aiding in vitro stability, such as preventing denaturation or aggregation beyond expected shelf life. The suitability of an excipient will generally vary depending on the route of administration, dosage form, active ingredient, and other factors. The term "hydrate" when used as a modifier of a compound means that the compound has less than one (eg hemihydrate), one (eg monohydrate) or more than one (eg dihydrate) A water molecule in the solid form of a compound. The term "difluoromethylornithine" when used per se refers to 2,5-diamino-2-(difluoromethyl)pentanoic acid in any of its forms, including non-salt and salt forms ( For example, difluoromethylornithine HCl), non-salt and salt forms of anhydrous and hydrated forms (such as difluoromethylornithine hydrochloride monohydrate), non-salt and salt forms of solvates, etc. Enantiomers (R andS form, which can also be identified asd andl form) and mixtures of such enantiomers (for example a racemic mixture or a mixture in which one of the enantiomers is enriched relative to the other). Specific forms of difluoromethylornithine include difluoromethylornithine hydrochloride monohydrate (aka CAS ID: 96020-91-6; MW: 236.65), difluoromethylornithine hydrochloride Salt (ie CAS ID: 68278-23-9; MW: 218.63) and free difluoromethylornithine (ie CAS ID: 70052-12-9; MW: 182.17). If necessary, the form of difluoromethylornithine has been further specified. In some embodiments, the difluoromethylornithine of the present invention is difluoromethylornithine hydrochloride monohydrate (ie CAS ID: 96020-91-6). The terms "difluoromethylornithine" and "DFMO" are used interchangeably herein. Other synonyms for difluoromethylornithine and DFMO include: α-Difluoromethylornithine, 2-(difluoromethyl)-DL-ornithine, 2-(difluoromethyl)ornithine acid, DL-α-difluoromethylornithine,N- Difluoromethylornithine, ornidyl, αδ-diamine-α-(difluoromethyl)valeric acid and 2,5-diamine-2(difluoro)valeric acid. As used herein, "substantially free" with respect to specified components is used herein to mean that none of the specified components are purposefully formulated into the composition and/or are present only as contaminants or in trace amounts. The total amount of a given component resulting from any unintended contamination of the composition is thus well below 0.05%, preferably below 0.01%. Optimally is a composition in which the specified component is not detectable in an amount by standard analytical methods. The term "fixed dose combination" or "FDC" refers to a combination of two drugs or active ingredients presented in a single dosage unit (such as a tablet or capsule) and thus administered with a defined dose; further as used herein, a "free dose "Combination" refers to the combination of two drugs or active ingredients administered simultaneously but in two different dosage unit forms. "Granulation" means the process of agglomerating powder particles into larger particles containing active pharmaceutical ingredients. "Dry granulation" refers to any process involving the steps of adding no liquid to a powdered starting material, agitating and drying to obtain a solid dosage form. The resulting granulated medicines can be further processed into various final dosage forms, such as capsules, lozenges, powder tablets, gels, buccal tablets, etc. Although the present invention supports the definitions of referring to alternatives only and "and/or", the term "or" is used in the claims to mean "and/or" unless expressly indicated to refer to alternatives only or the alternatives are mutually exclusive. As used herein, "another" may mean at least a second or more. As used herein, the term "patient" or "individual" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgene thereof type. In certain embodiments, the patient or individual is a primate. Non-limiting examples of human patients are adults, adolescents, infants and fetuses. As generally used herein, "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for contact with tissues, organs and/or body fluids of humans and animals without undue toxicity, irritation, allergic response or other problems or complications, those compounds, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable carrier", "pharmaceutical carrier" or simply "carrier" is a pharmaceutically acceptable substance formulated with an active ingredient drug involved in carrying, delivering and/or transporting a chemical agent. Drug carriers can be used to improve the delivery and effectiveness of drugs, including, for example, controlled release techniques to adjust drug bioavailability, reduce drug metabolism, and/or reduce drug toxicity. Certain drug carriers can increase the effectiveness of drug delivery to specific target sites. Examples of carriers include: liposomes, microparticles (eg, made of poly(lactic-co-glycolic acid) acid), albumin microparticles, synthetic polymers, nanofibers, nanotubes, protein-DNA complexes, protein Conjugates, red blood cells, virus particles and dendrimers. As defined herein, the term "physically separate" refers to a pharmaceutical oral fixed dose combination comprising components a) and b) formulated so that they are not mixed with each other in the same carrier, but separated. This separation helps to minimize the interaction between the two components especially when they are released. Usually physical separation means that the two components a) and b) are present in different compartments, such as layers, or in different physical forms of the formulation, such as granules or granules. It is not necessary that the two components a) and b) be further separated by an additional layer or coating, although this may optionally be appropriate. This physical separation of the two components a) and b) in one dosage form can be achieved by various means known in the art. In one embodiment, this is achieved by formulating the respective components a) and b) into separate layers, such as a multilayer or bilayer formulation. Specific examples of such deployment techniques are described herein. The term "adhesion" refers to the adherence of particles to the face of a compactor punch that includes letters, logos or designs on the face of the punch. The term "capping" refers to a break or crack in the cap or top of a tablet from the main body of the tablet. Capping can be caused by incompressible fine particles migrating as the air is pushed out during compression. The term "brittleness" refers herein to the tendency of a tablet to crumble, crumble or break after compression. It can be caused by several factors including poor tablet design (edges that are too sharp), low moisture content, insufficient binder, etc. In some aspects, the friability of a tablet sample is given in terms of % weight loss (ie, weight loss expressed as a percentage of the initial sample weight). In general, a maximum weight loss of no more than 1% is considered acceptable for most lozenges. As used herein, the term "release" refers to the method by which the pharmaceutical oral fixed dose combination is contacted with a fluid and the fluid transports the drug out of the dosage form into the fluid surrounding the dosage form. The combination of rate of delivery and duration of delivery exhibited by administration of a dosage form in a patient can be described as its in vivo release profile. The release profile of the dosage form can exhibit different rates and durations of release and can be continuous. Continuous release profiles include release profiles in which one or more active ingredients are released continuously at a constant or variable rate. When two or more components with different release profiles are combined in one dosage form, the resulting individual release profiles of the two components may be the same or different compared to a dosage form with only one of the components. Thus, the two components may influence each other's release profile, thereby resulting in a different release profile for each individual component. Two-component dosage forms may exhibit release profiles of the two components that are the same or different from each other. The release profile of a two-component dosage form in which each component has a different release profile can be described as "asynchronous". Such release profiles encompass (1) different sequential releases, wherein preferably component b) is released at a slower rate than component a), and (2) profiles wherein one of components a) and b) Alternatively, preferably component b) is continuously released, and the other of components a) and b), preferably component a), is adjusted for continuous release with a time delay. Combinations of two release profiles of one drug are also possible (eg 50% continuous release of drug and 50% continuous release of the same drug with a time delay). Immediate Release: For the purposes of this application, an immediate release formulation is a formulation that exhibits release of the active substance that is not intentionally modulated by a particular formulation design or method of manufacture. Modified release: For the purposes of this application, a modified release formulation is a formulation that exhibits the release of an active substance that has been intentionally modulated by a particular formulation design or manufacturing method. This modified release can generally be obtained by delaying the release time of one or both of the components (preferably component a)). Typically for the purposes of the present invention, modified release refers to release over 5 h, such as release over 3 h or even less. As used herein, modified release is meant to encompass a differential continuous release of the two components over time, or a delayed release, wherein one of these components, preferably component a), is released only after a lag time. Such modified release forms can be prepared by applying a release-modifying coating, such as a diffusion coat, to the drug substance or a core containing the drug substance, or by forming a release-modifying matrix in which the drug substance is embedded. The term "tablet" refers to a pharmacological composition in the form of small substantially solid pellets of any shape. Tablets may be cylindrical, spherical, oblong, capsule or irregular in shape. The term "tablet composition" refers to a substance included in a tablet. "Tablet composition ingredient" or "tablet ingredient" refers to a compound or substance included in a tablet composition. These may include, but are not limited to, the active agent and any excipients as well as low melting compounds and water soluble excipients. The above definitions supersede any conflicting definitions in any of the references incorporated herein by reference. However, the fact that certain terms are defined should not be taken as indicating that any term that is not defined is indeterminate. Rather, all terms used are believed to describe the invention in such a way that one of ordinary skill in the art can understand and practice the invention. Unit abbreviations used herein include result average (ar), kilogram force (kp), kilonewton (kN), percent weight/weight (%w/w), pounds per square inch (psi), relative humidity (RH) , color difference δE (dE) and rotations per minute (rpm).VIII. example The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of ordinary skill in the art should, in light of the present invention, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or a similar result without departing from the spirit and scope of the invention.example 1- Research and development of difluoromethylornithine HCl and Sulindac Combination Table In the development process of fixed dose combination (FDC) lozenges comprising difluoromethylornithine HCl and sulindac, several formulations were tested (Table 1). Parameters tested included tablet disintegration time, tablet hardness and tablet friability percentage. Formulation I was made into 900 mg lozenges by first mixing 1/3 of siliconized MCC (PROSOLV®) with difluoromethylornithine HCl in a 1 quart v-blender. Subsequently, sulindac and 1/3 of siliconized MCC (PROSOLV®) were premixed in polyethylene (PE) bags together with colloidal silicon dioxide (CARBOSIL®) and pregelatinized cornstarch (STARCH 1500®) Add to blender. The PE bag was rinsed with the remaining 1/3 of siliconized MCC (PROSOLV®) and added to the blender. The mixture was blended at about 25 rpm for 10 minutes and then blended again for 3 minutes before adding the hand screened magnesium stearate. This formulation was found to have some sticking to the punch surface and resulted in a rough tablet surface. Thus, for Formulation II, magnesium stearate increased from 0.5% to 1% and siliconized MCC decreased from 38.57% to 38.07%. Formulation II was manufactured as 900 mg lozenges by premixing CARBOSIL®, STARCH 1500® and sulindac in PE bags. Then, ½ of PROSOLV® and difluoromethylornithine HCl was added to an 8 quart v-blender along with the premix. The remaining ½ of PROSOLV® is used to rinse the PE bag and add to the blender. The mixture was blended for 10 minutes at about 25 rpm. The mixture was then removed from the blender and delumped through a Comill 039R screen, then returned to the v-blender for an additional 10 minutes of blending. Magnesium stearate, manually sieved through a 30 mesh (ie, 590 μm) screen, was then added to the v-blender by hand mixing and the mixture was blended for 3 minutes at approximately 25 rpm. The mixture was compressed into lozenges on a Key Model BBTS 10 bench. The resulting tablets were determined to have a disintegration time of about 29-32 seconds, a friability of 0.077% at 4 minutes and a friability of 0.17392% at 8 minutes, and a hardness of about 28 kp (Table 1). The lozenges were then film coated with 2.913% by weight OPADRY® Yellow (Colorcon) using an O'Hara Labcoat, 12'' disc, yielding 927 mg lozenges. The film-coated lozenges had a hardness of about 36.0-42.1 kp and a disintegration time of 1 minute 27 seconds to 1 minute 53 seconds. Formulation III was manufactured as 650 mg lozenges by premixing CARBOSIL®, part 2 of PROSOLV® and sulindac in PE bags. Then, ½ of PROSOLV® Part 1 and difluoromethylornithine were added to the 8 quart v-blender along with the premix. The remaining ½ of PROSOLV® part 1 is used to rinse the PE bag and add to the v-blender. The mixture was blended for 10 minutes at about 25 rpm. The mixture was then removed from the blender and delumped through a Comill 039R screen, then returned to the v-blender for an additional 10 minutes of blending. Magnesium stearate, manually sieved through a 30 mesh (ie, 590 μm) screen, was then added to the v-blender by hand mixing and the mixture was blended for 3 minutes at approximately 25 rpm. The mixture was compressed into lozenges on a Key Model BBTS 10 bench. The resulting tablets were determined to have a disintegration time of about 51-57 seconds, a friability of 0.2607%-0.3373% at 4 minutes and a friability of 0.8988%-1.008% at 8 minutes, and a hardness of about 13 kp. The lozenges were then film coated with 2.913 wt% OPADRY® Yellow (Colorcon) using an O'Hara Labcoat, 12'' disc, yielding 669.5 mg lozenges. The film-coated lozenges had a hardness of about 36.0-42.1 kp and a disintegration time of 1 minute 27 seconds to 1 minute 53 seconds. The weight of this formulation was reduced from 900 mg to 650 mg and STARCH 1500® was replaced with PROSOLV® to increase tablet strength. However, capping was observed during the brittleness test as well as during the film encapsulation process. Formulation IV was manufactured as 700 mg lozenges using the same method as Formulation III. The resulting lozenges were determined to have a disintegration time of 1 minute 10 seconds to about 1 minute 34 seconds, a friability of 0.1424%-0.1567% at 4 minutes and a friability of 0.3186%-0.5166% at 8 minutes, and a hardness of about 20 kp. The lozenges were then film coated with 2.913% by weight of OPADRY® Yellow (Colorcon) using O'Hara Labcoat, 12" discs, yielding 721 mg lozenges. The film-coated lozenges had a disintegration time of 1 minute 43 seconds to 2 minutes 7 seconds. In this formulation, the amount of PROSOLV® was increased and the tabular weight was increased from 650 mg to 700 mg. Although no capping was observed during friability testing, three tablets did have capping during film coating.surface 1 : Difluoromethylornithine HCL and Formulations of Sulindac Fixed-Dose Combination Tablets I-IV . Formulation I Formulation II Formulation III Formulation IV components Unit weight (mg) % W/W Unit weight (mg) % W/W Unit weight (mg) % W/W Unit weight (mg) % W/W Difluoromethylornithine HCl monohydrate racemate 375 41.67 375 41.67 375 57.69 375 53.571 Sulindac 75 8.33 75 8.33 75 11.54 75 10.714 Silicified MCC (Part 1) 347.13 38.57 342.63 38.07 149.5 23.0 199.6 28.514 Silicified MCC (Part 2) 0 0 0 0 41.075 6.32 41.075 5.868 pregelatinized cornstarch 96.12 10.68 96.12 10.68 0 0 0 0 colloidal silica 2.25 0.25 2.25 0.25 1.625 1.625 1.625 0.232 Magnesium stearate 4.5 0.5 9 1 7.8 7.8 7.7 1.1 Uncoated Tablet Weight 900 100 900 100 650 100 700 100 OPADRY® Yellow 03B92557 27.0 19.5 21.0 Coated Tablet Weight 927.0 669.5 721.0 Tablet properties Formulation II Formulation IV compression force NR 85psi Hardness (kp) ar 28 ar 20 disintegration time ar30 seconds ar 1 minute 30 seconds Brittleness (4 minutes) (%) 0.08 0.16 Brittleness (8 minutes) (%) 0.17 0.52 (one capping tablet) surface 2 : Difluoromethylornithine HCL and Exemplary formulations of sulindac fixed dose combination lozenges. components Unit weight (mg) % (w/w) Difluoromethylornithine HCl monohydrate racemate 375.00 52.011 Sulindac 75.00 10.402 Silicified Microcrystalline Cellulose 237.87 32.992 colloidal silica 1.63 0.226 Magnesium stearate 10.50 1.456 Core Tablet Weight 700.00 OPADRY® Yellow 21.00 2.913 Weight of film-coated tablets 721.00 100 surface 3 : Exemplary tablet manufacturing parameters. variable 7107/2 R3bis 7107/2 R4 7107/3 7107/5 R2 7107/5 R3 mixer Turbula Turbula Turbula Turbula Turbula mixing time 70 cycles 70 cycles 70 cycles 70 cycles 70 cycles Magnesium stearate 1.50% 1.50% 1.50% 1.50% 1.50% press machine Korsch Korsch Korsch Ronchi Ronchi Tool Size Tool Cover Engraving Top Engraving Bottom Scoring 17.5x8 Chrome/RC02 414C Ripple Logo No 17.5x8 Chrome/RC02 414C Ripple Logo No 17x9 R6 Chrome Neutral Neutral Breakable 16.5x7 Chrome 4141 Logo breakable 16.5x7 Chrome 4141 Logo breakable compression force 37 or 30 kN 37 kN 30 kN 37 kN 25kN pre-compression force 2.1kN 2.5 kN 2.0kN 3.7 kN 2.5 kN Test Results fracture none none none none none to stick none none none none none Top Engraving Density qualified qualified qualified qualified qualified Bottom Engraving Density qualified qualified qualified qualified qualified hardness NA 12.80 kp 8.14 kp 18.46 kp 16.62 kp breaking capacity NA yes yes none none disintegration time NA 1 min 15" to 1 min 25" 40 seconds to 45 seconds 2'15" to 2'32" 1'39" to 1'53" Brittleness at 4 minutes NA 0.08% 0.17% 0.21% 0.37% Friability at 30 minutes NA 1.15% 1.19% 1.80% 2.85% Tablet cracked/broken NA none none none none surface 4 : for instance 1 Materials for the formulations described in . Material supplier Difluoromethylornithine HCl monohydrate Scino Pharm Sulindac ZACH Silicified Microcrystalline Cellulose (MCC) (PROSOLV®) NF EP Starch 1500 (partially pregelatinized cornstarch) Colorcon Limited Colloidal Silica (CARBOSIL®) IMCD France SAS Magnesium stearate Mallinkroot—Tyco OPADRY® Yellow Colorcon Limited equipment PK blending master V-shaped blender (1 quart and 8 quart) Quadro Comill Model 197S with 0.039'' Screen Key Model BBTS 10 Table Ingot Press O'Hara Labcoat 12'' disc, 0.8 mm nozzle example 2- R&D formulations IV Formulation IV was further tested from Example 1 to determine that parameters could be varied to prevent capping and sticking. The first parameters tested were compression force and pre-compression force was added at about 5-15% of compression force (Table 5). In order to evaluate the compression force and pre-compression for formulation IV 700 mg lozenges to achieve a hardness of about 20 kp, several tests were performed. In the first trial, Equipment C was used to manufacture the final blend of Formulation IV 700 mg lozenges (Table 9). The manufacturing method involves premixing CARBOSIL®, part 2 of PROSOLV®, and sulindac in PE bags. Then, ½ of PROSOLV® Part 1 and difluoromethylornithine were added to a 10 quart v-blender along with the premix. The remaining ½ of PROSOLV® part 1 was used to rinse the PE bag and add to the v-blender. The mixture was blended at about 7 rpm for 35 minutes. The mixture was then removed from the blender and ground through a Frewitt TC150 1.0 mm screen, then returned to the v-blender for another 35 minutes of blending. Magnesium stearate was then manually screened through a 500 µm sieve and added to a v-blender to obtain the final blend by hand mixing at 7 rpm for 10 minutes. The compression step was carried out on a Courtoy Modul P ingot press equipped with five 17.5x8 mm engraved and chromed punches. The parameters were set so as to obtain a hardness between 17.0 kp and 22.5 kp. It was found that in the absence of preload, capping was observed. However, using pre-compression increases stiffness and avoids capping (Table 10). In addition, tablets formed by pre-compression are more resistant to abrasion (ie, less brittle). Also, the 16.5x8 mm punch used in the Key BBTS 10 table ingot press in Example 1 seems to be more prone to wear.surface 5 : test recipe IV Of Compression parameters. initial setting 7107/01 set 3 7107/01 set 2 Punch shape 16.5x8 mm smooth 17.5x8 mm engraving 17.5x8 mm engraving compression force 85 psi 34kN 35 kN Preload none none Yes (3 kN) Hardness (kp) ar 20 ar 13 (*) ar 17 disintegration time ar 1 minute 30 seconds ar 1 minute 20 seconds ar 2 minutes Brittleness (4 min) (%) 0.16 0.07 0.03 Brittleness (8 min) (%) 0.52 (1 capping tablet) NA NA Brittleness (10 min) (%) NA 0.27 0.13 Brittleness (30 min) (%) NA 1.79 (1 capping lozenge) 0.54 (without capping tablets) Thickness (mm) ar 6.1 ar 5.5 ar 5.4 NA: not applied (*) maximum hardness achievable without pre-compression In a second experiment, the punch surface was varied to determine its effect on formulation IV lozenges (Table 11). Equipment B was used in this trial to make the final blend of Formulation IV 700 mg lozenges. The manufacturing method involves premixing CARBOSIL®, part 2 of PROSOLV®, and sulindac in PE bags. Then, ½ of PROSOLV® Part 1 and difluoromethylornithine were added to a 10 quart v-blender along with the premix. The remaining ½ of PROSOLV® part 1 was used to rinse the PE bag and add to the v-blender. The mixture was blended at about 30 cycles per minute for 8 minutes and 30 seconds. The mixture was then removed from the blender and crushed through a CMA 1.0 mm screen, then returned to the v-blender for another 8.5 minutes of blending. Magnesium stearate was then manually screened through a 500 μm sieve and added to a v-blender by hand mixing at 30 cycles per minute for 2 minutes and 20 seconds to obtain the final blend. The compression step was carried out on a Korsch XL100 ingot press equipped with two 17.5x8 mm engraved and anti-stick chromed punches. The preload is set at 5-10% of the main compression force of approximately 30 kN. Several different punch surfaces were also tested, including chrome, carbon, tungsten, and Teflon versus stainless steel. In some embodiments, Teflon can be used to reduce sticking. To avoid sticking, several additional variables were tested, and high constraints were imposed at the beginning of compression. Neither lubricated with 1.1% magnesium stearate nor increased the number of lubrications from 70 rotations to 140 rotations to prevent sticking (Table 11 and Table 12). However, increasing the ratio of magnesium stearate to 1.5% did prevent sticking (Table 12) and a slight drop in tablet hardness of about 20%, but still very low brittleness of less than 0.1% after 4 minutes. When using two types of punches equipped with different types of breakage lines (17×9 mm and 16.5×7 mm), the breakability results correspond to the punches tested. Therefore, magnesium stearate was increased to 1.5% to prevent sticking and pre-compression prevented formulation IV capping.surface 6 :test 1 and test 2 middle formulation IV The batch weight. components Unit weight (mg) Experiment 1 Weight (g) Experiment 2 Weight (g) Difluoromethylornithine HCl 375 1339.500 1340.000 Sulindac 75 268.100 268.027 Silicified MCC (Part 1) 199.6 712.800 712.000 Silicified MCC (Part 2) 41.075 146.700 146.648 colloidal silica 1.625 5.796 5.8043 Magnesium stearate 7.7 27.515 27.504 Tablet weight 700.0 2500.411 2499.983 surface 7 : preparation IV Of Changes in magnesium stearate. 1.1% Magnesium Stearate Formula 1.3% magnesium stearate formulation (*) 1.5% magnesium stearate formulation (*) components Unit weight (mg) w/w (%) Unit weight (mg) w/w (%) Unit weight (mg) w/w (%) Difluoromethylornithine HCl 375.000 53.571 374.227 53.461 373.457 53.351 Sulindac 75.000 10.714 74.851 10.693 74.704 10.672 Silicified MCC (Part 1) 199.598 28.514 199.192 28.456 198.793 28.399 Silicified MCC (Part 2) 41.075 5.868 40.992 5.856 40.908 5.844 colloidal silica 1.625 0.232 1.624 0.232 1.617 0.231 Magnesium stearate 7.700 1.100 9.100 1.300 10.500 1.500 Tablet weight 700.0 100.00 700.0 100.00 700.0 100.00 (*) Formulation obtained after dilution to increase the percentage of magnesium stearate. The API concentration was therefore slightly below target.surface 8 : formulation IV The coating. components Unit weight (mg) Batch weight (g) uncoated lozenges 700.00 600.00 OPADRY® Yellow 03B92557 21.00 53.995 purified water 154.00 395.99 Coated Tablet Weight 721.00 653.995 surface 9 : For R&D formulations IV Of equipment. Device A device B device C PK Blend Master V-Blender 1 Qt & 8 Qt Turbula T10A Blender 10L Container Servolift Blender 10L Container Quadro Comill 197S 0.039'' Screen CMA T1 Conical Mill 1.00mm Screen Frewitt TC150 Conical Grinder 1.00mm Screen 0.500mm filter screen 0.500mm filter screen Key BBTS 10 Table Ingot Press Korsch XL100 Ingot Press Courtoy Modul P Ingot Presses O'Hara Labcoat 12'' pan Mini Glatt coater surface 10 : Test pre-compression force vs formulation IV The impact of the first test parameters and results. compression parameters 7107/01 set 3 7107/01 set 5 7107/01 set 2 7107/01 set 4 speed (tpm) 50 50 50 50 Pre-pressure (kN) / main pressure% 0.11 / 0% 1.43 / 5% 3.25 / 10% 4.68 / 15% Compression force(kN) 33.58 32.23 34.07 33.03 Punch (quantity) 5 5 5 5 Punch shape 17.5x8 mm Engraving 17.5x8 mm Engraving 17.5x8 mm Engraving 17.5x8 mm Engraving Punch surface treatment Anti-stick chrome plating Anti-stick chrome plating Anti-stick chrome plating Anti-stick chrome plating result test sampling 7107/01 set 3 7107/01 set 5 7107/01 set 2 7107/01 set 4 Weight (mg) RSD (%) 20 lozenges 702.28 1.18 699.14 1.00 703.5 1.06 701.17 0.73 Hardness (kp) 10 lozenges 11.5 to 14.4 (average: 13.2) 15.2 to 17.9 (average: 16.6) 15.8 to 18.4 (average: 17.3) 17.0 to 18.7 (average: 17.9) Brittleness (%) 4 minutes 10 minutes 30 minutes According to Pharmacopoeia 0.07/no capping 0.27/no capping 1.79/ 1 capping 0.07/without top crack 0.20/without top crack 0.67/without top crack 0.03/without capping 0.13/without capping 0.54/without capping 0.08/without capping 0.19/without capping 0.59/without capping Disintegration time (minutes) 3 lozenges 1 minute 08 seconds to 1 minute 40 seconds 1 minute 39 seconds to 2 minutes 17 seconds 1 minute 51 seconds to 2 minutes 11 seconds 1 minute 41 seconds to 1 minute 57 seconds Thickness (mm) 10 lozenges 5.4 to 5.6 5.4 to 5.5 5.4 to 5.5 5.4 to 5.5 to stick partial adhesion partial adhesion partial adhesion partial adhesion surface 11 : Test punch surface against formulation IV The influence of the second test parameters and results. final blend 7107/02 set 2 7107/02 set 5 7107/02 set 6 7107/02 set 7 7107/02 set 8 Ratio of magnesium stearate (%) 1.1 1.1 1.1 1.1 1.1 Final Blend (Spin) 140 140 140 140 140 compression parameters speed (tpm) 40 40 40 40 40 Preload(kN) 2.5 2.2 2.2 2.1 2.1 Compression force(kN) 30 30 30 30 30 Punch (quantity) 2 2 2 2 2 Punch shape 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving Punch surface treatment Anti-adhesion chrome RC-02 Anti-adhesion with Carbon RB-01 Anti-sticking with Tungsten RD-03 Anti-sticking with Teflon RF-03 Steel (without anti-stick coating) result test sampling 7107/02 set 2 7107/02 set 5 7107/02 set 6 7107/02 set 7 7107/02 set 8 Weight (mg) / RSD (%) 20 lozenges 697.12 / 0.38 NA NA NA NA Hardness (kp) 5 lozenges 15.4 to 16.3 NA NA NA NA Brittleness (%) 4 minutes 10 minutes 30 minutes According to Pharmacopoeia 0.02/without capping 0.04/without capping 0.69/without capping NA NA NA NA Disintegration time (minutes) 3 lozenges 0 minute 58 seconds to 1 minute 00 seconds NA NA NA NA Thickness (mm) 10 lozenges 5.5 to 5.5 NA NA NA NA to stick 10 lozenges partial adhesion partial adhesion partial adhesion very slightly sticky partial adhesion surface 12 : Test final blend duration and magnesium stearate for formulation IV The influence of the second test parameters and results. 7107/02 set 1 7107/02 set 2 7107/02 set 3 7107/02 set 4 7107/02 set 10 final blend Ratio of magnesium stearate (%) 1.1 1.1 1.5 1.5 1.3 Final mixing duration (rotation) 70 140 70 70 140 compression parameters speed (tpm) 40 40 40 40 40 Preload(kN) 3.5 2.5 2.1 2.5 2.2 Compression force(kN) ＞＞30 30 30 37 37 Punch (quantity) 2 2 2 2 2 Punch shape 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving 17.5x8 mm engraving Punch surface treatment Anti-stick chrome plating Anti-stick chrome plating Anti-stick chrome plating Anti-stick chrome plating Anti-stick chrome plating result test sampling Weight (mg) / RSD (%) 20 lozenges 704.01 (*) / 0.23 697.12 / 0.38 695.19 / 0.38 702.61 / 0.39 703.24 / 0.29 Hardness (kp) 5 lozenges 17.3 to 17.9 15.4 to 16.3 12.4 to 13.4 11.9 to 14.1 13.4 to 14.7 Brittleness (%) 4 minutes 10 minutes 30 minutes According to Pharmacopoeia NA NA NA 0.02/without capping 0.04/without capping 0.69/without capping 0.03/without top crack 0.15/without top crack 1.01/without top crack 0.08/without top crack 0.11/without top crack 1.15/without top crack 0.05/without capping 0.19/without capping 1.02/without capping Disintegration time (minutes) 3 lozenges 1 minute 15 seconds to 1 minute 20 seconds 0 minute 58 seconds to 1 minute 00 seconds 1 minute 00 seconds to 1 minute 10 seconds 1 minute 15 seconds to 1 minute 25 seconds 1 minute 30 seconds to 1 minute 45 seconds Thickness (mm) 10 lozenges 5.3 to 5.4 5.5 to 5.5 5.5 to 5.5 5.5 to 5.5 5.5 to 5.6 to stick 10 lozenges Less sticking, clean some lower punches Adhesion reduction The pole sticks slightly to the upper punch. Not sticking to the lower punch Not adhered but tends to split during hardness testing Slightly sticks to the upper punch (*) on 10 lozengessurface 13 : Test compression parameters against formulations IV The impact of the test parameters and results. 7107/03 set 1 7107/05 set 1 7107/05 set 2 7107/05 set 3 final blend Ratio of magnesium stearate (%) 1.5 1.5 1.5 1.5 compression parameters speed (tpm) 40 40 40 40 Preload(kN) 2.0 5.0 3.7 2.5 Compression force(kN) 30 twenty four 37 25 Punch (quantity) 2 2 2 2 Punch shape 17x9R6mm breakable 16.5x7mm breakable 16.5x7mm breakable 16.5x7mm breakable Punch surface treatment Anti-stick chrome Anti-stick chrome Anti-stick chrome Anti-stick chrome result test sampling 7107/03 set 1 7107/05 set 1 7107/05 set 2 7107/05 set 3 Weight (mg) / RSD (%) 20 lozenges 700.20 (*) / 0.49 705.29 / 0.59 709.62 / 0.64 700.08 / 0.54 Rupture test RSD (%) above 1/2 30 lozenges 0.97 NA 3.19 2.91 Hardness (kp) 5 lozenges 7.6 to 8.8 (**) 18.6 to 19.7 17.3 to 19.3 16.1 to 16.9 Brittleness (%) 4 minutes 10 minutes 30 minutes According to Pharmacopoeia 0.17/without capping 0.32/without capping 1.19/without capping 0.12/without top crack 0.47/without top crack 1.52/without top crack 0.21/without top crack 0.51/without top crack 1.80/without top crack 0.37/without top crack 1.04/without top crack 2.85/without top crack Disintegration time (minutes) 3 lozenges 0 minutes 40 seconds to 0 minutes 45 seconds 1 minute 38 seconds to 1 minute 43 seconds 2 minutes 15 seconds to 2 minutes 32 seconds 1 minute 39 seconds to 1 minute 53 seconds Thickness (mm) 10 lozenges 5.3 to 5.3 6.6 to 6.7 6.5 to 6.7 6.6 to 6.7 to stick 10 lozenges no adhesion no adhesion no adhesion no adhesion (*) on 30 lozenges (**) on 10 lozenges NA: Not applied The stability of Formulation IV combination lozenges, difluoromethylornithine single lozenges and sulindac single lozenges was tested. Stability analysis of formulation IV lozenges was performed at 6 months using the Karl Fischer titration method to determine the water content (Figure 1). In Figure 1 , it is shown that combination tablets of Formulation IV have lower water absorption over six months compared to difluoromethylornithine single tablets. Water can affect drug potency and drug dissolution; for example water can increase drug degradation rate by hydrolysis (Gerhardt, 2009). Thus, in some embodiments, the combination lozenges provided herein are more stable than either or both of the single active agent lozenges. Finally, the dissolution profile of Formulation IV was also tested. Dissolution studies were performed in 50 mM sodium phosphate buffer medium at 7.2 pH using a paddle stirring element at 75 rpm (USP <711> Dissolution Apparatus II (Paddles)) (Figure 2A-2B). Validation method for level II of dissolved difluoromethylornithine and sulindac. No mutual interference was observed between the active pharmaceutical ingredients difluoromethylornithine and sulindac themselves and the dissolution medium, phosphate buffer solution or excipients. Surprisingly, it was observed that fixed dose combinations of Formulation IV had overlapping in vitro dissolution profiles compared to single agent lozenges.example 3- Pharmaceutical Excipients and Coating Compatibility A non-cGMP pharmaceutical excipient compatibility study was performed on difluoromethylornithine HCl/sulindac combination lozenges. A series of samples were used to evaluate appearance, HPLC analysis and XRPD properties. Tests include PVP, HPMC, lactose, EXPLOTAB^tm , Ac-Di-Sol®, PROSOLV®, STARCH 1500® and OPADRY® Yellow excipients. Samples prepared for excipient compatibility except difluoromethylornithine HCl:sulindac formulation was 5:1 and difluoromethylornithine HCl:sulindac:H₂ Formulation O is about 6:1:0.3, which is a 1:1 physical mixture of API and excipients. The total mass of most samples was about 750 mg. Preparation involved weighing components into 20cc scintillation vials, sealing and vortexing for approximately 30 seconds. Samples were then stored in a 40°C/75% RH stability chamber for four weeks. The caps on the vials were tightened loosely, and the vials were stored in a chamber protected from light. Shape observations were made by visual inspection of vials prepared for HPLC analysis. Excipient compatibility samples were extracted with buffer containing 50% acetonitrile (50 mM phosphate buffer pH 2.55). Samples containing only sulindac were extracted by weighing out the sample portion (approximately 150 mg) and pre-determined volumes so that the final concentrations of difluoromethylornithine and sulindac were 9.5 mg/mL and 0.1 mg/mL, respectively to prepare. The remainder of the compatibility samples were prepared by quantitative transfer using predetermined volumes of extraction solvent such that the final concentrations of difluoromethylornithine and sulindac were about the same as above. Excipient compatibility samples were analyzed using a method capable of detecting the active agent, difluoromethylornithine and sulindac (Figure 4A). The method employs gradient reversed-phase HPLC with ultraviolet (UV) detection at 195 nm. XRPD analysis was performed on a Bruker AXS D8 Advance system with Bragg-Brentano configuration using CuKα radiation. Samples were analyzed at room temperature using the following parameters: 40 kV; 40 mA; 1° divergence; and anti-scatter slit; measurement method in continuous mode, 2 - 40° 2Θ, 0.05° gradient, and 1 sec/step time . Samples between 3 mg and 25 mg were analyzed using the rotating, top-filled steel sample holder in the nine-position autosampler accessory. Calibrate the system using traceable standards. The results are shown in Figures 4B-4C. Difluoromethylornithine HCl with PVP K30 started to exhibit wetness in the 2 week sample and became liquid after 4 weeks. Sulindac with PVPK30 showed sample adhesion after 2 weeks and continued after 4 weeks. The PVPK30 vehicle only started to exhibit moisture in the 2 week sample and became liquid after 4 weeks. The same phenomenon was observed for the difluoromethylornithine HCl sample but not for the sulindac sample. The HPLC analysis results for most of the samples tested did not show a unique trend (increase or decrease) over the different time points. Although several samples had unusually low analytical values, analytical levels showed more increasing trends or remained relatively constant over the 4 week period. The sulindac/difluoromethylornithine ProSolv SMCC90 sample was observed to have the highest variation in analytical results. The analytical value at the 4 week time point was 10.0% higher than the initial analytical result. This variation can be attributed to method (not validated) and sample consistency at different time points. Although the acceptable random analytical error for the validation method is 2%, the variability of this method is unknown. With the exception of some samples, the analytical values for each of the samples tested over the different time points were within the normally acceptable 2% random error of the analytical method. There were no unique trends for API, difluoromethylornithine and sulindac under the stress conditions tested. The results of this study indicated that the API (difluoromethylornithine HCl/sulindac) were both compatible with the potential excipients. Pharmaceutical excipient compatibility studies were performed by XRPD analysis to determine the crystallinity of the API with potential formulation excipients for the difluoromethylornithine HCl/sulindac combination product. XRPD results showed no interaction between API and excipients after four weeks at 40°C/75% RH. The indicated APIs (difluoromethylornithine HCl/sulindac) were all compatible with the potential excipients. Coating tests were performed on tablets to determine the effect on stability at 1 and 3 months of moisture content at 25°C/60% RH or 40°C/75% RH. Coatings include OPADRY® Yellow (Colorcon, 03B92557), OPADRY® White (Colorcon Y-1-7000), OPADRY® II White (Colorcon 85F18422) and OPADRY® Clear (Colorcon YS-3 -7413). Color visual inspection was taken to assess the overall color difference or DE between the stabilized lozenges and the original coated lozenges. Tablet color was tested using a Datacolor Spectraflash 600 Series Spectrophotometer. Data were analyzed using the Commission Internationale de l'Eclairage (CIE) L* a* b* system. In the L* a* b* system, colors are expressed as coordinates in three-dimensional space. Lightness and darkness are plotted on the L* axis, where L=100 represents pure white and L=0 represents pure black. The a* and b* axes represent two complementary color pairs of red/green and blue/yellow, respectively. By drawing colors in geometric shapes, the difference between two colors (total color difference = E*) can be determined by calculating the distance between two points using the following equation. DE* = [(L*1 - L*2)2 + (a*1 - a*2)2 + (b*1 - b*2)2]1/2 Each tablet was analyzed at each weight gain of each coating formulation using Datacolor. The closer the DE value is to zero, the closer the tested tablet color is to the color standard (initial sample). The Colorcon standard spectrum for the white coating (passed QC test) will have a DE value of less than 1.5. All stability samples with white film coats exceeded 1.5 DE and therefore would fail the Colorcon standard QC test (Table 14). Clear coated lozenges were also well above the value of 1.5.surface 14 : In stable coated tablets DE value. 3% wg Y-1-7000 (white) 4% wg Y-1-7000 (white) 3% wg 85F18422 (white) 4% wg 85F18422 (white) 3% wg 03B92557 (yellow) 4% wg 03B92557 (yellow) 3% wg YS-3-7413 (clear) 1 month 25/60 1.81 1.64 2.56 2.8 0.27 0.32 1.15 3 months 25/60 1.97 1.94 2.96 2.31 0.35 0.22 1.1 1 mo 40/75 1.91 2.47 3.58 2.39 0.3 0.29 4.29 3 months 40/75 2.71 2.66 2.72 3.31 0.64 0.58 7.6 The best DE results were found for the tablets coated with the yellow formulation. The DE value is much lower than 1.5. A DE value (total color difference) of 1 or lower is considered imperceptible to the human eye. Typical internal specifications for Colorcon for yellow coating tend to be a DE value of 2.5-3. Therefore, OPADRY® Yellow is used to coat combination lozenges.example 4- Fixed co-formulation of difluoromethylornithine / Bioequivalence Study of Sulindac A pilot study was performed to compare co-formulated lozenges containing difluoromethylornithine/sulindac after oral administration with those administered alone or co-administered with difluoromethylornithine/sulindac in normal healthy individuals under fasting conditions. Pharmacokinetic parameters of difluoromethylornithine, sulindac sulindac sulfide, and sulindac sulfide in plasma compared to individual lozenges of ornithine or sulindac. The secondary objective of this study was to determine the safety and tolerability of the difluoromethylornithine/sulindac co-formulated lozenges compared to administration of the individual formulations alone or co-administered in normal healthy individuals. The study included twelve individuals, male or female, at least 18 years of age but no older than 60 years of age. The main inclusion criteria are: light smoker, never smoker or former smoker; body mass index (BMI) ≥18.50 kg/m² And <30.00 kg/m² ; no clinically significant abnormalities were found in the 12-lead ECG performed (the subject must be in the supine position for 10 minutes prior to the ECG, and the ECG was taken before all requested blood draws); the female subject tested negative for pregnancy; and based on medical history, comprehensive Physical examination (including vital signs) and laboratory tests (general biochemistry, hematology and urinalysis) were healthy. Individuals were treated in four treatment groups consisting of: • Treatment 1: Co-formulate a single 750/150 mg dose of difluoromethylornithine 375 mg/sulindac 75 mg lozenges (2 x 375/75 mg lozenges) • Treatment 2: Single 750 mg dose of difluoromethylornithine 250 mg lozenges (3 x 250 mg lozenges) • Treatment 3: Single 150 mg dose of sulindac 150 mg lozenge (1 x 150 mg lozenge) • Treatment 4: Concomitant administration of a single 150 mg dose of sulindac 150 mg lozenges (1 x 150 mg lozenges) and a single 750 mg dose of difluoromethylornithine 250 mg lozenges (3 x 250 mg lozenges) mg dose Individuals were assigned to 4 different treatments over a 28-day period. A single oral dose to the assigned treatment was administered under fasted conditions during each study period. Treatment doses were separated by a wash-out of 7 calendar days. A total of 120 blood samples were collected for each individual at 80 time instants. The first blood sample was collected before drug administration, while other blood samples were collected after drug administration 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, Collect after 16, 24, 36 and 48 hours. Analytes were measured by HPLC with MS/MS detection. The analytical range is 35.0 ng/mL to 35000.0 ng/mL for difluoromethylornithine, 30.0 ng/mL to 15000.0 ng/mL for sulindac, and 10.0 ng/mL to 8000.0 ng for sulindac and sulindac sulfide /mL. Safety was assessed by assessing adverse events (AEs), standard laboratory evaluations, vital signs, and ECG.Mathematical Model and Statistical Method of Pharmacokinetic Parameters : The main absorption and distribution parameters were calculated using non-compartmental methods with log-linear terminal assumptions. The trapezoidal rule was used to estimate the area under the curve. The final assessment is based on maximizing the coefficient of determination. The pharmacokinetic parameter of this test is C_max , T_max 、AUC_0-T 、AUC_0-∞ 、AUC_0-T/∞ , lambda_Z and T_half . Statistical analysis is based on a parametric ANOVA model of pharmacokinetic parameters; for C_max 、AUC_0-T and AUC_0-∞ The 90% confidence interval on both sides of the ratio of the geometric method is based on the ln transformation data; T_max Converted by sort. The ANOVA model used fixed factors of order, period, and treatment; random factors were individuals nested within order. Pharmacokinetic parameters include C_max (maximum observed plasma concentration); T_max (time of maximum observed plasma concentration, if it occurs at more than one time point, then T_max defined as the first time point with this value); T_LQC (time to last observed quantifiable plasma concentration); AUC_0-T (from 0 to T using the linear trapezoidal method_LQC Calculated cumulative area under the plasma concentration-time curve); AUC_0-∞ (The area under the plasma concentration-time curve approaches infinite, calculated as AUC_0-T + C_LQC /λz, where C_LQC for time T_LQC Estimated concentration below); AUC_0-T/∞ (AUC_0-T Relative to AUC_0-∞ relative percentage); T_LIN (the time point at the beginning of the log-linear elimination phase); λz (the apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log-concentration versus time curve); and T_half (Final elimination half-life, calculated as ln(2)/λz).surface 15 : Pharmacokinetic parameters of difluoromethylornithine parameter Treatment -1 (n=12) Treatment -2 (n=12) Treatment -4 (n=12) average value CV (%) average value CV (%) average value CV (%) C _max (ng/mL) 10643.8 (21.6) 10234.6 (19.9) 10012.8 (25.5) ln (C _max ) 9.2525 (2.2) 9.2134 (2.3) 9.1822 (2.8) T _max ( hours )* 3.25 (2.00-6.00) 3.50 (2.00-5.00) 4.50 (2.50-5.00) AUC _0-T (ng h/mL) 71459.8 (20.4) 68962.3 (20.2) 69914.9 (18.3) ln (AUC _0-T ) 11.1562 (1.9) 11.1229 (1.8) 11.1407 (1.6) AUC _0-∞ (ng h/mL) 71839.3 (20.3) 69301.2 (20.0) 70326.0 (18.1) ln (AUC _0-∞ ) 11.1619 (1.9) 11.1281 (1.8) 11.1468 (1.6) AUC _0-T/∞ (%) 99.44 (0.3) 99.48 (0.2) 99.39 (0.3) λ _Z ( hour ^-1 ) 0.1453 (25.0) 0.1642 (21.5) 0.1630 (26.3) T _half ( hour ) 5.07 (27.3) 4.43 (24.9) 4.65 (39.0) * Median (range)surface 16 : Pharmacokinetic parameters of sulindac parameter Treatment -1 (n=12)** Treatment -3 (n=12)** Treatment - 4 (n=12)*** average value CV (%) average value CV (%) average value CV (%) C _max (ng/mL) 4553.4 (31.6) 5236.1 (39.2) 5188.5 (42.9) ln (C _max ) 8.3788 (3.7) 8.4946 (4.7) 8.4562 (5.7) T _max (hours)* 1.54 (0.75-5.00) 1.50 (1.00-2.50) 1.50 (0.75-5.00) AUC _0-T (ng h/mL) 11268.3 (32.2) 11569.7 (31.4) 11340.8 (43.9) ln (AUC _0-T ) 9.2823 (3.5) 9.3114 (3.4) 9.2621 (4.2) AUC _0-∞ (ng h/mL) 11579.4 (39.9) 12687.8 (34.9) 12023.7 (49.3) ln (AUC _0-∞ ) 9.2896 (4.2) 9.3924 (3.9) 9.3019 (4.8) AUC _0-T/∞ (%) 96.73 (4.9) 98.14 (1.2) 97.58 (1.6) λ _Z (hour ^-1 ) 0.2810 (48.0) 0.3408 (45.9) 0.2034 (58.0) T _half (hour) 4.97 (142.9) 2.88 (83.5) 4.61 (55.3) * Median (range) ** for AUC_0-∞ , lambda_Z and T_half n=7 *** for AUC_0-∞ , lambda_Z and T_half n=8Guidelines for Bioequivalence : Statistical inference of difluoromethylornithine based on the bioequivalence approach, using the ratio of geometric LSmeans, where the parameter C is transformed for ln_max 、AUC_0-T and AUC_0-∞ The corresponding 90% confidence intervals for the index calculations of the differences between Treatment 1 vs. Treatment 2, Treatment 2 vs. Treatment 4, and Treatment 1 vs. Treatment 4 were compared with the 80.00% to 125.00% range. Statistical inference of sulindac was based on the bioequivalence method using ratios of geometric LSmeans where the parameter C was transformed for ln_max 、AUC_0-T and AUC_0-∞ The corresponding 90% confidence intervals calculated for the difference indices between Treatment 1 versus Treatment 3, Treatment 3 versus Treatment 4, and Treatment 1 versus Treatment 4 were compared with the range 80.00% to 125.00%. The same criteria were applied for sulindac sulfide and sulindac sulfide, and the results presented supportive evidence for comparable therapeutic results.safety results : A total of 12 subjects entered the study, and all subjects received 4 treatments under the study. No serious adverse events (SAEs) and deaths were reported by any individual participating in this study. No subjects were withdrawn by investigators for safety reasons. A total of 4 treatment-emergent adverse events (TEAEs) were reported by 4 (33%) of the 12 individuals participating in the study. Of these events, 2 occurred after treatment 1 dosing, 1 occurred after treatment 3 dosing and the remaining one occurred after treatment 4 dosing. Subjects dosed with Treatment 2 did not report any TEAEs. Half of the TEAEs experienced during the study were considered related to drug administration. TEAEs in this study had a low incidence; 1 subject (8%) per treatment group experienced a TEAE. Dry mouth was reported after Treatment 4 administration, upper respiratory tract infection was reported after Treatment 3 administration and vascular puncture site abrasions and headache were each reported after Treatment 1 administration. The incidence of TEAEs was the same for subjects dosed with Treatment 3 and Treatment 4 (8%), and slightly lower than the incidence of TEAEs reported for subjects dosed with Treatment 1 (17%). Drug-related TEAEs were reported to have the same incidence as subjects dosed with Treatment 1 and Treatment 4 (8%), whereas subjects dosed with Treatment 3 experienced no drug-related TEAEs. TEAEs experienced during the study were considered mild (3/4, 75%) and moderate (1/4, 25%) in intensity. None of the subjects experienced serious TEAEs during the study. All abnormal clinical laboratory values were more or less above or below their reference ranges, and none were considered clinically significant by the investigator. In addition, there were no clinically significant abnormalities in the vital signs and ECG of the subjects in this study. All physical examinations were judged to be normal. Overall, the drugs tested were generally safe and were well tolerated by the individuals included in this study.processing 1 with processing 2 Comparison between difluoromethylornithine : Pharmacokinetic results show the C of difluoromethylornithine_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratios and corresponding 90% confidence intervals are included in the range of 80.00% to 125.00%. The results of this comparison indicate that Treatment 1 and Treatment 2 met the bioequivalence criteria when administered under fasting conditions, and exhibited DFM bioavailability in the DFM/Sulindac-containing regimen. Comparability between co-formulated lozenges and lozenges containing only difluoromethylornithine.surface 17 : processing 1 relative to processing 2 Summary of statistical analysis of difluoromethylornithine in parameter Intra-individual CV (%) Geometry LSMEANS* Ratio (%) 90% Confidence Limit (%) Treatment -1 (n=12) Treatment -2 (n=12) lower limit upper limit _Cmax 16.8 10430.9 10030.8 103.99 92.42 117.01 AUC0 _-T 13.5 69998.7 67701.4 103.39 94.03 113.69 AUC _0-∞ 13.4 70395.4 68056.2 103.44 94.17 113.61 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mLprocessing 2 with processing 4 Comparison between difluoromethylornithine : Pharmacokinetic results show the C of difluoromethylornithine_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratios and corresponding 90% confidence intervals are included in the range of 80.00% to 125.00%. The results of this comparison indicate that when administered under fasted conditions, Treatment 2 and Treatment 4 met the bioequivalence criteria and demonstrated that individual lozenges co-administered sulindac and difluoromethylornithine did not affect individual administration Bioavailability of difluoromethylornithine.surface 18 : processing 2 relative to processing 4 Summary of statistical analysis of difluoromethylornithine in parameter Intra-individual CV (%) Geometry LSMEANS* ratio(%) 90% Confidence Limit (%) Treatment -2 (n=12) Treatment -4 (n=12) lower limit upper limit _Cmax 16.8 10030.8 9722.7 103.17 91.69 116.09 AUC0 _-T 13.5 67701.4 68916.4 98.24 89.34 108.02 AUC _0-∞ 13.4 68056.2 69338.0 98.15 89.36 107.81 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mLprocessing 1 with processing 4 Comparison between difluoromethylornithine : Pharmacokinetic results show the C of difluoromethylornithine_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratios and corresponding 90% confidence intervals are included in the range of 80.00% to 125.00%. The results of this comparison indicate that Treatment 1 and Treatment 4 meet the bioequivalence criteria when administered under fasting conditions, and demonstrate the same effect for co-formulated lozenges containing difluoromethylornithine/sulindac as for co-administration containing The bioavailability of difluoromethylornithine was similar for individual lozenges of either difluoromethylornithine or sulindac.surface 19 : processing 1 relative to processing 4 Summary of statistical analysis of difluoromethylornithine in parameter Intra-individual CV (%) Geometry LSMEANS* ratio(%) 90% Confidence Limit (%) Treatment -1 (n=12) Treatment -4 (n=12) lower limit upper limit _Cmax 16.8 10030.8 9722.7 107.28 95.35 120.72 AUC0 _-T 13.5 67701.4 68916.4 101.57 92.37 111.68 AUC _0-∞ 13.4 68056.2 69338.0 101.53 92.43 111.51 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mLprocessing 1 with processing 3 Comparison Between Sulindac : Pharmacokinetic results show that the C of sulindac_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval (90CI) are not all included in the range of 80.00% to 125.00%. C_max The lower limit of the 90CI is lower than the 80.00% limit. Since the ratios ranged from 80.00% to 125.00% of all PK parameters, intra-individual variability could account for C_max The case where the lower limit exceeds the range of BE. The results obtained for this comparison demonstrate that the sample size used in this pilot test was insufficient to demonstrate equivalence of sulindac bioavailability for co-formulated lozenges and sulindac alone.surface 20 : processing 1 relative to processing 3 Summary of Statistical Analysis of Sulindac parameter Intra-individual CV (%) Geometry LSMEANS* Ratio (%) 90% Confidence Limit (%) Treatment -1 (n=12)** Treatment -3 (n=12)** lower limit upper limit _Cmax 24.6 4353.6 4888.5 89.06 75.04 105.69 AUC0 _-T 11.9 10746.4 11063.6 97.13 89.34 105.60 AUC _0-∞ 13.6 12029.4 12743.6 94.40 82.27 108.30 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mL **for AUC_0-∞ , n=7 Based on these data, the within-individual change incorporating variability between all comparisons, C_max is about 24.6%, and AUC_0-T is about 12%. Statistically, the estimated number of individuals meeting the 80.00% to 125.00% bioequivalence range (statistical prior power of at least 80%) for Future pivotal studies will be approximately 54. The inclusion of 60 individuals should be sufficient to account for the possibility of under- and variation in estimated CV within individuals.processing 3 with processing 4 Comparison Between Sulindac : Pharmacokinetic results show that the C of sulindac_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratios and corresponding 90% confidence intervals are included in the range of 80.00% to 125.00%. The results of this comparison indicate that Treatment 3 and Treatment 4 meet the bioequivalence criteria when administered under fasted conditions and demonstrate that co-administration of individual lozenges containing difluoromethylornithine or sulindac does not affect individual administration Bioavailability of sulindac over time.surface twenty one : processing 3 relative to processing 4 Summary of Statistical Analysis of Sulindac parameter Intra-individual CV (%) Geometry LSMEANS* Ratio (%) 90% Confidence Limit (%) Treatment -3 (n=12)** Treatment -4 (n=12)** lower limit upper limit _Cmax 24.6 4888.5 4704.2 103.92 87.56 123.32 AUC0 _-T 11.9 11063.6 10530.9 105.06 96.63 114.22 AUC _0-∞ 13.6 12743.6 11834.3 107.68 93.31 124.27 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mL **for AUC_0-∞ , n=7processing 1 with processing 4 Comparison Between Sulindac : Pharmacokinetic results show that the C of sulindac_max 、AUC_0-T and AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval (90CI) are not all included in the range of 80.00% to 125.00%. C_max The lower limit of the 90CI is lower than the 80.00% limit. Since the ratios ranged from 80.00% to 125.00% of all PK parameters, intra-individual variability could account for C_max The case where the lower limit exceeds the range of BE. The results obtained for this comparison demonstrated that the sample size used in this pilot study was insufficient to demonstrate the bioavailability of sulindac for co-formulated tablets and co-administered individual tablets containing difluoromethylornithine or sulindac bioequivalence.surface twenty two : processing 1 relative to processing 4 Summary of Statistical Analysis of Sulindac parameter Intra-individual CV (%) Geometry LSMEANS* Ratio (%) 90% Confidence Limit (%) Treatment -1 (n=12)** Treatment -4 (n=12)** lower limit upper limit _Cmax 24.6 4353.6 4704.2 92.55 77.98 109.83 AUC0 _-T 11.9 10746.4 10530.9 102.05 93.86 110.94 AUC _0-∞ 13.6 12029.4 11834.3 101.65 88.09 117.30 *C_max The unit is ng/mL and AUC_0-T and AUC_0-∞ The unit is ng h/mL **for AUC_0-∞ , n=8 Based on these data, the within-individual change incorporating variability between all comparisons, C_max is about 24.6%, and AUC_0-T is about 12%. Statistically, the number of individuals estimated to meet the 80.00% to 125.00% bioequivalence range (statistical prior power of at least 80%) for Future pivotal studies will be approximately 36. The inclusion of 40 individuals should be sufficient to account for the possibility of under- and variation in estimated CV within individuals.* * * All compositions and/or methods disclosed and claimed herein can be made and performed in accordance with the present invention without undue experimentation. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be clear to those skilled in the art that changes may be made in the methods and methods described herein without departing from the concept, spirit and scope of the invention in the step or sequence of steps. More specifically, it will be apparent that certain agents that are chemically and physiologically related may be substituted for those described herein while obtaining the same or similar results. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.references The following references are specifically incorporated herein by reference to the extent that they provide exemplary procedures or other details supplementary to those set forth herein. U.S. Patent 3,647,858 U.S. Patent 3,654,349 U.S. Patent 4,330,559 U.S. Patent 4,413,141 U.S. Patent 5,814,625 U.S. Patent 5,843,929 U.S. Patent 6,258,845 U.S. Patent 6,428,809 U.S. Patent 6,702,683 U.S. Patent 8,329,636 U.S. Patent 9,121,852 U.S. Patent Publication US2013/0217743 U.S. Patent Publication US2015/0301060 PCT Patent Publication WO2014/070767 PCT Patent Publication WO2015/195120 Albertset al. ,J. Cell. Biochem. Supp ., (22):18-23, 1995. AMA Drug Evaluations Annual, 1814-1815, 1994. Baileyet al. ,Cancer Prev Res (Phila) 3 , 35-47, 2010. Barryet al. ,J. Natl. Cancer Inst ., 98(20):1494-500, 2006. Bediet al., Cancer Res ., 55(9):1811-1816, 1995. Bellofernandezet al., Proc. Natl. Acad. Sci. USA, 90:7804-8, 1993. Childset al. ,Cell. Molec. Life Sci ., 60:1394-1406, 2003. Du Boiset al., Cancer Res. , 56:733-737, 1996. Erdmanet al., Carcinogenesis , 20:1709-13, 1999. European Pharmacopoeia, Strasbourg: Council of Europe, 8^{the th} Ed., 2014. Fultz and Gerner,Mol. Carcinog ., 34:10-8, 2002. Gerhardt,Pharmaceutical Processes, 13(1), 2009. Gerneret al. ,Cancer Epidemiol. Biomarkers Prev ., 3:325-330, 1994. Gerner, E.W. & Meyskens, F.L., Jr.,Nat Rev Cancer 4 , 781-92, 2004. Giardielloet al. ,Cancer Res ., (57):199-201, 1997. Hanifet al. ,Biochemical Pharmacology , (52):237-245, 1996. Hubneret al., Clin. Cancer Res ., 14(8):2303-9, 2008. Ignatenkoet al. ,Cancer Biol. ., 5(12):1658-64, 2006. Japanese Pharmacopoeia, Tokyo: Society of Japanese Pharmacopoeia, 16^{the th} Ed., 2011. Kingsnorthet al. ,Cancer Res., 43(9):4035-8, 1983. Ladenheimet al. ,Gastroenterology , 108:1083-1087, 1995. Lanzaet al. ,Arch. Intern. Med. , 155:1371-1377, 1995. Lee, Y.S. & Dutta, A.,Genes Dev 21, 1025-30, 2007. Lipkin,J. Cell Biochem. Suppl. , 28-29:144-7, 1997. Lippman,Nat. Clin. Pract. Oncol., 3(10):523, 2006. loveet al., J. Natl. Cancer Inst. ., 85:732-7, 1993. Luk and Baylin,N. Engl. J. Med ., 311(2):80-83, 1984. Lupulescu,Cancer Detect. ., 20(6):634-637, 1996. Maejimaet al ,Chemical Pharmacology Bulletin , 45(3): 518-524, 1997. Martinezet al., Proc. Natl. Acad. Sci. USA, 100:7859-64, 2003. McLarenet al. ,Cancer Prev. Res ., 1(7):514-21, 2008. Meyskenset al. ,Cancer Prev Res (Phila) 1 , 32-8, 2008. Meyskenset al. ,J. Natl. Cancer Inst ., 86(15):1122-1130, 1994. Meyskenset al., J. Natl. Cancer Inst. ., 90(16):1212-8, 1998. Muscatet al., Cancer , 74:1847-1854, 1994. Narisawaet al. ,Cancer Res ., 41(5):1954-1957, 1981. Nigroet al., Cancer Lett., (35):183-8, 1987. Nowelset al., Cancer. Biochem. Biophys. ,(8):257-63, 1986. Pegg,Biochem ., 234(2):249-262, 1986. Physician's Desk Reference, Medical Economics Data, Montville, N.J., 1745-1747, 1999 Piazzaet al. ,Cancer Res ., (55):311 3116, 1995. Piazzaet al. ,Cancer Res ., (57):2452-2459, 1997a. Piazzaet al., Cancer Res ., (57):2909-2915, 1997b. Pollard and Luckert,Cancer Res ., 49:6471-6473, 1989. Psaty and Potter,N. Engl. J. Med., 355(9):950-2, 2006. Raoet al. ,Cancer Res ., (55):1464-1472, 1995. Reddyet al. ,Cancer Res ., (50):2562-2568, 1990. Reddyet al. ,Cancer Res. , 47:5340-5346, 1987. Simoneauet al. ,Cancer Epidemiol Biomarkers Prev 17 , 292-9, 2008. Simoneauet al., J. Natl. Cancer Inst ., 93:57-9, 2001. Singh and Reddy,Annals. NY Acad. Sci. , (768):205-209, 1995. Singhet al. ,Carcinogenesis , (15):1317-1323, 1994. Strejanet al., Cell Immunol ., 84(1):171-184, 1984. Suet al. ,science , (256):668-670, 1992. Temperoet al. ,Cancer Res ., 49(21):5793-7, 1989. Thomas and Thomas,J. Cell Mol. Med ., 7:113-26, 2003. Thompsonet al., Cancer Res, ( 45):1170-3, 1985. Thompsonet al., J. Natl. Cancer Inst ., (87):125-1260, 1995. United States Pharmacopeia and National Formulary (USP 39-NF 34). Rockville, MD; 2015. Vander Heiden, M.G.Nat Rev Drug Discov 10 , 671-84, 2011. Vane and Botting,Adv Exp Med Biol ., 433:131-8, 1997. Wallace,Eur. J. Clin. Invest ., 30:1-3, 2000. Wanget al. ,Clin Cancer Res 17 , 2570-80, 2011. Weekset al., Proc. Nat'l Acad. Sci. USA, (79):6028-32, 1982. Zellet al., Cancer Prev. Res ., 2(3):209-12, 2009. Zhanget al. ,Genes Dev 26 , 461-73, 2012.

The following drawings form a part of this specification and are included to further illustrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. Figure 1 : Stability analysis of prototype batch 7107/04 of 700 mg lozenges of difluoromethylornithine HCl monohydrate (375 mg) and sulindac (75 mg). The lozenges have a 3% w/w coating. Samples were analyzed at time zero (T0) and at 6 months (T6) using the validated Karl Fischer titration method for determination of water content. Samples were stored in HDPE bottles with or without caps in proven stability chambers. Values represent the percentage of water for each tablet under the indicated conditions. Figures 2A - 2B : Results of dissolution analysis of coated tablet batches 7107/04 and 6A001 . Reference lozenges containing 250 mg difluoromethylornithine HCl monohydrate and commercially available 150 mg sulindac were used for comparison. Co-formulated lozenges contained 375 mg difluoromethylornithine HCl monohydrate with a 3% w/w coating and 75 mg sulindac. Figure 3 : A simplified flow chart depicting the manufacturing process of a lozenge containing difluoromethylornithine HCl monohydrate and sulindac. Figures 4A - 4C : (A) Representative HPLC chromatography of difluoromethylornithine HCl monohydrate and sulindac co-formulated tablets demonstrating the ability to measure selected impurities . (BC) X-ray powder diffraction (XRPD) patterns of difluoromethylornithine HCl monohydrate and sulindac active ingredients mixed with lozenge excipients at time zero, 2 weeks and 4 weeks. Lack of changes supports excipient compatibility and polymorph stability.

Claims (20)

A composition comprising a fixed dose combination in a single dosage unit of (a) about 375 mg of eflornithine hydrochloride monohydrate, and (b) about 75 mg of sulindac Acid (sulindac), wherein the composition further comprises magnesium stearate in an amount of about 1% by weight to about 1.5% by weight. The composition according to claim 1, wherein the difluoromethylornithine hydrochloride monohydrate is a racemic mixture of two enantiomers. The composition as claimed in item 2, wherein the amount of difluoromethylornithine hydrochloride monohydrate racemate is 375mg. The composition as claimed in item 1, wherein the amount of sulindac is 75mg. The composition according to claim 1, further comprising an excipient. The composition according to claim 5, wherein the excipient is starch, colloidal silicon dioxide or silicified microcrystalline cellulose. The composition according to claim 5, wherein the excipient is colloidal silicon dioxide. The composition according to claim 7, wherein the composition further comprises a second excipient. The composition according to claim 8, wherein the second excipient is silicified microcrystalline cellulose. The composition as claimed in item 1, wherein the amount of magnesium stearate is about 1.5% by weight. The composition according to claim 1, wherein the composition is in the form of capsules, lozenges, mini-tablets, granules, pellets, solutions, gels, creams, foams or patches. The composition according to claim 11, wherein the composition is in the form of lozenges. The composition according to claim 12, wherein the weight of the lozenge is about 675 mg to about 725 mg. The composition as claimed in item 13, wherein the weight of the tablet is about 700 mg. The composition according to claim 12, wherein the tablet further comprises a coating. The composition according to claim 15, wherein the coating comprises hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol and yellow iron oxide. The composition as claimed in item 15, wherein the coating amount is about 2% by weight to about 4% by weight. The composition as claimed in item 15, wherein the weight of the lozenge is about 700 mg to about 725 mg. The composition as claimed in item 18, wherein the weight of the lozenge is about 721 mg. A use of the composition according to any one of claims 1 to 19, which is used to prepare a medicament for preventing and/or treating familial adenomatous polyposis (FAP) in patients in need.