TW201726124A - 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 generally relates to the field of cancer biology and medicine. More specifically, it relates to a composition for preventing and treating cancerous tumors.

Cancer cells have the ability to recruit multiple pathways to meet their increased need for specific metabolites (Vander Heiden, 2011). Non-steroidal 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 cancer in a rat model of AOM treatment. The sulindac, a metabolite of NSAID sulindac, lacks COX inhibitory activity and induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b) and is found in several rodent models of carcinogenesis. Tumor development is inhibited (Thompson et al, 1995; Piazza et al, 1995, 1997a). Alpha-difluoromethylornithine (DFMO) is an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC) and results in intracellular concentration loss of putrescine and its derivatives, spermidine (Pegg , 1988). In experimental animal models, DFMO is a potent inhibitor of carcinogenesis, which is particularly active in preventing carcinogens in many organs from inducing epithelial cancers, including those in the colon (Weeks et al., 1982; Thompson et al. , 1985; Nowels et al., 1986; Nigro et al., 1987). The main obstacle to the transfer of cancer chemoprevention studies into clinical practice is the efficacy and toxicity of micropharmaceuticals that outweigh the benefits (Psaty and Potter, 2006; Lippman, 2006). For example, a long-term daily oral administration of D,L- α-difluoromethylornithine (DFMO, difluoromethylornithine) and sulindac polyamine inhibitory combination in colorectal adenoma (CRA) Significant efficacy in patients (Meyskens et al, 2008), however, treatment with moderate subclinical ototoxicity (McLaren et al, 2008) and a greater number of cardiovascular events in patients with high baseline cardiovascular risk (Zell et al., 2009) related. It has been recognized in the field of medicine and is described in U.S. Patent Nos. 6,428,809 and 6,702,683, in contrast to the application of a plurality of individual doses of two or more drugs at regular intervals, in the form of a unit dosage form. The convenience of more or more active pharmaceutical ingredients. Potential advantages for patients and clinicians include (1) minimizing or eliminating local and/or systemic side effects; (2) more effective treatment for complications; (3) improved multiple medications; and (4) Better patient compliance for overall disease management, which can result in lower costs due to fewer visits to physicians, reduced hospitalization, and improved patient health. Fixed-dose combinations of two or more formulations that are combined or co-formulated in a single dosage form are suitable for use in a multi-drug regimen that requires improved clinical effectiveness, enhanced patient compliance, and simplified administration. However, the development of pharmaceutical formulations for solid oral dosage forms is still complex for research and development standards and commercial manufacturing levels for single active pharmaceutical ingredient (API) formulations. For more than one API, additional concurrency factors are expected, including (1) drug-drug interactions, (2) drug-excipient interactions, (3) simultaneous release profiles, (4) differential release profiles, and (5) The blending uniformity of each drug component. In view of these obstacles, the development of fixed dose combinations with the same or similar release profiles as a single entity drug typically represents a considerable challenge. A fixed-dose combination of difluoromethylornithine and sulindac that overcomes some or all of these challenges will be quite effective in the effective treatment and/or prevention of a wide range of diseases or conditions, including familial adenomatous polyposis (FAP). The potential impact.

In one aspect, the invention provides a composition comprising a pharmaceutically effective amount of a difluoromethylornithine and a pharmaceutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) or a metabolite thereof in a fixed dose combination. 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, the difluoromethylornithine is a difluoromethylornithine hydrochloride monohydrate racemate. In some embodiments, the difluoromethylornithine hydrochloride monohydrate is a racemic mixture of its two enantiomers. In some embodiments, the difluoromethylornithine hydrochloride monohydrate is a substantially optically pure formulation. In some embodiments, the difluoromethylornithine hydrochloride monohydrate is L-difluoromethylornithine hydrochloride monohydrate or D-difluoromethylornithine hydrochloride monohydrate Things. In some embodiments, the difluoromethylornithine is an anhydrous free base difluoromethylornithine. In some embodiments, the difluoromethylornithine is present in an amount from about 10 mg to about 1000 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 250 mg to about 500 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 300 mg to about 450 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 350 mg to about 400 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 35% to about 60% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 40% to about 55% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 50% to about 55% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 52% to about 54% by weight. In some embodiments, the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from 52% to 54% by weight. In some embodiments, the difluoromethylornithine is present in an amount of about 375 mg. In some embodiments, the amount of the difluoromethylornithine hydrochloride monohydrate racemate is 375 mg. In some embodiments, sulindac is present in an amount from about 10 mg to about 1500 mg. In some embodiments, sulindac is present in an amount from about 50 mg to about 100 mg. In some embodiments, sulindac is present in an amount from about 70 mg to about 80 mg. In some embodiments, 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% by weight to about 20% by weight. In some embodiments, sulindac is present in an amount from about 8% by weight 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 from 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 formulation further comprises an excipient. In some embodiments, the excipient is starch, colloidal ceria or deuterated microcrystalline cellulose. In some embodiments, the excipient is colloidal ceria. In some embodiments, the formulation further comprises a second excipient. In some embodiments, the second excipient is deuterated 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 composition is in the form of a capsule, lozenge, micro-tablet, granule, pellet, solution, gel, cream, foam or patch. In some embodiments, the composition is in the form of a tablet, such as a single layer tablet. In some embodiments, the lozenge has a weight of from about 10 mg to about 2,500 mg. In some embodiments, the lozenge has a weight of from about 250 mg to about 1,500 mg. In some embodiments, the lozenge has a weight of from about 650 mg to about 1,000 mg. In some embodiments, the lozenge has a weight of from about 675 mg to about 725 mg. In some embodiments, the tablet has a weight of about 700 mg. In some embodiments, the weight of the capsule, minitablet, granule or pellet is from about 10 mg to about 2,500 mg. In some embodiments, the weight of the capsule, mini-tablet, granule or pellet is from about 250 mg to about 1,500 mg. In some embodiments, the weight of the capsule, minitablet, granule or pellet is from about 650 mg to about 1,000 mg. In some embodiments, the weight of the capsule, minitablet, granule or pellet is 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 reactive coating. In some embodiments, the coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP), phthalic acid Hydroxypropylmethylcellulose formate (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 or succinic acid hydroxypropyl methylcellulose (HPMCAS). In some embodiments, the coating masks the taste of difluoromethylornithine. In some embodiments, the coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow. In some embodiments, the amount of coating is from about 1% to about 5% by weight. In some embodiments, the amount of coating is from 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 amount of coating is about 21 mg. In some embodiments, the lozenge comprising the coating has a weight of from about 675 mg to about 750 mg. In some embodiments, the lozenge comprising the coating has a weight of 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, 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 and a medicinal agent provided herein A fixed dose combination of an effective amount of sulindac. In some embodiments, the method further comprises administering to the patient a second combination of a fixed dose combination comprising 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 is followed by a first administration at intervals of 1 second to 1 hour. In some embodiments, both the first and second compositions are formulated as tablets 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, gastric cancer, blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer, or esophageal cancer. In some embodiments, the colon cancer is a familial adenomatous polyposis. In some embodiments, the cancer is a neuroendocrine tumor. In some embodiments, the neuroendocrine tumor is a neuroblastoma. In some embodiments, the condition is a dermatological condition. In some embodiments, the skin condition is facial hirsutism. In some embodiments, the composition is administered orally, intra-arterially, intravenously, or topically. In some embodiments, the composition is administered orally. In some embodiments, the composition is 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, a method of preparing a lozenge comprising about 375 mg of difluoromethylornithine hydrochloride and about 75 mg of sulindac is provided, comprising: (a) premixed sulindac and fu Forming a first mixture; (b) mixing the first mixture with a second mixture comprising difluoromethylornithine and an excipient to form a blend; (c) sieving the blend to form a granule a blend; (d) adding a lubricant to the particulate blend to obtain a final blend; and (e) applying a compressive force to the final blend to form a tablet. In some embodiments, the method further comprises mixing the particulate 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 ceria and the second excipient is deuterated microcrystalline cellulose. In some embodiments, the excipient of the second mixture is deuterated microcrystalline cellulose. In some embodiments, the pre-mixing is carried out in a polyethylene coated container. In some embodiments, the mixing is performed in a diffusion blender. In some embodiments, the lubricant is magnesium stearate. In some embodiments, prior to step (d), 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 prior to step (e), wherein the blend is compressed with a force lower than the force of step (e) to pre-compact the blend In addition, the compressive force of step (e) is used to pre-compress the blend to form a tablet. In some embodiments, the pre-compression step prevents tablet capping. In some embodiments, the compressive force of the pre-compression step is applied from 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 from 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 from 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 tablet. In some embodiments, the coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow. Other objects, features, and advantages of the present invention will be apparent from the embodiments. It is to be understood that the various embodiments of the preferred embodiments of the invention, Only given by way of explanation.

The present application claims the benefit of U.S. Provisional Application No. 62/248,810, filed on Oct. 30, 2015, and U.S. Provisional Application No. 62/358,698, filed on The way is incorporated in this article. In several aspects, a composition is provided for a fixed dose combination (FDC) of difluoromethylornithine and sulindac. Methods of making the fixed dose combinations of the present invention are also provided that overcome the problems associated with current methods. Manufacturing methods have been designed to address the issues including drug-drug interactions, drug-excipient interactions, and blending uniformity of individual drug components. Thus, the fixed dose combination of the present invention can be used to minimize local and/or systemic side effects, provide more effective treatment, improve multiple administration, and provide better patient compliance.I. Familial adenomatous polyposis Excessive polyamine formation has been involved in the development of epithelial cancer, especially colorectal cancer. Polyamines are small, ubiquitous molecules involved in a variety of processes including, for example, transcription, RNA stabilization, and ion channel gating (Wallace, 2000). The first enzyme ornithine decarboxylase (ODC) in polyamine synthesis is critical for normal development and tissue repair in mammals but is downregulated in most adult tissues (Gerner and Meyskens, 2004). . Controlling multiple abnormalities in polyamine metabolism and delivery leads to increased levels of polyamines that promote tumorigenesis in several tissues (Thomas and Thomas, 2003). Familial adenomatous polyposis (FAP) is a syndrome associated with high risk of colon and other cancers. FAP is caused by colonic adenomatous polyposis (APC Mutation of tumor suppressor genes results in, and APC signaling displays ODC expression in mouse models that regulate human cells (Fultz and Gerner, 2002) and FAP (Erdman et al, 1999). Polyamine metabolism is up-regulated in the intestinal epithelial tissue of humans with FAP (Giardiello et al., 1997). Wild typeAPC Performance resulted in decreased ODC performance, while mutation of APC resulted in increased ODC performance. The APC-dependent regulatory mechanism of ODC involves E-box transcription factors, including transcriptional activatorsc-MYC Transcriptional 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 genes for optimal growth in most organisms and are down-regulated in non-proliferating and/or adult cells and tissues (Gerner and Meyskens, 2004). As reviewed elsewhere, polyamines affect specific cell phenotypes by partially affecting the pattern of gene expression (Childs et al., 2003). Familial adenomatous polyposis (FAP), a hereditary polyposis syndrome, is the result of germline mutations in the colon adenomatous polyposis (APC) tumor suppressor gene (Su et al., 1992). This variable-performing autosomal dominant line is associated with the development of hundreds of colon adenomas, which develop adenocarcinoma at the age of forty, 20 years earlier than the average age of diagnosis of incidental colon cancer (Bussey, 1990). In previous studies of individuals with symptoms of FAP, polyamine spermidine and spermine and their diamines were detected in normal colorectal biopsy when compared to normal family member controls. The level of precursor putrescine increased (Giardiello et al., 1997). The activity of the first and rate-limiting enzyme ornithine decarboxylase (ODC) in mammalian polyamine synthesis is also elevated in normal colonic mucosal biopsy from the surface of FAP patients (Giardiello et al., 1997; Luk And Baylin, 1984). These findings have received attention as polyamines are necessary for optimal cell proliferation (Pegg, 1986). In addition, the use of the enzyme-activated irreversible inhibitor DFMO to suppress ODC activity inhibits colon cancer in carcinogen-treated rodents (Kingsnorth et al., 1983; Tempero et al., 1989). A total of mutants with FAPAPC /Apc Genotype Min (multiple intestinal neoplasia) mice serve as a suitable experimental animal model for human FAP patients (Lipkin, 1997). Min mice develop more than 100 gastrointestinal adenomas/adenocarcinomas throughout the gastrointestinal tract over a 120-day life span, resulting in GI bleeding, occlusion, and death. Combination therapy with DFMO and sulindac is shown to be effective in reducing adenomas in these mice. See U.S. Patent No. 6,258,845 and Gerner and Meyskens, 2004, which is incorporated herein by reference.II. Difluoromethylornithine The term "difluoromethylornithine", when used in its own right and without context, means 2,5-diamine-2-(difluoromethyl)pentanoic acid in any form, including non-salt and salt forms. (eg, difluoromethylornithine HCl), anhydrous and hydrated forms of the non-salt and salt forms (eg, difluoromethylornithine hydrochloride monohydrate), solvates of the non-salt and salt forms, Its enantiomer (R andS Form, which can also be identified asd andl Form) and mixtures of such enantiomers (for example racemic mixtures). By "substantially optically pure formulation" is meant a formulation containing about 5% by weight or less of the first enantiomer of the opposite enantiomer. Specific forms of difluoromethylornithine include difluoromethylornithine hydrochloride monohydrate (ie, CAS ID: 96020-91-6; MW: 236.65), difluoromethyl ornithine hydrochloride Salt (also known as CAS ID: 68278-23-9; MW: 218.63) and anhydrous free base difluoromethylornithine (also known as CAS ID: 70052-12-9; MW: 182.17). A specific form of difluoromethylornithine is 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 synonymous terms of 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)pentanoic acid and 2,5-diamine-2-(difluoromethyl)pentanoic acid. Difluoromethylornithine is an irreversible inhibitor of enzyme 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 synergistic effects with other anti-tumor agents. Difluoromethylornithine display reduces APC-dependent intestinal tumorigenesis in mice (Erdman et al., 1999). Oral administration of difluoromethylornithine to humans daily 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 non-steroidal anti-inflammatory drugs (NSAID) sulindac have been reported to significantly reduce adenoma recurrence rates in individuals with colon adenomas when compared to placebo in randomized clinical trials (Meyskens) Et al., 2008). Difluoromethylornithine was initially synthesized by Centre de Recherche Merrell, Strasbourg. Currently approved by the U.S. Food and Drug Administration (FDA) includes: ̇ African sleep disease. High-dose systemic IV dosage form, not for sale (Sanofi/WHO) ̇ hirsutism (excessive hair growth induced by male hormones) topical dosage form Although the FDA has not approved an oral formulation of difluoromethylornithine, it has been approved for topical and topical Injection form. Vaniqa® is a cream containing 15% w/w difluoromethylornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous difluoromethyl bird in the cream for topical administration, respectively. Amine (EU), 13.9% w/w anhydrous difluoromethylornithine hydrochloride (US). Ornidyl® is a solution of difluoromethylornithine HCl suitable for injection or infusion. It is supplied at a strength of 200 mg of difluoromethylornithine hydrochloride monohydrate per ml (20 g/100 mL). Difluoromethylornithine and its use in the treatment of benign prostatic hypertrophy are described in U.S. Patent Nos. 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 has been reported to reduce the concentration of putrescine and spermidine in cells in which these polyamines are normally actively produced. In addition, difluoromethylornithine display can 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, such as many disease states characterized by rapid cell proliferation, is accompanied by an abnormal increase in polyamine concentration. Difluoromethylornithine can be potentially administered continuously with a significant anti-tumor effect. This drug is 0.4 g/m per day² The low dose is relatively non-toxic to humans, while producing inhibition of putrescine synthesis in tumors. Studies in a rat tumor model have shown that difluoromethylornithine infusion can produce a 90% reduction in the level of tumor putrescine without suppressing the number of peripheral platelets. Side effects observed with difluoromethylornithine include 4 g/m per day² The effect of the high dose on the hearing disappears when the difluoromethylornithine is interrupted. 0.4 g/m per day when administered for up to one year² These effects on hearing were not observed at lower doses (Meyskens et al., 1994). In addition, it was found that several vertigo/dizziness conditions disappeared when the drug was stopped. Thrombocytopenia uses a high "therapeutic" dose of difluoromethylornithine (>1.0 g/m per day)² The study was mainly reported and first reported in cancer patients who had previously undergone chemotherapy or patients with bone marrow damage. Although the toxicity associated with difluoromethylornithine therapy is generally not as severe as other types of chemotherapy, it has been found to promote dose-related thrombocytopenia in limited clinical trials. In addition, studies in rats showed that continuous infusion of difluoromethylornithine for 12 days significantly reduced platelet count compared to controls. Other studies have obtained similar observations in which thrombocytopenia is the primary toxicity of continuous intravenous difluoromethylornithine therapy. These findings indicate that difluoromethylornithine significantly inhibits the ODC activity of bone marrow precursors of megakaryocytes. Difluoromethylornithine inhibits proliferative repair methods such as epithelial wound healing. Phase III clinical trials assessed recurrence of adenomatous polyps after 36 months of treatment with DFMO plus sulindac or a placebo. Temporary hearing loss is a known toxicity for treatment with DFMO, so a comprehensive approach to the analysis of continuous air conduction sonic patterns has been developed. The general estimation equation method evaluates the mean difference between changes in air conduction pure tone thresholds between treatment groups, while calculating intra-individual correlation due to repeated measurements at frequency. Baseline values, age, and frequency were adjusted based on 290 individuals compared with placebo-treated individuals (95% confidence interval, -0.64 to 1.63 dB; P=0.39), individuals treated with DFMO plus sulindac There was a mean difference of 0.50 dB between patients with DFMO plus sulindac and a mean margin of <2 dB compared with placebo-treated patients. 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. NSAID NSAID is a non-steroidal anti-inflammatory agent. In addition to anti-inflammatory effects, it has been reported to have analgesic, antipyretic and platelet-inhibiting effects. It is used, for example, to treat chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. It has been reported to act by blocking the synthesis of prostaglandins by inhibiting the conversion of arachidonic acid to a cyclic endoperoxide (prostaglandin precursor) cyclooxygenase. Inhibition of prostaglandin synthesis explains its analgesic, antipyretic and platelet-inhibiting effects; other mechanisms may contribute to its anti-inflammatory effects. Certain NSAIDs may also inhibit lipoxygenase or phospholipase C, or may modulate T cell function. See AMA Drug Evaluations Annual, 1814-5, 1994. Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, piroxicam (Reddy et al, 1990; Singh et al, 1994), indomethacin (Narisawa, 1981) and sulindac (Piazza, etc.) Human, 1997; Rao et al., 1995) effectively inhibited colon cancer development in a rat model of AOM treatment. NSAID also inhibits tumor development with activated Ki-ras (Singh and Reddy, 1995). NSAID appears to inhibit carcinogenesis via induction of apoptosis in tumor cells (Bedi et al, 1995; Lupulescu, 1996; Piazza et al, 1995; Piazza et al, 1997b). Several studies have shown 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 via prostaglandin-dependent and independent mechanisms (Alberts et al, 1995; Piazza et al, 1997a; Thompson et al, 1995; Hanif, 1996). The sulindac, a metabolite of NSAID sulindac, lacks COX inhibitory activity and induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b) and is found in several rodent models of carcinogenesis. Tumor development is inhibited (Thompson et al, 1995; Piazza et al, 1995, 1997a). The effects of several NSAIDs in human clinical trials have been tested. Complete Phase Ia test of ibuprofen (one month) and find prostaglandin E in flat mucosa even at a dose of 300 mg/day₂ (PGE₂ ) The level is significantly reduced. The dose of 300 mg ibuprofen is extremely low (therapeutic dose range is between 1200-3000 mg/day or greater) and toxicity is unlikely to be discovered even over the long term. However, in animal chemopreventive models, ibuprofen is not as effective as other NSAIDs.A. aspirin Aspirin, also known as acetyl salicylic acid, is a salicylate drug, often used as an analgesic to relieve a small amount of pain and pain, used as an antipyretic to reduce fever and used as an anti-inflammatory drug therapy. Aspirin was first isolated in 1897 by the German company Bayer's chemist Felix Hoffmann. The main metabolite of aspirin, salicylic acid, is an integral part of human and animal metabolism. Although many of humans are attributable to diets, a significant portion are endogenously synthesized. Today, aspirin is one of the most widely used agents in the world and is estimated to consume 40,000 tons per year. In countries where aspirin is a registered trademark owned by Bayer, the general term is acetaminosalicylic acid (ASA). Aspirin also has an anti-platelet effect by inhibiting thromboxane production, which normally binds platelet molecules together to create patches on damaged walls of blood vessels. Because platelet patches can become too large locally and downstream and also block blood flow, aspirin is also used at low doses for long periods of time to help prevent heart attacks, strokes, and blood clot formation in humans at high risk of blood clots. It also establishes that low doses of aspirin can be administered immediately after a heart attack to reduce the risk of a second heart attack or heart tissue death. Aspirin is effective in preventing certain types of cancer, especially colorectal cancer. Adverse effects of oral aspirin include gastrointestinal ulcers, gastric bleeding, and tinnitus, especially at higher doses. In children and adolescents, aspirin is no longer designated to control symptoms of influenza or symptoms of chickenpox or other viral diseases due to Reye's syndrome risk. Aspirin is part of a group of agents known as non-steroidal anti-inflammatory drugs (NSAIDs), but differs in mechanism of action from most other NSAIDs. 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 for others) Salicylates are indeed irreversibly so, and unlike other drugs, affect the COX-1 variant of the enzyme rather than the COX-2 variant.B. Sulindac and its major metabolites , Sulindac and sulindac sulfide Sulindac is a non-steroidal, anti-inflammatory steroid derivative having the following chemical name: (Z)-5-fluoro-2-methyl-1-((4-(methylsulfinyl)phenyl)) -1H-indole-3-acetic acid (Physician's Desk Reference, 1999). Without being bound by theory, the fluorenylene moiety is converted in vivo by reversible reduction to a sulphide metabolite and by irreversible oxidation to a quinone metabolite (exisulind). See U.S. Patent No. 6,258,845, incorporated herein by reference. The sulindac, which inhibits Ki-ras activation, is also metabolized into two different molecules, which have different ability to inhibit COX, but are all capable of exerting a chemopreventive effect by inducing apoptosis. Sulindac is deficient in COX inhibitory activity and is most likely to promote induction of apoptosis in a manner unrelated to prostaglandin synthesis. Obtained indications indicate that the sulfide derivative is at least one of the biologically active compounds. Based on this, sulindac can be considered as a prodrug. Sulolinil® can be obtained in the form of, for example, 150 mg and 200 mg tablets. The most common dose for adults is 150 to 200 mg twice a day, with a maximum daily dose of 400 mg. After oral administration, about 90% of the drug is absorbed. The peak plasma level is reached in about 2 hours in fasting 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 sulfide metabolites was 16.4 hours. Formulations of sulindac are contemplated by U.S. Patent Nos. 3,647,858 and 3,654,349 each of which is incorporated herein in its entirety by reference. Sulfate is indicated for the acute and long-term relief of symptoms and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gout and acute pain in the shoulder. Analgesic and anti-inflammatory effects exerted by sulindac (400 mg daily) with aspirin (4 g per day), ibuprofen (1200 mg per day), indometacin (125 mg per day) and benzene The effect achieved by butyl ketone (400 to 600 mg per day) is comparable. Side effects of sulindac include mild gastrointestinal effects in almost 20% of patients, abdominal pain and nausea as the most frequent discomfort. CNS side effects are found in up to 10% of patients, with sleep, headache and tension being the most frequently reported. Rash and scrapie occur in 5% of patients. Chronic treatment with sulindac can cause severe gastrointestinal toxicity 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, U.S. Patent Nos. 5,814,625 and 5,843,929, the disclosures of each of which are incorporated herein by reference, are incorporated herein by reference. Although at least one study in incidental adenomas showed no such effect (Ladenheim et al., 1995), sulindac displays adenoma regression in familial adenomatous polyposis (FAP) patients (Muscat et al., 1994). . Sulindac and its anthraquinone metabolite, esculin, have been tested and continue to be clinically tested for the prevention and treatment of several cancer types.C. Piroxicam Piroxicam is a non-steroidal anti-inflammatory agent that is well established in the treatment of rheumatoid arthritis and osteoarthritis with the following chemical names: 1,1-dioxy-4-hydroxy-2-methyl-N -2-pyridyl-2H -1,2-benzothiazide-3-carboxamide. It also shows its usefulness in the treatment of musculoskeletal disorders, dysmenorrhea and post-operative pain. Its longer half-life allows it to be administered once a day. If administered rectally, the drug is shown to be effective. Gastrointestinal discomfort is the most commonly reported side effect. Although piroxicam exhibits a side effect in the recent IIb trial, piroxicam is shown to be an effective chemopreventive agent in animal models (Pollard and Luckert, 1989; Reddy et al., 1987). A large comprehensive analysis of the side effects of NSAIDs also indicates that piroxicam has more side effects than other NSAIDs (Lanza et al., 1995). Although DFMO exerts a greater inhibitory effect on Ki-ras mutations and tumorigenesis than piroxicam when administered separately (Reddy et al., 1990), the combination of DFMO and piroxicam is in the colon. A synergistic chemopreventive effect was demonstrated in a rat model of AOM treatment of cancer (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. Senecab (Celecoxib) Senecoxib is a non-steroidal anti-inflammatory agent that is well established in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, ankylosing spondylitis, and reduction in the number of colon and rectal polyps in patients with FAP. 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide. Senecabu is sold by Pfizer under the brand names Celebrex, Celebra and Onsenal. Celecoxib is a selective COX-2 inhibitor. Side effects of seneoxib include a 30% increase in heart and vascular disease rates. In addition, the risk of gastrointestinal side effects is greater than 80%.E. NSAID Combination In some embodiments, a combination of various NSAIDs can 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 can be used with celecoxib. Examples of NSAIDs that can 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, teloxicam Tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic, meclofenamic, flufen Flufenamic, tolfenamic, rofecoxib, rofecoxib, valdecoxib, parecoxib, lumiricoxib 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 cancer cell growth in a patient, and/or prevent cancer cells from developing 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, esophageal cancer, head and neck cancer, testicular cancer, colon cancer, cervical cancer, lymphatic cancer, and blood cancer. . In some embodiments, the composition can be used to treat and/or prevent colon cancer, familial adenomatous polyposis (FAP), pancreatic cancer, and/or neuroblastoma. In some embodiments, the compositions provided herein can be used to treat a patient exhibiting pre-cancerous conditions, and thus prevent cancer onset. Target cells and tissues for such prophylactic treatment include polyps and other precancerous lesions, pre-malignant diseases, pre-neoplastic or other abnormal phenotypes indicative of possible progression to cancer status. For example, the compositions provided herein can be used to prevent adenomas with little additional toxicity. A total of mutants with FAPAPC/apc Genotype Min (multiple intestinal neoplasia) mice serve as a suitable experimental animal model for human FAP patients (Lipkin, 1997). Min mice develop more than 100 gastrointestinal adenomas/adenocarcinomas throughout the gastrointestinal tract over a 120-day life span, resulting in GI bleeding, occlusion, and death. Combination therapy with DFMO and sulindac is shown to be effective in reducing adenomas in these mice. See U.S. Patent No. 6,258,845, hereby incorporated herein entirely incorporated by reference.V. Fixed dose combination and route of administration In one aspect, the invention provides a composition comprising a pharmaceutically effective amount of a difluoromethylornithine and a pharmaceutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) or a metabolite thereof in a fixed dose combination. 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, the difluoromethylornithine is a difluoromethylornithine hydrochloride monohydrate racemate. In some embodiments, the difluoromethylornithine hydrochloride monohydrate is a racemic mixture of its two enantiomers. In some embodiments, the difluoromethylornithine is present in an amount from about 10 mg to about 1000 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 250 mg to about 500 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 300 mg to about 450 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 350 mg to about 400 mg. In some embodiments, the difluoromethylornithine is present in an amount from about 35% to about 60% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 40% to about 55% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 50% to about 55% by weight. In some embodiments, the difluoromethylornithine is present in an amount from about 52% to about 54% by weight. In some embodiments, the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from 52% to 54% by weight. In some embodiments, the difluoromethylornithine is present in an amount of about 375 mg. In some embodiments, the amount of the difluoromethylornithine hydrochloride monohydrate racemate is 375 mg. In some embodiments, sulindac is present in an amount from about 10 mg to about 1500 mg. In some embodiments, sulindac is present in an amount from about 50 mg to about 100 mg. In some embodiments, sulindac is present in an amount from about 70 mg to about 80 mg. In some embodiments, 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% by weight to about 20% by weight. In some embodiments, sulindac is present in an amount from about 8% by weight 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 from 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 formulation further comprises an excipient. In some embodiments, the excipient is starch, colloidal ceria or deuterated microcrystalline cellulose. In some embodiments, the excipient is colloidal ceria. In some embodiments, the formulation further comprises a second excipient. In some embodiments, the second excipient is deuterated 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 composition is in the form of a capsule, lozenge, micro-tablet, granule, pellet, solution, gel, cream, foam or patch. In some embodiments, the composition is in the form of a tablet, such as a single layer tablet. In some embodiments, the lozenge has a weight of from about 650 mg to about 1,000 mg. In some embodiments, the lozenge has a weight of from about 675 mg to about 725 mg. In some embodiments, the tablet has a weight of 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 reactive coating. In some embodiments, the coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP), phthalic acid Hydroxypropylmethylcellulose formate (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 or succinic acid hydroxypropyl methylcellulose (HPMCAS). In some embodiments, the coating masks the taste of difluoromethylornithine. In some embodiments, the coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow. In some embodiments, the amount of coating is from about 1% to about 5% by weight. In some embodiments, the amount of coating is from 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 amount of coating is about 21 mg. In some embodiments, the lozenge comprising the coating has a weight of from about 675 mg to about 750 mg. In some embodiments, the lozenge comprising the coating has a weight of 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 composition is in the form of a capsule, lozenge, micro-tablet, granule, pellet, solution, gel, cream, foam or patch. In some embodiments, the composition is a solid and takes the form of a lozenge, such as a single layer tablet. In some embodiments, the tablet is coated with a film. In some aspects, the invention provides oral fixed dose combination formulations of difluoromethylornithine and 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 senecyclobut. In some preferred embodiments, the NSAID is sulindac. In some embodiments, the pharmaceutical compositions and formulations of the present invention are for use in the intestine, such as orally, and are also used in the rectal or parenteral, wherein the compositions comprise, alone or together with a pharmaceutical auxiliary (excipient) a pharmaceutically active compound. The pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dosage form, such as coated lozenges, lozenges, capsules or suppositories, and ampoules. It is prepared in a manner known per se, for example using conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, a pharmaceutical preparation for oral use can be prepared by combining the active compound with a solid excipient, if it is desired to granulate the mixture obtained, and if necessary or necessary, after the addition of a suitable auxiliary substance, the mixture or granule is processed into an ingot. The agent or coated tablet core is obtained. In a preferred embodiment, the mixture of active ingredient and excipient is formulated in the form of a tablet. Appropriate coatings can be applied to increase palatability or delay absorption. For example, the coating can be applied to a tablet to mask the unpleasant taste of the active compound (such as DFMO), or to maintain and/or delay release of the active molecule to a particular area in the gastrointestinal tract. The therapeutic compound can be administered orally, for example, with an inert diluent or an absorbable edible carrier. Therapeutic compounds and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into a lozenge or directly incorporated into the individual's diet. For oral therapeutic administration, the therapeutic compound can be combined with excipients and used in the form of ingestible lozenges, buccal tablets, dragees, capsules, elixirs, suspensions, syrups or powders. In certain embodiments, the troches and/or capsules provided herein comprise the active ingredient and a powdery carrier such as lactose, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents can be used to prepare compressed tablets. In other embodiments, tablets and capsules can be made for immediate or modified release. In some embodiments, the lozenges and/or capsules are manufactured as a sustained release product to provide a sustained release of the drug over a period of hours. In some embodiments, the compressed tablet is sugar coated and/or film coated to mask unpleasant taste and/or prevent the tablet from coming into contact with the atmosphere. In some embodiments, the tablet is coated 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 multiparticulates comprising particles of different amounts of the first component and the second component, such as multi-particles coated with a modified release coating. In some such embodiments, the troche or capsule may disintegrate or dissolve in the oral cavity, stomach, small intestine, terminal ileum, or colon. In some such embodiments, the tablet or capsule can release multiple particles having a modified release profile. In some embodiments, the invention provides a pharmaceutical oral fixed dose combination in the form of a multi-layer tablet. The multilayer tablet has at least two layers (two-layer tablet) 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 being in each of the two layers. In some embodiments, in addition to the two layers, the tablet also contains other layers containing only the carrier, and which may function, for example, as a separate layer or an outer coating. In some embodiments, if more than two layers are present, the components may be present in more than one layer as long as they are not present together in the same layer. In certain embodiments, a single layer tablet is preferred, but all of the information detailed below applies equally to a multilayer tablet. In some embodiments, the fixed dose combination can be formulated to provide a population ranging from about 0.1 μM to about 1000 μM and preferably from about 1 μM to 100 μM and more preferably from about 1 μM to about 50 μM. The average steady state plasma concentration level of difluoromethylornithine and/or sulindac.A. Pharmaceutically acceptable excipients In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some such embodiments, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable diluent, a pharmaceutically acceptable disintegrant, a pharmaceutically acceptable binder, and a pharmaceutically acceptable An acceptable stabilizer, a pharmaceutically acceptable lubricant, a pharmaceutically acceptable pigment or a pharmaceutically acceptable slip aid. In a fixed dose combination formulation of the invention, the active ingredient may be mixed in a weight ratio of from 1:0.25 to 1:20 with a pharmaceutically acceptable excipient. Diluents useful in the pharmaceutical formulations of the present invention include, but are not limited to, microcrystalline cellulose ("MCC"), deuterated MCC (eg, PROSOLVTM HD 90), microcellulose, lactose, starch, pregelatinized starch, Sugar, mannitol, sorbitol, glucose binder, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tricalcium phosphate, magnesium carbonate, magnesium oxide and any mixture. Preferably, the diluent is deuterated MCC. The diluent is used in an amount of from about 5% by weight to about 95% by weight, based on the total weight of the formulation, and preferably in an amount of from about 25% by weight to about 40% by weight, such as from about 30% by weight to about 35% by weight. The amount used. In some aspects, the diluent can be a soluble diluent. When a diluent is used, its ratio to the active ingredient in each discrete layer is extremely important. The term "soluble diluent" means a diluent which is dissolved in water, lactose, Ludipress (BASF, lactose, crospovidone, and povidone) (93:3.5:3.5, a mixture of w/w (%)), mannitol and sorbitol. The disintegrant is used to promote swelling and disintegration of the tablet after exposure to the fluid in the oral and/or gastrointestinal tract. Examples of disintegrants suitable for use in the fixed dose combination formulations of the present invention include crospovidone, sodium starch glycolate, croscarmellose sodium, low substituted hydroxypropylcellulose, starch, alginic acid Or its sodium salt and mixtures thereof. Other disintegrants that can be used in the pharmaceutical formulations of the invention include, but are not limited to, methylcellulose, microcrystalline cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose (eg, AC-DI-SOLTM) , PRIMELLOSETM), povidone, guar gum, magnesium aluminum silicate, colloidal cerium oxide (eg AEROSILTM, CARBOSIL^TM ), polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate, (eg, EXPLOTABTM), sodium alginate, and any mixture thereof. Preferably, the disintegrant is colloidal ceria. The disintegrant can be used in an amount of from about 0.1% by weight to about 30% by weight, based on the total weight of the formulation, and is preferably used in an amount of from about 0.2% by weight to about 5% by weight. The compositions of the present invention may comprise a lubricant. Adhesion can occur when the particles themselves attach to the punch face of the tablet press. Lubricants are used to promote powder flow and reduce friction between the tablet punch face and the tablet punch and between the tablet surface and the mold wall. For example, lubricants include 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 preferably comprises from 0.25 wt% to 2 wt%, and preferably about 1.5 wt%, of the solid dosage form. In an exemplary formulation, the lubricant is magnesium stearate present in an amount of about 1.5% by weight to prevent adhesion. Binders can be used in the pharmaceutical compositions of the present invention to aid in holding the tablets together after compression. Examples of binders suitable for use in the present invention are gum arabic, guar gum, alginic acid, carbomers (e.g., CarbopolTM products), dextrin, maltodextrin, methylcellulose, ethylcellulose. , hydroxyethyl cellulose, hydroxypropyl cellulose (eg KLUCELTM), hydroxypropyl methylcellulose (eg METHOCELTM), sodium carboxymethylcellulose, liquid glucose, magnesium aluminum citrate, polymethyl Acrylate, polyvinylpyrrolidone (eg, povidone K-90 D, KOLLIDONTM), copovidone (PLASDONETM), gelatin, starch, and any mixture thereof. Preferably, the binder is starch. In the present invention, the binder preferably comprises from about 1% to about 15% by weight of the solid dosage form. In other embodiments, the solid dosage form does not comprise a binder. In certain embodiments, the stabilizer useful in the fixed dose combination formulations of the present invention can be an antioxidant. The use of antioxidants promotes the stability of the active ingredient against adverse reactions with other pharmaceutically acceptable additives and against changes caused by heat or moisture over time. For example, the antioxidants are ascorbic acid and its esters, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha-tocopherol, cysteine, citric acid, gallic acid Ester, sodium hydrogen sulfate, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA), and any mixture thereof.B. Tablet manufacturing method Another aspect of the invention provides a method of making a tablet disclosed herein, comprising a tablet comprising difluoromethylornithine and sulindac. In some embodiments, the active agent is prepared by sieving at least one active agent and one or more excipients via a desired mesh size screen, and then using a fast mixer granulator, planetary mixer, mass Mixer, strip mixer, fluid bed processor or any other suitable device. Blends may be granulated in a low or high shear mixer, a fluidized bed granulator, and the like, such as by adding an alcohol or hydroalcoholic or aqueous solution or suspension with or without a binder Granulation is carried out by dry granulation. The granules can be dried using a tray dryer, a fluidized bed dryer, a rotary cone vacuum dryer, and the like. The granules can be sized using an oscillating granulator or comminuting mill or any other conventional equipment equipped with a suitable screen. Alternatively, the granules are prepared by extrusion and spheronization or rolling. Additionally, the manufacture of the granules containing the active agent can include mixing or rolling with a directly compressible excipient. In other embodiments of the invention, the small tablets (micro-tablets) can be made by compressing the granules using molds and punches of various sizes and shapes (as needed). Optionally, the coating may be applied to the tablet, if desired, using techniques known to those skilled in the art, such as spraying, dip coating, fluid bed coating, and the like. In certain embodiments of the invention, a suitable solvent system, such as an alcohol, hydroalcoholic, aqueous or organic solvent system, can be used to facilitate processing.1. Granulation Granulation is a process in which powder particles adhering to one another are made, thereby producing larger, multiparticulate entities or particles. In embodiments of the invention, the particles obtained by dry or wet techniques may be blended with one or more lubricants and/or anti-adhesives and subsequently filled into a single capsule or filled into different sizes. In the capsule, such that a smaller capsule can be filled into another larger capsule. In one embodiment, dry granulation by compression is used to prepare a solid dosage composition. In dry granulation, the powder blend is pressed by applying a common force to the powder, thereby resulting in a considerable size increase. In some aspects, the tablet is used in a dry granulation process in which a tablet press is used in the pressing process. In other aspects, the roller press is used for dry granulation including a feed system, a press unit, and a downsizing unit. In this method, the powder is pressed between two rolls by applying a force which is the most important parameter in the dry granulation process. The applied force is expressed in units of kN/cm, which is the force per width of the roll. Occasionally, the pressure is also indicated in Pakistan. However, this represents only the pressure in the hydraulic system and is not actually a suitable unit of measurement for the force applied to the powder. The powder will be pressed to a predefined strip thickness given the force given by the amount of powder delivered to the roll. In other embodiments, wet granulation is used to prepare a solid dosage composition. The wet granulated powder improves the fluidity and compression plasticity of the compressed mixture. In wet granulation, the granules are formed by adding a granulating liquid to a bed of powder, which is subjected to an impeller (in a high shear granulator), a screw (in a twin screw granulator) or air (in In fluidized bed granulators) effects. Agitation is generated in the system and the components within the wetting formulation cause the preliminary powder particles to aggregate to produce wet particles. The granulated liquid (fluid) contains a solvent which must be volatile so that it can be removed by drying and is non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The liquid solution may be an aqueous or solvent type. Aqueous solutions have the advantage of being safer than organic solvent treatments. Tablets can also be formed by tumbling melt granulation (TMG) substantially as described in Maejima et al., 1997, which is incorporated herein by reference. Rolling melt granulation can be used to prepare molten particles. It can be done in a tumble mixer. The molten low melting point compound is sprayed onto the crystalline sugar and powdered sugar in the blender and mixed until the particles form. In this case, the low melting component is a binder and the crystalline sugar is a seed. An alternative method is to combine an unmelted low melting component, a crystalline sugar (such as sucrose or maltose), and a water soluble component (such as mannitol or lactose) in a powder form in a tumble mixer, and mix while heating to a low melting point binder. The melting point or higher melting point. The seed crystal should be a crystalline or granular water soluble component (sugar) such as granular mannitol, crystalline maltose, crystalline sucrose or any other sugar. An example of a tumble mixer is a double shell blender (V-shaped blender) or any other shape of a tumble mixer. Heating can be achieved by circulating hot air through the granulator chamber and by heating the bottom surface of the chamber. When the seed material and the powder tablet component circulate in the heated chamber, the low melting point compound melts and adheres to the seed crystal. The unmelted powder material adheres to the seed crystal bond and melts the low melting point material. The spherical beads formed by this method are then cooled and sieved through a sieve to remove the unadhered powder. Spray coagulation or granulation can also be used to form the lozenge compositions of the present invention. Spray coagulation includes molten droplets of the atomized composition comprising a low melting point compound on the surface or preferably other tablet ingredients. Equipment that can be used for spray coagulation includes a spray dryer (such as a Nero spray dryer) and a fluidized bed coater/granulation with a top spray (eg, a Glatt fluid bed coater/granulator). In a preferred embodiment, a preferred water soluble excipient, more preferably the sugar is suspended in the molten low melting component and spray condensed to form fast dissolving granules. After the spray coagulation, the resulting composition was allowed to cool and coagulate. After the mixture is coagulated, it is screened or sieved and mixed with the remaining tablet ingredients. Spray coagulation methods which melt the instant granules comprising any combination of low melting point compounds and other tablet ingredients and spray condense onto other tablet ingredients are within the scope of the invention. It is also within the scope of the invention to combine all of the tablet ingredients comprising the low melting point compound, to melt the low melting point compound and to spray the mixture onto the surface.2. Blending In certain embodiments, the mixture is blended after granulation. Blending in solid dosage manufacturing achieves blending uniformity and dispenses lubricant. In some aspects, the blending step is designed to achieve homogeneity of all components prior to the final blend of the lubricant. However, blended powders are problematic 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 a suitable container, such as a diffusion blender or a diffusion mixer. An example of a tumble mixer is a double shell blender (V-shaped blender) or any other shape of a tumble mixer.3. compression When a tablet composition is prepared, it can be formed into various shapes. In a preferred embodiment, the tablet composition is compressed into a shape. This method can comprise placing the tablet composition in a form and applying pressure to the composition such that the composition assumes a surface shape in the form of contact with the composition. Compressing into a tablet form can be accomplished by a tablet press. The tablet press includes a lower punch adapted to the bottom mold and a punch having a corresponding shape and size that enters the top mold cavity after the ingot material falls into the mold cavity. The tablet is formed by the pressure applied to the lower punch and the upper punch. Tablets of the present invention typically have a hardness of about 20 kP or less; preferably tablets have a hardness of about 15 kP or less. Typical compression pressures range from about 5 kN to about 40 kN and will vary based on the desired size and tablet hardness. In some aspects, the compression pressure is from about 25 kN to about 35 kN. In a particular aspect, the compression pressure is less than about 37 kN, such as less than about 30 kN, such as less than about 25 kN. Hydraulic presses (such as Carver Press) or rotary lozenge presses (such as Stokes Versa Press) are suitable means of compressing the lozenge 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 rotating machine, to form an ingot, which is equipped with a grinder or fluid energy grinder or ball mill or colloid mill or roller mill equipped with a suitable screen. A machine or hammer mill and the like obtain a milled active ingot. A pre-compression step can be used to prevent the tablet from cracking. Top split refers to a crack or crack in the top or top of a tablet from the bulk of the tablet. The top crack can be caused by incompressible fine particles that migrate when air is pushed out during compression. For example, pre-compression can be about 5%, 10%, or 15% of the primary compressive force. In a preferred embodiment, the tablet is pre-compressed into a form at a pressure of no more than about 10 kN, preferably less than 5 kN. For example, 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 a 10 kN compression tablet is within the scope of the invention. In a particular aspect, 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. Membrane coat The compositions or solid dosage forms according to the invention may also be coated with a film coating, an enteric coating, a conditioning release coating, a protective coating or an anti-adhesive coating. The compositions of the present invention may be coated with an enteric coating. By coating an enteric coating or coating is meant a pharmaceutically acceptable coating which prevents release of the active agent in the stomach and allows release in the upper part of the intestine. In other embodiments, an enteric coating is applied to delay release of the active agent to the terminal ileum or release to the colon. The enteric coating can be added as an overcoat when the release coating is adjusted. The enteric coating polymer can be used alone or in combination in the enteric coating formulation. The enteric coating can be designed as a single layer or as a multilayer 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 copolymer, derived from methacrylic acid And a copolymer of the ester thereof, containing at least 40% methacrylic acid; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose succinate or polyvinyl acetate phthalate. Examples of polymers suitable for enteric coating include, for example, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP). , hydroxypropyl methylcellulose 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, EUDRAGITTM L 30D (MA-EA, 1:1), EUDRAGITTM 100 55 (MA-EA, 3:1), succinic acid hydroxypropyl methylcellulose (HPMCAS), SURETERIC (PVAP), AQUATERICTM (CAP), shellac or AQOATTM (HPMCAS). Targeted colonic delivery systems that can be used with the present invention are known and use materials such as: hydroxypropylcellulose; microcrystalline cellulose (MCE, AVICELTM from FMC Corp.); poly(ethylene-vinyl acetate) Ester) (60:40) copolymer (EVAC from Aldrich Chemical Co.); 2-hydroxyethyl methacrylate (HEMA); MMA; N,N'-bis(methacryloyloxyethyl) HEMA:MMA:MA terpolymer synthesized in the presence of oxycarbonylamino)-azobenzene; azo polymer; coated enteric coating timed release system (TIME CLOCK from Pharmaceutical Profiles, Ltd., UK) ®) and pectin calcium acetate and osmotic small pump systems (ALZA corp.). In some embodiments, the film coat comprises a polymer such as hydroxypropylcellulose (HPC), ethylcellulose (EC), hydroxypropylmethylcellulose (HMPC), hydroxyethylcellulose (HEC) , sodium carboxymethyl cellulose (CMC), poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), dimethylaminoethyl methacrylate-methacrylate copolymer or acrylic acid Ethyl-methyl methacrylate copolymer (EA-MMA). In some embodiments, the composition has a modified release coating. The modified release coating can be a pH reactive coating that will deliver the active agent (eg, to the colorectal tract when exposed to a particular pH). In some embodiments, the pH reactive coating is a pH reactive polymer that will dissolve when exposed to a pH greater than or equal to about 6; although the pH reactive polymer can dissolve at a pH greater than or equal to about 5 . The pH reactive polymer can be, for example, a polymeric compound such as EUDRAGITTM RS and EUDRAGITTM RL. The EUDRAGITTM product forms a latex dispersion of approximately 30D weight. Since EUDRAGITTM RS 30D is designed for slow release as a coating that is poorly permeable, it is designed for rapid release because EUDRAGITTM RS 30D is relatively well permeable as a coating. These two polymers are generally used in combination. As covered herein, the allowable ratio of EUDRAGITTM RS 30D/EUDRAGITTM RL 30D is from about 10:0 to about 8:2. Ethylcellulose or S100 or other equivalent polymers designed for intestinal or colorectal release can also be used in place of the above EUDRAGITTM RS/EUDRAGITTM RL combination. Optionally, the method comprises the step of film coating the tablet. The film coat can be completed in any suitable manner. Suitable film coats are known to us and are commercially available or can be made according to known methods. Typically the film coating material is a polymeric film coating material comprising materials such as polyethylene glycol, talc, and color former. Suitable coating materials are methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic polymer, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalic acid Ester, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol, sodium carboxymethyl cellulose, 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 coat is hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow. For example, the film coat is OPADRY® Yellow (Colorcon). Typically, the film coating material is applied in this amount to provide a film coat of from 1% to 6% by weight of the coated film-coating agent, such as from 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 may also be added to the coating material. In some embodiments, the coating of the lozenge can improve palatability to mask unpleasant taste of active ingredients such as DFMO. For example, a lozenge coating composition can include a cellulosic polymer, a plasticizer, a sweetener, or a powdered flavor composition, the powdered flavor composition comprising a flavoring agent associated with a solid carrier.C. Investment schedule and plan In some embodiments, the agent can be administered in a conventional time course. As used herein, conventional time history refers to a predetermined specified time period. The regular time course may cover the same or different time periods as long as the time schedule is predetermined. For example, a routine schedule can involve two days of dosing, daily dosing, every two days, every three days, every four days, every five days, every six days. , weekly, monthly, or any set number of days or weeks. Alternatively, the predetermined regular schedule may involve two consecutive days of administration for the first week, followed by daily administration for several months, and the like. In other embodiments, the invention provides a dosage form that can be administered orally and that is dependent on or independent of food intake. Thus, for example, the medicament can be taken every morning and/or every night, regardless of whether the individual is eating or not.VI. Diagnosis and treatment of patients In some embodiments, the method of treatment may be supplemented with a diagnostic method to improve efficacy and/or minimize anti-cancer therapy toxicity, including administration of a composition provided herein. Such methods are described, for example, in U.S. Patent Nos. 8,329,636 and 9,121,852, U.S. Patent Publication Nos. US 2013/0217743, and U.S. Pat. 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 of the dual genes of the ODC1 gene promoter is G. In some embodiments, the genotype at position +316 of the two dual genes of the patient's ODC1 gene promoter can be GG. In some embodiments, the genotype at position +316 of the two dual genes of the patient's ODC1 gene promoter can be GA. Detected about the complete model of adenoma recurrenceODC1 Statistically significant interactions between genotypes and treatments resulted in adenoma recurrence patterns in placebo patients: GG 50%, GA 35%, AA 29% vs. difluoromethylornithine/sulindac patients: GG 11% , GA 14%, AA 57%. The adenoma inhibitory effect of difluoromethylornithine and sulindac has a major G-type junction compared to a previously reported reduction in the risk of recurrent adenoma in patients with CRA receiving aspirin with at least one A-pair gene.ODC1 The genotypes are larger among their patients (Martinez et al, 2003; Barry et al, 2006; Hubner et al, 2008). These results show a position +316 compared to patients with GG genotypeODC1 The A-pair gene vector differs in response to long-term exposure to difluoromethylornithine and sulindac, in which the A-pair gene vector has less beneficial effects on adenoma recurrence, and especially in AA homozygous zygotes, it is possible The risk of developing ototoxicity is elevated. 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, the test determining at least oneODC1 Promoter gene dual gene position +316 patient genotype; and (b) if the result indicatesODC1 Where the patient's genotype at position +316 of at least one of the promoter genes is +G, then the composition provided herein is administered to the patient. In some embodiments, the invention provides a method for treating a risk factor for colorectal cancer in a patient, comprising: (a) obtaining a result from a test, the test determining at least oneODC1 Promoter gene dual gene position +316 patient genotype; and (b) if the result indicatesODC1 The patient genotype at position +316 of at least one of the promoter genes is G, and the composition provided herein is administered to the patient, wherein the methods prevent the formation of new abnormal duct lesions, new glands in the patient Tumor polyps or new dysplastic adenomas. See U.S. Patent No. 8,329,636, incorporated herein by reference. In some embodiments, the invention provides methods for the prophylactic or curative treatment of familial adenomatous polyposis (FAP) or neuroblastoma in a patient, comprising: (a) obtaining results from a test, the test determining at least oneODC1 Promoter gene dual gene position +316 patient genotype; and (b) if the result indicatesODC1 Where the patient's genotype at position +316 of at least one of the promoter genes is +G, then the composition provided herein is administered to the patient. In some embodiments, the invention provides a method for treating a risk factor for familial adenomatous polyposis or neuroblastoma in a patient, comprising: (a) obtaining a result from a test, the test determining at least oneODC1 Promoter gene dual gene position +316 patient genotype; and (b) if the result indicatesODC1 The patient genotype at position +316 of at least one of the promoter genes is G, and the composition provided herein is administered to the patient, wherein the methods prevent the formation of new abnormal duct lesions, new glands in the patient Tumor polyps or new dysplastic adenomas. See U.S. Patent No. 9,121,852, incorporated herein by reference. In some embodiments, the invention provides a method for treating a patient having a 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 Organize polyamine levels and/or tissue polyamine flux. In some of these embodiments, the low dietary polyamine intake is 300 μM polyamine or less per day. In some such embodiments the cancer is colorectal cancer. See US Patent Publication No. US 2013/0217743, which is incorporated herein by reference. In some embodiments, the invention provides a method for the prophylactic or curative treatment of cancer in a patient, comprising: (a) obtaining a result from a test, the test determining the cancer cell from the patientLet-7 Performance levels of non-coding RNA, HMGA2 protein and/or LIN28 protein; and (b) if the results indicate patient cancer presentation and referenceLet-7 Non-coding RNA performance levelLet-7 The non-coding RNA exhibits a reduced level of expression, and the level of expression of the HMGA2 protein is increased compared to the level of performance of the reference HMGA2 protein and/or the level of expression of the LIN28 protein is increased compared to the performance level of the reference LIN28 protein, and the composition provided herein is administered to the patient. . In some such embodiments, the reference level is the level observed in a non-affected individual or the level observed in a non-cancer cell from a patient. In some such embodiments, "obtaining" includes providing a cancer sample from a patient and assessing the cancer cells from the sampleLet-7 The performance level of non-coding RNA, HMGA2 protein or LIN28 protein. In some of these embodiments, "AssessmentLet The performance level of -7 non-coding RNA includes quantitative PCR or Northern blotting. In some such embodiments, "evaluating the performance level of HMGA2 protein or LIN28 protein" comprises immunohistochemistry or ELISA. In some such embodiments, the sample is blood or tissue, such as tumor tissue. In some such embodiments, the patient is a human. In some such 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, esophagus Cancer, cervical cancer, head and neck cancer, non-melanoma skin cancer or glioblastoma. In some such embodiments, the method further comprises (c) obtaining a result from the test, the test determining the second cancer cell from the patient at the second time pointLet-7 The performance of the non-coding RNA is followed by administration of at least one dose of the ODC inhibitor. In some such embodiments, the method further comprises observingLet-7 The increase in non-coding RNA is less or increases, increasing the amount of ODC inhibitor administered to the patient. In some such embodiments, the method further comprises obtaining a self-test that determines the performance of the HMGA2 protein or LIN28 protein at the second time point in the second cancer cell from the patient, followed by administration of at least one dose of ODC Inhibitor. In some such embodiments, the method further comprises increasing the amount of ODC inhibitor administered to the patient if no decrease or decrease in HMGA2 protein or LIN28 protein is observed. In some such embodiments, the method further comprises (i) obtaining a result from the test, the test determiningODC1 a patient promoter genotype at position +316 of at least one dual gene of the gene promoter; and (ii) if the result is indicativeODC1 Where the patient's genotype at position +316 of at least one of the gene promoters is G, then the composition provided herein is administered to the patient. In some embodiments, the method comprises diagnosing a cancer or precancerous condition in the patient, comprising obtaining a sample from the patient and (b) determining from the sampleLet-7 Performance level of at least two markers of a population consisting of non-coding RNA, LIN28 protein, and HMGA2 protein, wherein the sample is in the sample relative to the reference levelLet-7 If the performance level of non-coding RNA is decreased or the LIN28 protein or HMGA2 protein is increased, the patient is diagnosed as having cancer or precancerous conditions. In some embodiments, the fixed dose combination of the invention is directed to having a low cell or tissueLet-7 The standard patient is administered. In other aspects, the compositions of the invention are administered to a patient having a high cell or tissue HMGA2 level. In other aspects, the compositions of the invention are administered to a patient having a high cell or tissue LIN28 level. See US Patent Publication No. US2015/0301060, which is incorporated herein by reference. In some embodiments, a method for the prophylactic or curative treatment of a cancer in a patient is provided, comprising: (a) obtaining a result from a test, the test determining at least oneODC1 The location of the dual gene +263 patient genotype; and (b) if the result indicatesODC1 The patient's genotype at position +263 of at least one of the dual genes is T, and the composition provided herein is administered to the patient. In some of these embodiments, the test can be determined in the patientODC1 The position of one of the dual genes of the gene + nucleotide base at 263. In some embodiments, the test can be determined in a patientODC1 The position of the two dual genes of the gene + nucleotide base at 263. In some embodiments, the results can be indicatedODC1 The patient's genotype at the position of the two dual genes of the gene +263 is TT. In some embodiments, the results can be indicatedODC1 The location of the two dual genes of the gene +263 patient genotype is TG. In some such embodiments, the method can further comprise obtaining a result from the test, the test determining at least oneODC1 Patient genotype at position +316 of the dual gene, and if the result indicatesODC1 The patient's genotype at position +316 of at least one of the dual genes is G, and only the compositions provided herein are administered to the patient. In another aspect, a method for treating a risk factor for colorectal cancer in a patient, comprising: (a) obtaining a result from a test, the test determining at least oneODC1 The location of the dual gene +263 patient genotype; and (b) if the result indicatesODC1 The patient's genotype at position +263 of at least one of the genes is T, and the composition provided herein is administered to the patient, wherein the method prevents the formation of new abnormal duct lesions, new adenomatous polyps or New dysplastic adenoma. In another aspect, a method for preventing cancer development or recurrence in a patient having a corresponding risk is provided, comprising: (a) obtaining a result from a test, the test determining at least oneODC1 The location of the dual gene +263 patient genotype; and (b) if the result indicatesODC1 The patient's genotype at position +263 of at least one of the dual genes is T, and the composition provided herein is administered to the patient. See PCT Patent Publication No. WO 2015/195120, which is incorporated herein by reference. In a variation of any of the above embodiments, the cancerous tumor can 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 cancer, esophageal cancer, cervical cancer, head and neck cancer, non-melanoma skin cancer or glioblastoma. In some embodiments, the cancerous tumor can be colorectal cancer. In some embodiments, the colorectal cancer can be stage I. In some embodiments, the colorectal cancer can be stage II. In some embodiments, the colorectal cancer can be stage III. In some embodiments, the colorectal cancer can be stage IV. In variations of any of the above embodiments, the method prevents the formation of new advanced colorectal neoplasms in the patient. In some embodiments, the method prevents the formation of a new right-sided advanced colorectal neoplasm. In some embodiments, the method prevents the formation of a new left-sided advanced colorectal neoplasm. In variations of any of the above embodiments, the patient can be identified as having one or more adenomatous polyps in the colon, rectum or appendix. In some embodiments, the patient can be identified as having one or more advanced colorectal neoplasms. In some embodiments, the patient can be identified as having one or more left superior colorectal neoplasms. In some embodiments, the patient can be identified as having one or more right-sided advanced colorectal neoplasms. In some embodiments, the patient can be diagnosed with familial adenomatous polyposis. In some embodiments, the patient can be diagnosed with Lynch syndrome. In some embodiments, the patient can be diagnosed with a familial colorectal cancer type X. In some embodiments, the patient may meet the Amsterdam Criteria or Amsterdam Criteria II. In some embodiments, the patient may have a history of resecting one or more colorectal adenomas. In some embodiments, the patient may have intraepithelial neoplasia or precancerous lesion-related ODC hyperactivity. In some embodiments, the patient may have intraepithelial neoplasia or precancerous lesions and elevated cellular polyamine levels. In a variation of any of the above embodiments, the patient is a human.VII. definition As used in this specification, "a" or "an" can mean one or more. As used in conjunction with the word "comprising", the term "a" or "an" can mean one or more than one. Throughout this application, the term "about" is used to indicate that the value includes the device, the inherent variation in the error of the method used to determine the value, or the change in the study individual. As used herein, the term "bioavailability" refers to the extent 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 a composition according to the invention will result in improved bioavailability compared to the bioavailability obtained after administration of the active substance in a conventional lozenge; or The bioavailability is at least the same or improved compared to the bioavailability obtained after administration of a commercial product containing the same amount of the same active substance. In particular, it is desirable to obtain a faster and larger and/or more phasing capture of the active compound, and thereby provide a reduction in administration dose or a decrease in the number of administrations per day. The terms "composition," "pharmaceutical composition," "mixture," and "formulation" are used synonymously and interchangeably herein. The terms "including", "having" and "including" are open-ended verbs. Any form or tense of one or more of such verbs, such as "comprises", "comprising", "has", "having", "includes" And "including" are also open-ended. For example, any method of "comprising", "having" or "including" one or more steps is not limited to having only one or more of the steps and also encompassing other unrecited steps. The term "derivative thereof" means any chemically modified polysaccharide in which at least one of the monomeric sugar units is modified by substituting an atom or a molecular group or a bond. In one embodiment, the derivative is a salt thereof. The salt is, for example, a salt with a suitable inorganic acid such as a hydrohalic acid, sulfuric acid or phosphoric acid, such as a hydrochloride, a hydrobromide, a sulfate, a hydrogensulfate or a hydrogen phosphate; and a salt of a suitable carboxylic acid, Lower alkanoic acids such as, for example, hydroxylated, such as acetic acid, glycolic acid, propionic acid, lactic acid or pivalic acid, optionally hydroxylated and/or pendant oxy-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 aralipid carboxylic acids, such as benzoic acid, nicotine An acid or a mandelic acid; and a salt suitable for an aliphatic or aromatic sulfonic acid or an N-substituted amine sulfonic acid, such as a methanesulfonate, a besylate, a p-toluenesulfonate orN- Cyclohexylamine sulfonate (cyclamate). The term "disintegration" as used herein refers to a process in which a pharmaceutical oral fixed dose combination is typically dispersed into individual particles by means of a fluid and dispersed. When the solid oral dosage form is in a state in which any solid oral dosage form residue other than the insoluble coating or capsule shell fragments (if present) remaining on the test equipment screen is non-feelable according to USP <701> When it is soft, it will reach disintegration. The fluid used to determine the disintegration characteristics is water, such as tap water or deionized water. The disintegration time is measured using standard methods known to those skilled in the art, see the coordination procedures set forth in the pharmacopoeia USP <701> and EP 2.9.1 and JP. The term "dissolving" as used herein refers to a solid material, here a method in which the active ingredient is dispersed in a molecular form in a medium. The dissolution rate of the active ingredient of the pharmaceutical oral fixed dose combination of the present invention is defined by the amount of the drug substance entering the solution per unit time under standardized conditions of the liquid/solid interface, temperature and solvent composition. The dissolution rate is measured using standard methods known to those skilled in the art, see the coordination procedures set forth in the pharmacopoeia USP <711> and EP 2.9.3 and JP. For the purposes of the present invention, tests for measuring the dissolution of individual active ingredients are carried out according to the pharmacopeia USP <711> at the pH as set forth herein for the different examples. Specifically, the test was carried out using a paddle stirring element at 75 rpm (rotation/minute). The dissolution medium is preferably a buffer, typically a phosphate buffer (e.g., at pH 7.2). The molar concentration of the buffer is preferably 0.1 M. "Active ingredient" (Al) (also referred to as active compound, active substance, active agent, pharmaceutical agent, pharmaceutical agent, biologically active molecule or therapeutic compound) is a component of a biologically active drug or insecticide. Similar terms the active pharmaceutical ingredient (API) and bulk activity are also used in pharmaceuticals, and the term active substance can be used in insecticide formulations. "pharmaceutical drug" (also known as medicine, pharmaceutical preparation, pharmaceutical composition, pharmaceutical preparation, pharmaceutical product, medicinal product, medicine, medicine, medicine or simply medicine) )) is a drug used to diagnose, cure, treat or prevent diseases. The active ingredient (Al) (as defined above) is a component of a biologically active drug or insecticide. Similar terms the active pharmaceutical ingredient (API) and bulk activity are also used in pharmaceuticals, and the term active substance can be used in insecticide formulations. Certain pharmaceutical and insecticide products may contain more than one active ingredient. Inert ingredients are often referred to as excipients in the pharmaceutical context as compared to the active ingredient. As used in this specification and/or the scope of the claims, the term "effective" means sufficient to achieve desired, desired, or desired results. When used in the context of treating a patient or an individual with a compound, "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" means that when administered to an individual or patient to treat or prevent a disease, it is sufficient to affect The amount of the compound that is treated or prevented by the 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 yet experienced or indicated any or all of the pathology of the disease. Or symptomatic, and/or (2) slowing the pathology or symptomatic episode of the disease in the individual or patient, the individual or patient may be at risk and/or susceptible to the disease but has not experienced or indicated any of the disease or All pathology or symptomology. "Treatment/treating" includes (1) inhibiting a disease in an individual or patient experiencing or showing the pathology or symptom of the disease (eg, curbing pathology and/or further development of the syndrome), (2) improving the experience or A disease (eg, reversal of pathology and/or symptomology) in an individual or patient showing the pathology or symptom of the disease and/or (3) a disease in an individual or patient who experiences or exhibits the pathology or symptom of the disease Any measurable decrease occurs. "Prodrug" means a compound which is metabolically converted in vivo to an inhibitor according to the invention. The prodrug may or may not have activity relative to the protein of interest to which it is administered. For example, a compound containing a hydroxyl group can be administered as an ester which is converted into a hydroxy compound by hydrolysis in vivo. Suitable esters which can be converted into hydroxy compounds in vivo include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, butyls Acid esters, fumarates, maleic acid esters, methylene-bis-β-hydroxynaphthoformate, gentisate, isethionate, di-p-toluene Tertyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylamine sulfonate, quinate, amino acid ester and the like ester. Similarly, a compound containing an amine group can be administered as a guanamine which is converted into an amine compound by in vivo hydrolysis. An "excipient" is a pharmaceutically acceptable substance that is formulated with an active ingredient of a pharmaceutical, a pharmaceutical composition, a formulation, or a drug delivery system. Excipients can be used, for example, to stabilize the composition, to swell the composition (and thus often referred to as "expanding agent", "filler" or "diluent" when used for this purpose) or to make the active ingredient in the final dosage form Increased efficacy, such as promoting drug absorption, reducing viscosity or enhancing solubility. Excipients include pharmaceutically acceptable versions of anti-adhesives, binders, coatings, colors, disintegrants, flavoring agents, slip agents, lubricants, preservatives, adsorbents, sweeteners, and vehicles. The primary excipient that acts as a medium to convey the active ingredient is commonly referred to as a vehicle. Excipients can also be used in the manufacturing process to assist in the operation of the active substance, for example, in addition to assisting in vitro stability, such as preventing denaturation or agglutination beyond the expected shelf life, such as by promoting powder flowability or non-adhesion. The suitability of the excipient will generally vary depending on the route of administration, the dosage form, the active ingredient, and other factors. The term "hydrate" when used as a modifier to a compound means that the compound has less than one (eg, hemihydrate), one (eg, monohydrate), or greater than one (eg, dihydrate) associated with each compound molecule, such as A solid form of water molecule of a compound. The term "difluoromethylornithine" when used in itself means 2,5-diamine-2-(difluoromethyl)pentanoic acid in any of its forms, including non-salt and salt forms ( For example, difluoromethylornithine HCl), anhydrous and hydrated forms of the non-salt and salt forms (eg, difluoromethylornithine hydrochloride monohydrate), solvates of the non-salt and salt forms, EnantiomerR andS Form, which can also be identified asd andl Form) and mixtures of such enantiomers (for example a mixture of one of a racemic mixture or an enantiomer relative to the other). Specific forms of difluoromethylornithine include difluoromethylornithine hydrochloride monohydrate (ie, CAS ID: 96020-91-6; MW: 236.65), difluoromethyl ornithine hydrochloride Salt (also known as CAS ID: 68278-23-9; MW: 218.63) and free difluoromethylornithine (also known as CAS ID: 70052-12-9; MW: 182.17). The form of difluoromethylornithine is 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. Other synonymous terms of difluoromethylornithine and DFMO include: α-difluoromethylornithine, 2-(difluoromethyl)-DL-ornithine, 2-(difluoromethyl)guanine Acid, DL-α-difluoromethylornithine,N- Difluoromethylornithine, ornidyl, αδ-diamine-α-(difluoromethyl)pentanoic acid and 2,5-diamine-2(difluoro)pentanoic acid. As used herein, "substantially free" with respect to a given component is used herein to mean that none of the specified components are purposefully formulated into the composition and/or only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of the composition is therefore well below 0.05%, preferably below 0.01%. Most preferably, the amount of the specified component is not detected by standard analytical methods. The term "fixed dose combination" or "FDC" refers to a combination of two drugs or active ingredients that are presented in a single dosage unit (eg, a lozenge or capsule) and are therefore administered at defined dosages; further as used herein, "free dose" "Combination" means a combination of two drugs or active ingredients that are administered simultaneously but in two different dosage unit forms. "Pelletization" refers to a process in which powder particles are coalesced into larger particles containing active pharmaceutical ingredients. By "dry granulation" is meant any method comprising the step of not adding a liquid to a powder starting material, agitating and drying to obtain a solid dosage form. The resulting granulated drug can be further processed into various final dosage forms such as capsules, lozenges, powders, gels, buccal tablets and the like. The term "or" is used in the context of the claims to mean "and/or" unless the <RTI ID=0.0> </ RTI> </ RTI> <RTIgt; 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 its transgenic gene. kind. In certain embodiments, the patient or individual is a primate. Non-limiting examples of human patients are adults, adolescents, infants, and fetuses. As used herein, "pharmaceutically acceptable" means that it is suitable for contact with tissues, organs and/or body fluids of humans and animals without reasonable toxicity, irritation, allergic reaction or other problems within the scope of sound medical judgment. Or complications, their compounds, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable carrier," "drug carrier," or "carrier alone" is a pharmaceutically acceptable material that is formulated with the active ingredient in the delivery, delivery, and/or delivery of the chemical. Drug carriers can be used to improve the delivery and effectiveness of the drug, 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 a particular target site. Examples of the carrier include: liposomes, microparticles (for example, made of poly(lactic-co-glycolic acid) acid), albumin microparticles, synthetic polymers, nanofibers, nanotubes, protein-DNA complexes, proteins Conjugates, red blood cells, viral particles and dendrimers. As defined herein, the term "physically separated" refers to a pharmaceutical oral fixed dose combination comprising components a) and b) formulated so as not to be mixed with one another but separated from each other. This separation helps to minimize the interaction between the two components, especially when they are released. Generally physical separation means that the two components a) and b) are present in different compartments, such as layers, or in the form of different entities, such as granules or granules, in the formulation. The two components a) and b) need not be further separated by additional layers or coatings, although this may be suitable as 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 individual components a) and b) into a separate layer, such as a multilayer or two-layer formulation. This document describes specific examples of such compounding techniques. The term "adhesion" refers to the surface of a tablet press that adheres particles to the letters, logos or designs included on the punch face. The term "topping" refers to a crack or crack in the top or top of a tablet from the bulk of the tablet. The top crack can be caused by incompressible fine particles that migrate when air is pushed out during compression. The term "brittleness" as used herein refers to the tendency of the tablet to break, break or break after compression. It can be caused by a number of factors, including poor tablet design (too sharp edges), low moisture content, insufficient binder, and the like. In some aspects, the brittleness of the tablet sample is given in terms of weight loss % (i.e., 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 a method of bringing a pharmaceutical oral fixed dose combination into contact with a fluid and transferring the drug out of the dosage form into a fluid surrounding the dosage form. The combination of delivery rate and duration of delivery exhibited by a given 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. The continuous release profile includes a release profile of one or more active ingredients that are continuously released at a constant or variable rate. When two or more components having different release profiles are combined in one dosage form, the resulting individual release profile of the two components may be the same or different than the dosage form having only one of the components. Thus, the two components can affect each other's release profile, thereby resulting in different release profiles for the individual components. The two-component dosage form can exhibit a release profile of the two components that are the same or different from each other. The release profile of a two component dosage form with different release profiles for each component can be described as "asynchronous". Such release profiles encompass (1) different continuous releases, wherein preferably component b) is released at a slower rate than component a), and (2) a curve wherein one of components a) and b) Preferably, component b) is continuously released, and the other of components a) and b), preferably component a), is adjusted to provide continuous release with time delay. A combination of two release profiles for a drug is also possible (eg, 50% drug continuous release and 50% identical drug with time delay continuous release). Immediate Release: For the purposes of this application, the immediate release formulation is a formulation that exhibits the release of the active substance, which is not intentionally adjusted by a particular formulation design or manufacturing method. Modulated release: For the purposes of this application, a modified release formulation is a formulation that exhibits release of an active substance that is intentionally adjusted by a particular formulation design or manufacturing method. This modulating 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, a modified release means release for more than 5 h, such as release for more than 3 h or even less. As used herein, modified release is meant to encompass a continuous release, or delayed release, of the two components over time, wherein one of the components, preferably component a), is released only after the lag time. Such modified release forms can be prepared by applying a release modifying coating, such as a diffusion coating, to the drug substance or to the core of the drug substance, or by forming a release modifying matrix that embeds the drug substance. The term "tablet" refers to a pharmacological composition in the form of small, substantially solid pellets of any shape. The shape of the tablet can be cylindrical, spherical, rectangular, saclike or irregular. The term "tablet composition" means a substance included in a tablet. The "tablet composition component" or "tablet component" means a compound or substance included in a tablet composition. These may include, but are not limited to, active agents and any excipients as well as low melting point 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 considered as indicating that any term that is not defined is uncertain. Rather, the terms used in the description of the invention are intended to be understood by those skilled in the art. The unit abbreviations used herein include the 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 rotation per minute (rpm).VIII. Instance The following examples are included to demonstrate preferred embodiments of the invention. It will be appreciated by those skilled in the art that the techniques disclosed in the examples which follow represent a <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; It will be apparent to those skilled in the art, however, that <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;Instance 1- Development of difluoromethylornithine HCl and Sulindac acid combination table In a development method for a fixed dose combination (FDC) lozenge containing difluoromethylornithine HCl and sulindac, several formulations were tested (Table 1). The parameters tested included tablet disintegration time, tablet hardness and percent fragility of the tablet. Formulation I was made into a 900 mg lozenge by first mixing 1/3 of deuterated MCC (PROSOLV®) with difluoromethylornithine HCl in a 1 quart v-blender. Subsequently, sulindac and 1/3 of the purified MCC (PROSOLV®) were premixed in a polyethylene (PE) bag and combined with colloidal cerium oxide (CARBOSIL®) and pregelatinized corn starch (STARCH 1500®). Add to the blender. The PE bag was rinsed with the remaining 1/3 of the deuterated 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 the manual screening of magnesium stearate was added. This formulation was found to have some adhesion to the surface of the punch and resulted in a rough tablet surface. Thus, for Formulation II, magnesium stearate was increased from 0.5% to 1% and deuterated MCC was reduced from 38.57% to 38.07%. Formulation II was made into a 900 mg lozenge by premixing CARBOSIL®, STARCH 1500® and sulindac in a PE bag. Subsequently, 1⁄2 of PROSOLV® and difluoromethylornithine HCl were added to the 8 quart v-blender together with the premix. The remaining 1⁄2 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 via a Comill 039R screen, then returned to the v-blender for additional 10 minutes. Subsequently, magnesium stearate manually screened through 30 mesh (i.e., 590 μm) screens was added to the v-blender by hand mixing and the mixture was blended at about 25 rpm for 3 minutes. The mixture was compressed into tablets on a Key Model BBTS 10 bench. The resulting tablet was measured to have a disintegration time of about 29-32 seconds, 0.077% brittleness at 4 minutes, and 0.17392% brittleness at 8 minutes and a hardness of about 28 kp (Table 1). The tablet was then coated with O'Hara Labcoat, a 12" disk coated with 2.913% by weight of OPADRY® Yellow (Colorcon) to yield a 927 mg tablet. The film-coated tablet has 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 made into a 650 mg tablet by premixing CARBOSIL®, Part 2 of PROSOLV®, and sulindac in a PE bag. Subsequently, 1⁄2 of PROSOLV® Part 1 and difluoromethylornithine were added to the 8 quart v-blender together with the premix. The remaining 1⁄2 of the PROSOLV® Part 1 was used to rinse the PE bag and was added to the v-blender. The mixture was blended for 10 minutes at about 25 rpm. The mixture was then removed from the blender and the block was removed via a Comill 039R screen and then returned to the v-blender for additional 10 minutes. Subsequently, magnesium stearate manually screened through 30 mesh (i.e., 590 μm) screens was added to the v-blender by hand mixing and the mixture was blended at about 25 rpm for 3 minutes. The mixture was compressed into tablets on a Key Model BBTS 10 bench. The obtained tablet was measured to have a disintegration time of about 51 to 57 seconds, 0.2607% to 0.3373% brittleness at 4 minutes, and 0.8988% to 1.008% brittleness at 8 minutes and a hardness of about 13 kp. The tablet was then coated with O'Hara Labcoat, a 12" disk coated with 2.913% by weight of OPADRY® Yellow (Colorcon) to yield 669.5 mg of tablet. The film-coated tablet has 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 lozenge strength. However, a top crack was observed during the fragility test as well as during the film coating process. Formulation IV was made into a 700 mg lozenge using the same method as Formulation III. The resulting tablet was measured to have a disintegration time of from 1 minute 10 seconds to about 1 minute 34 seconds, from 0.1424% to 0.1567% brittleness at 4 minutes, and from 0.3186% to 0.5166% brittleness at 8 minutes and a hardness of about 20 kp. The tablet was then coated with O'Hara Labcoat and the 12'' disc was coated with 2.913% by weight of OPADRY® Yellow (Colorcon) to yield a 721 mg lozenge. The film-coated tablet has a disintegration time of from 1 minute 43 seconds to 2 minutes 7 seconds. In this formulation, increase the amount of PROSOLV® and increase the weight of the table from 650 mg to 700 mg. Although no top cracking was observed during the brittleness test, the three lozenges did have a top crack during film coating.table 1 : Difluoromethylornithine HCL and Formulation of sulindac fixed-dose combination lozenge I-IV . table 2 :difluoromethylornithine HCL and An exemplary formulation of a sulindac fixed dose combination lozenge. table 3 : Exemplary tablet manufacturing parameters. table 4 : for instance 1 The materials of the formulations described in the materials. Instance 2- R&D formulation IV Formulation IV was further tested from Example 1 to determine changes in parameters to prevent capping and adhesion. The first parameter tested was compressive force and a pre-compression force was added with a compression force of about 5-15% (Table 5). In order to evaluate the compressive force and pre-pressure for the formulation IV 700 mg tablet to a hardness of about 20 kp, several tests were performed. In the first test, equipment C was used to make a final blend of Formulation IV 700 mg tablets (Table 9). The manufacturing method involves premixing CARBOSIL®, part 2 of PROSOLV®, and sulindac in a PE bag. Subsequently, 1⁄2 of PROSOLV® Part 1 and difluoromethylornithine were added to the 10 quart v-blender together with the premix. The remaining 1⁄2 of the PROSOLV® section 1 is 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 comminuted through a Frewitt TC150 1.0 mm screen, then returned to the v-blender for re-blending for 35 minutes. Subsequently, magnesium stearate was manually screened through a 500 μm sieve and added to a v-blender by manual mixing at 7 rpm for 10 minutes to obtain a final blend. The compression step was carried out on a Courtoy Modul P ingot press equipped with five 17.5 x 8 mm engraved and chrome-plated punches. Set the parameters to obtain a hardness between 17.0 kp and 22.5 kp. It was found that no cavitation was observed without pre-stress. However, the pre-pressure was used to increase the hardness and avoid cracking (Table 10). In addition, tablets formed from pre-stress are more resistant to abrasion (i.e., less fragile). In addition, the 16.5 x 8 mm punch used in the Key BBTS 10 table ingot press of Example 1 appeared to be more prone to wear.table 5 : Test formulations IV It Compress parameters. NA: Not applied (*) Maximum hardness achievable without pre-compression In the second test, the surface of the punch was changed to determine its effect on Formulation IV tablets (Table 11). Equipment B was used in this test to make a final blend of Formulation IV 700 mg tablets. The manufacturing method involves premixing CARBOSIL®, part 2 of PROSOLV®, and sulindac in a PE bag. Subsequently, 1⁄2 of PROSOLV® Part 1 and difluoromethylornithine were added to the 10 quart v-blender together with the premix. The remaining 1⁄2 of the PROSOLV® section 1 is used to rinse the PE bag and add to the v-blender. The mixture was blended for 8 minutes and 30 seconds at about 30 cycles per minute. The mixture was then removed from the blender and comminuted through a CMA 1.0 mm screen, then returned to the v-blender for re-blending for 8.5 minutes. Subsequently, magnesium stearate was manually screened through a 500 μm sieve and added to a v-blender by manually mixing for 2 minutes and 20 seconds at 30 cycles per minute to obtain a final blend. The compression step was carried out on a Korsch XL100 ingot press equipped with two 17.5 x 8 mm engraved and anti-adhesive chrome-plated punches. The pre-pressure is set to approximately 30 kN of the main compressive force of 5-10%. Several different punch surfaces were also tested, including chromium, carbon, tungsten and Teflon versus stainless steel. In some embodiments, Teflon can be used to reduce adhesion. To avoid sticking, test a few extra variables and apply a high constraint at the beginning of compression. Neither the 1.1% magnesium stearate nor the 70 rotations were added to the 140 rotations to prevent sticking (Tables 11 and 12). However, increasing the ratio of magnesium stearate to 1.5% did prevent adhesion (Table 12) and the tablet hardness decreased slightly by about 20%, but the brittleness after less than 0.1% after 4 minutes was still extremely low. When two types of punches with different types of break lines (17 x 9 mm and 16.5 x 7 mm) were used, the rupturability results were in accordance with the punches tested. Thus, increasing magnesium stearate to 1.5% prevents adhesion and pre-compression prevents the formulation IV from cracking.table 6 :test 1 and test 2 in Formulation IV Batch weight. table 7 : Formulations IV It The amount of change in magnesium stearate. (*) Formula obtained after dilution to increase the percentage of magnesium stearate. The API concentration is therefore slightly below the target.table 8 : Formulation IV Coating. table 9 : for the development of formulations IV It device. table 10 : Testing pre-compression force versus formulation IV The first test parameters and results of the impact. table 11 : Test punch surface pair formulation IV The second test parameters and results of the impact. table 12 : Test final mixing duration and magnesium stearate to the formulation IV The second test parameters and results of the impact. (*) on 10 tabletstable 13 : Test compression parameters for formulations IV Test parameters and results of the impact. (*) On 30 tablets (**) on 10 tablets NA: No application test formulation IV combination tablets, difluoromethylornithine single tablets and sulindac single tablet stability Sex. The stability analysis of the formulation IV lozenge was carried out at 6 months using a Karl Fischer titration method to determine the water content (Fig. 1). In Figure 1, the combination lozenge showing Formulation IV had a lower water uptake after six months compared to the difluoromethylornithine monopatch. Water can affect drug efficacy and drug dissolution; for example, water can increase the rate of drug degradation by hydrolysis (Gerhardt, 2009). Thus, in some embodiments, the combination lozenges provided herein are more stable than one or both of the single active agent lozenges. Finally, the dissolution profile of Formulation IV was also tested. Dissolution studies were performed in a 50 mM sodium phosphate buffer medium at 7.2 pH using a paddle stirring element at 75 rpm (USP <711> Dissolution Apparatus II (Paddle)) (Figures 2A-2B). The verification method is about the level II of dissolving difluoromethylornithine and sulindac. No interference was observed between the active pharmaceutical ingredients difluoromethylornithine and sulindac itself and the dissolution medium, phosphate buffer solution or excipient. Surprisingly, it was observed that the fixed dose combination of Formulation IV had an overlapping in vitro dissolution profile compared to a single drug lozenge.Instance 3- Pharmaceutical excipients and coating compatibility A non-cGMP pharmaceutical excipient compatibility study on a difluoromethylornithine HCl/sulindac combination lozenge was conducted. Shape, HPLC analysis and XRPD characteristics were evaluated using a series of samples. Tests include PVP, HPMC, lactose, EXPLOTAB^TM Excipients for Ac-Di-Sol®, PROSOLV®, STARCH 1500® and OPADRY® Yellow. Samples prepared for excipient compatibility except for the difluoromethylornithine HCl: sulindac formulation was 5:1 and difluoromethylornithine HCl: sulindac: H₂ The O formulation is a 1:1 physical mixture of API and excipient, except for about 6:1:0.3. The total mass of most samples is approximately 750 mg. Preparation involves weighing the components into a 20 cc scintillation vial, blocking and vortexing for about 30 seconds. The sample was then stored in a 40 ° C / 75% RH stability chamber. Loosen the lid on the vial loosely and store the vial in the chamber to protect it from light. Profile observations were performed by visual inspection of vials prepared for HPLC analysis. Excipient-compatible samples were extracted with 50% acetonitrile in buffer (50 mM phosphate buffer pH 2.55). Samples containing only sulindac were weighed out of the sample fraction (approximately 150 mg) and extracted in a predetermined volume such 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 compatible sample was prepared by quantitative transfer using a predetermined volume of extraction solvent such that the final concentration of difluoromethylornithine and sulindac was about the same as above. Excipient-compatible samples were analyzed using a method capable of detecting the active agent, difluoromethylornithine and sulindac (Fig. 4A). The method uses a gradient reverse phase HPLC with 195 nm ultraviolet (UV) detection. XRPD analysis was performed using CuK alpha radiation on a Bruker AXS D8 Advance system with a Bragg-Brentano configuration. Samples were analyzed at room temperature using the following parameters: 40 kV; 40 mA; 1° divergence; and anti-scatter slits; measurement in continuous mode, 2 - 40 ° 2 Θ, 0.05 ° gradient and 1 sec / step time . Samples between 3 mg and 25 mg were analyzed using a rotating, top-filled steel sample holder in nine position autosampler fittings. Calibrate the system with traceable standards. The results are shown in Figures 4B to 4C. Difluoromethylornithine HCl with PVP K30 began to show moisture 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 excipient began to show moisture only in the 2 week sample and became liquid after 4 weeks. The same phenomenon was observed for the difluoromethylornithine HCl sample, but no similar phenomenon was observed for the sulindac sample. The HPLC analysis results for most of the samples tested did not show a unique trend (increased or decreased) at different time points. Although multiple samples have unusually low analytical values, the analytical levels exhibit more increasing trends or remain relatively constant over a 4 week period. The sulindac/difluoromethylornithine ProSolv SMCC90 sample was observed to have the highest change in the analysis results. The analytical value at the 4 week time point was 10.0% higher than the initial analysis result. This change can be attributed to the method (unverified) and sample consistency at different time points. Although the acceptable random analysis error of the verification method is 2%, the variability of this method is unknown. Except for some samples, the analytical values for each of the samples tested at different time points were within the normally acceptable 2% random error of the analytical method. There is no unique tendency for API, difluoromethylornithine and sulindac under the stress conditions tested. The results of this study indicate that the API (difluoromethylornithine HCl/sulindac) is compatible with 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. The XRPD results showed no interaction between the API and the vehicle after four weeks at 40 ° C / 75% RH. This indicator API (difluoromethylornithine HCl/sulindac) is compatible with potential excipients. The coating test was carried out on a tablet to determine the effect on stability at 25 ° C / 60% RH or 40 ° C / 75% RH moisture content at 1 month and 3 months. The coating includes OPADRY® Yellow (Colorcon, 03B92557), OPADRY® White (Colorcon Y-1-7000), OPADRY® II White (Colorcon 85F18422) and OPADRY® Clear (Colorcon YS-3) in 3% or 4% by weight. -7413). Color visual inspection was taken to evaluate the overall color difference or DE between the stable tablet and the initial coated tablet. The color of the lozenge was tested using a Datacolor Spectraflash 600 Series spectrophotometer. The data was analyzed using the Commission Internationale de l'Eclairage (CIE) L* a* b* system. In the L* a* b* system, the color is represented as a coordinate in three-dimensional space. Luminance 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 plotting the color in a geometric shape, the difference between the two colors (the overall color difference = E*) can be determined by calculating the distance between the two points using the following equation. DE* = [(L*1 - L*2)2 + (a*1 - a*2)2 + (b*1 - b*2)2]1/2 Using Datacolor, analysis in various coating formulations Each of the tablets is increased in weight. The closer the DE value is to zero, the closer the color of the tested tablet is to the color standard (initial sample). The Colorcon standard spectrum of the white coating (by QC test) will be a DE value of less than 1.5. All samples with white film stability exceeded 1.5 DE and therefore would not pass the Colorcon standard QC test (Table 14). The clear coated lozenge is also well above the value of 1.5.table 14 : in the form of a stable coated lozenge DE value. The best DE results were found to be a lozenge coated with a yellow formulation. The DE value is much lower than 1.5. A DE value of 1 or less (total color difference) is considered to be imperceptible to the human eye. The typical internal specification of the yellow coated Colorcon tends to be a DE value of 2.5-3. Therefore, OPADRY® Yellow is used to coat the combined lozenge.Instance 4- Fixed co-regulation of difluoromethylornithine / Bioequivalence study of sulindac A preliminary test is performed to compare the administration of a difluoromethyl group with a co-adjusted tablet containing difluoromethylornithine/sulindac, and a normal healthy individual under fasting conditions. Pharmacokinetic parameters of difluoromethylornithine, sulindac sulindac sulfide, and sulindac in plasma compared to individual tablets of ornithine or sulindac. The second objective of this study was to determine the safety and tolerability of difluoromethylornithine/sulindac co-adjusted tablets compared to individual formulations administered alone or co-administered in normal healthy individuals. The study consisted of twelve individuals, male or female, at least 18 years old but not older than 60 years old. Mainly including guidelines: mild smokers, non-smokers or former smokers; body mass index (BMI) ≥ 18.50 kg / m² And <30.00 kg/m² The 12-lead ECG performed (the individual must be in the supine position for 10 minutes before ECG and ECG before all requested blood draws) did not find clinically significant abnormalities; females were negative for pregnancy testing; and based on medical history, comprehensive Physical examinations (including vital signs) and laboratory tests (general biochemistry, hematology, and urine tests) are healthy. Individuals were treated in the following four treatment groups: • Treatment 1: co-administered a single 750/ of difluoromethylornithine 375 mg/sulindac 75 mg lozenge (2 x 375/75 mg lozenge) 150 mg dose • Treatment 2: a single 750 mg dose of difluoromethyl ornithine 250 mg lozenge (3 x 250 mg lozenge) • Treatment 3: Single 150 mg dose of sulindac 150 mg lozenge (1 x 150 Mg tablet) • Treatment 4: Single 150 mg dose of sulindac 150 mg tablet (1 x 150 mg tablet) and 250 mg tablet of difluoromethyl ornithine (3 x 250 mg tablet) A single 750 mg dose was assigned to each individual for 4 different treatments over a 28 day period. A single oral dose assigned to the treatment was administered under fasting conditions during each study period. The treatment was separated by a wash-out of 7 calendar days. Each body collected a total of 120 blood samples at 80 times. The first blood sample is collected before the drug is administered, while the other blood samples are administered at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, Collected after 16, 24, 36 and 48 hours. The analyte was measured by HPLC with MS/MS detection. The analysis ranged from 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 (AE), standard laboratory evaluations, vital signs, and ECG.Mathematical model and statistical method of pharmacokinetic parameters : The main absorption and distribution parameters were calculated using a non-compartmental method with a log-linear finality hypothesis. The trapezoidal rule is used to estimate the area under the curve. The final assessment is based on maximizing the determination factor. The pharmacokinetic parameter for this test is C_Max , T_Max , AUC_0-T , AUC_0-∞ , AUC_0-T/∞ λ_Z And T_Half . Statistical analysis of parameters based on pharmacokinetic parameters ANOVA model; for C_Max , AUC_0-T And AUC_0-∞ 90% confidence interval on both sides of the geometric method ratio based on ln conversion data; T_Max Sorted conversion. The ANOVA model uses fixed factors for sequence, time period, and processing; random factors are individuals nested within the sequence. Pharmacokinetic parameters include C_Max (maximum observed plasma concentration); T_Max (Maximum time to observe plasma concentration, if it occurs more than one time point, then T_Max Defined as the first time point with this value); T_LQC (The last observed time to quantify plasma concentration); AUC_0-T (Using linear trapezoidal method from 0 to T_LQC Calculated cumulative area under the plasma concentration time curve); AUC_0-∞ (The plasma concentration time curve approaches the infinite area, calculated as AUC_0-T + C_LQC /λz, where C_LQC For time T_LQC Estimated concentration); AUC_0-T/∞ (AUC_0-T Relative to AUC_0-∞ Relative percentage); T_LIN (time point at the beginning of the log-linear elimination period); λz (significant elimination rate constant, estimated by linear regression of the logarithmic concentration versus the linear portion of the end of the time curve); and T_Half (Final elimination half-life, calculated as ln(2) / λz).table 15 : pharmacokinetic parameters of difluoromethylornithine *median (range)table 16 : Pharmacokinetic parameters of sulindac *Median (range) ** for AUC_0-∞ λ_Z And T_Half n=7 *** for AUC_0-∞ λ_Z And T_Half n=8Guidelines for bioequivalence : Statistical inference of difluoromethylornithine based on the bioequivalence method, using the ratio of geometric LSmeans, where the parameter C is converted from ln_Max , AUC_0-T And AUC_0-∞ The corresponding 90% confidence interval for Process 1 versus Process 2, Process 2 vs. Process 4, and Process 1 vs. Process 4 is compared to the 80.00% to 125.00% range. Statistical inference of sulindac based on the bioequivalence method using the ratio of geometric LSmeans, where the parameter ln is converted for ln_Max , AUC_0-T And AUC_0-∞ The corresponding 90% confidence interval for Process 1 versus Process 3, Process 3 vs. Process 4, and Process 1 versus Process 4 is calculated from the range of 80.00% to 125.00%. The same criteria apply to sulindac sulfide and sulindac citrate, and the results present supporting evidence of comparable therapeutic outcomes.Safety result : A total of 12 individuals entered the study and all individuals received 4 treatments under the study. None of the individuals involved in the study reported serious adverse events (SAE) and death. No individual was withdrawn by the investigator for safety reasons. Four (33%) of the 12 individuals enrolled in the study reported a total of 4 treatment-induced adverse events (TEAEs). Of these events, two occurred after the administration process 1, one after the treatment 3, and the remaining one after the treatment 4 was administered. Individuals who were treated with treatment 2 did not report any TEAE. One and a half TEAEs experienced during the study period were considered to be related to drug administration. The TEAE in this study had a low incidence; one subject (8%) per treatment group experienced TEAE. After the treatment of 4 doses, the dry mouth was reported, and after the treatment was administered, the upper respiratory tract infection was reported and after the treatment 1 was administered, the vascular puncture site was scratched and headache was reported. The incidence of TEAE was the same for individuals treated with Treatment 3 and Treatment 4 (8%) and slightly lower than the incidence of TEAE reported by individuals treated with Treatment 1 (17%). The drug-related TEAE was reported to have the same incidence as the individual administered with Treatment 1 and Treatment 4 (8%), whereas the individual administered with Treatment 3 did not experience the drug-related TEAE. The TEAE experienced during the study considered mild (3/4, 75%) and moderate (1/4, 25%) in intensity. None of the individuals experienced severe TEAE during the study. All abnormal clinical laboratory values were more or less above or below their reference range, 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 individual in this study. All medical examinations were judged to be normal. Overall, the drugs tested were generally safe and the individuals included in this study were well tolerated for the drugs tested.Processing 1 And processing 2 Comparison between difluoromethylornithine : pharmacokinetic results reveal C of difluoromethylornithine_Max , AUC_0-T And AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval are included in the range of 80.00% to 125.00%. This comparison indicates that when treatment 1 and treatment 2 were administered under fasting conditions, the bioequivalence criteria were met and the bioavailability of difluoromethylornithine was shown to contain difluoromethylornithine/sulindac. The co-adjusted tablet is equivalent to a tablet containing only difluoromethylornithine.table 17 : Processing 1 Relative to processing 2 Summary of Statistical Analysis of Difluoromethylornithine * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mLProcessing 2 And processing 4 Comparison between difluoromethylornithine : pharmacokinetic results reveal C of difluoromethylornithine_Max , AUC_0-T And AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval are included in the range of 80.00% to 125.00%. This comparison indicates that when treatment 2 and treatment 4 were administered under fasting conditions, the bioequivalence criteria were met, and individual lozenges exhibiting co-administration of sulindac and difluoromethylornithine did not affect separate administration. The bioavailability of difluoromethylornithine.table 18 : Processing 2 Relative to processing 4 Summary of Statistical Analysis of Difluoromethylornithine * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mLProcessing 1 And processing 4 Comparison between difluoromethylornithine : pharmacokinetic results reveal C of difluoromethylornithine_Max , AUC_0-T And AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval are included in the range of 80.00% to 125.00%. This comparison indicates that bioequivalence criteria are met when Treatment 1 and Treatment 4 are administered under fasting conditions, and are presented for co-administered formulations containing difluoromethylornithine/sulindac and co-administered The bioavailability of difluoromethylornithine of each of the individual tablets of difluoromethylornithine or sulindac is similar.table 19 : Processing 1 Relative to processing 4 Summary of Statistical Analysis of Difluoromethylornithine * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mLProcessing 1 And processing 3 Comparison of sulindac : Pharmacokinetic results show 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 90CI is below the 80.00% limit. Since the ratio is in the range of 80.00% to 125.00% of all PK parameters, the intra-individual variability may indicate C_Max The lower limit is outside the range of BE. The results obtained for this comparison show that the sample size used in this preliminary test is not sufficient to demonstrate the equivalence of the sulindac bioavailability of the co-adjusted tablet and sulindac alone.table 20 : Processing 1 Relative to processing 3 Overview of statistical analysis of sulindac * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mL ** for AUC_0-∞ , n=7 based on the data, incorporating invariant intra-individual changes between all comparisons, C_Max Is about 24.6%, and AUC_0-T It is about 12%. Statistically, given that the expected treatment 1 and treatment 3 ratios of geometric LSmeans should be within 90% and 110%, it is estimated that the number of individuals that meet the 80.00% to 125.00% bioequivalence range (statistical prior efficacy is at least 80%) is The key research for the future will be about 54. The inclusion of 60 individuals should be sufficient to account for the possibility of loss and variation of CV within the estimated individual.Processing 3 And processing 4 Comparison of sulindac : Pharmacokinetic results show C of sulindac_Max , AUC_0-T And AUC_0-∞ The geometric LSmean ratio and the corresponding 90% confidence interval are included in the range of 80.00% to 125.00%. The results of this comparison indicate that when Treatment 3 and Treatment 4 were administered under fasting conditions, the bioequivalence criteria were met and it was demonstrated that co-administration of individual lozenges containing difluoromethylornithine or sulindac did not affect separate administration. The availability of sulindac with the time.table twenty one : Processing 3 Relative to processing 4 Overview of statistical analysis of sulindac * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mL ** for AUC_0-∞ , n=7Processing 1 And processing 4 Comparison of sulindac : Pharmacokinetic results show 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 90CI is below the 80.00% limit. Since the ratio is in the range of 80.00% to 125.00% of all PK parameters, the intra-individual variability may indicate C_Max The lower limit is outside the range of BE. The results obtained for this comparison demonstrate that the sample used in this preliminary test is not large enough to demonstrate co-dosing and co-administration of sulindac bioavailability with individual lozenges containing difluoromethylornithine or sulindac. Bioequivalence.table twenty two : Processing 1 Relative to processing 4 Overview of statistical analysis of sulindac * C_Max Unit is ng/mL and AUC_0-T And AUC_0-∞ The unit is ng·h/mL ** for AUC_0-∞ , n=8 based on the data, incorporating invariant intra-individual changes between all comparisons, C_Max Is about 24.6%, and AUC_0-T It is about 12%. Statistically, given that the expected treatment 1 and treatment 4 ratios for geometric LSmeans should be within 92.5% and 107.5%, it is estimated that the number of individuals that meet the 80.00% to 125.00% bioequivalence range (statistical prior efficacy is at least 80%) is The key research for the future will be about 36. The inclusion of 40 individuals should be sufficient to account for the possibility of loss and variation of CV within the estimated individual.* * * All of the compositions and/or methods disclosed and claimed herein can be made and executed in accordance with the present invention without undue experimentation. Although the compositions and methods of the present invention have been described in terms of the preferred embodiments, it will be apparent to those skilled in the art that the present invention can be applied to the methods and methods described herein without departing from the spirit, scope and scope of the invention. The steps or steps are in the order. More specifically, it is apparent that certain agents that are chemically and physiologically related may be substituted for the agents described herein while achieving the same or similar results. All such similar substitutes and modifications, which are 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 hereby expressly incorporated by reference in their entirety to the extent of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure. US Patent 3,647,858 US Patent 3,654,349 US Patent 4,330,559 US Patent 4,413,141 US Patent 5,814,625 US Patent 5,843,929 US Patent 6,258,845 US Patent 6,428,809 US Patent 6,702,683 US Patent 8,329,636 US Patent 9,121,852 US Patent Publication US2013/0217743 US 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. DuBoisEt al., Cancer Res. , 56:733-737, 1996. ErdmanEt al., Carcinogenesis , 20:1709-13, 1999. European Pharmacopoeia, Strasbourg: Council of Europe, 8^Th Ed., 2014. Fultz and Gerner,Mol. Carcinog ., 34:10-8, 2002. Gerhardt,Pharmaceutical Processes, 13(1), 2009. GernerEt al. ,Cancer Epidemoil. 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. Ther ., 5(12):1658-64, 2006. Japanese Pharmacopoeia, Tokyp: Society of Japanese Pharmacopoeia, 16^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. Prev ., 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 figures 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 the detailed description of the specific embodiments presented herein. Figure 1 : Stability analysis of prototype batch 7107/04 of difluoromethylornithine HCl monohydrate (375 mg) and sulindac (75 mg) 700 mg tablet. Tablets have a 3% w/w coating. The samples were analyzed at time zero (T0) and at 6 months (T6) using a validated Karl Fischer titration method to determine the water content. Samples were stored in HDPE bottles with or without lids in a validated stability chamber. Values represent the percentage of water in each tablet under specified conditions. Figures 2A-2B: Results coating dissolving lozenges batch analysis of the 7107/04 and 6A001. A reference tablet comprising 250 mg of difluoromethylornithine HCl monohydrate and commercially available 150 mg of sulindac was used for comparison. The co-formulated lozenge contained 375 mg of difluoromethylornithine HCl monohydrate with a 3% w/w coating and 75 mg of sulindac. Figure 3 : depicts a simplified flow of a process for the manufacture of tablets containing difluoromethylornithine HCl monohydrate and sulindac. 4A to 4C: (A) show the measurement capability of the impurities eflornithine HCl monohydrate and Sulindac were selected lozenges formulated Typical HPLC chromatograms of. (BC) X-ray powder diffraction (XRPD) pattern of difluoromethylornithine HCl monohydrate and sulindac active ingredient mixed with a tablet excipient at time zero, two weeks and four weeks. The lack of support supports excipient compatibility and polymorph stability.

Claims (94)

A composition comprising a fixed dose combination of a pharmaceutically effective amount of eflornithine and a pharmaceutically effective amount of a non-steroidal anti-inflammatory drug (NSAID) or a metabolite thereof. The composition of claim 1, wherein the fixed dose combination is a pharmaceutically effective amount of difluoromethylornithine and a pharmaceutically effective amount of sulindac. The composition of claim 2, wherein the difluoromethylornithine is difluoromethylornithine hydrochloride monohydrate. The composition of claim 3, wherein the difluoromethylornithine hydrochloride monohydrate is a racemic mixture of the two enantiomers. The composition of claim 3, wherein the difluoromethylornithine hydrochloride monohydrate is a substantially optically pure preparation. The composition of claim 4, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 10 mg to about 1000 mg. The composition of claim 6 wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 250 mg to about 500 mg. The composition of claim 7, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 300 mg to about 450 mg. The composition of claim 8 wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 350 mg to about 400 mg. The composition of claim 9, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is about 375 mg. The composition of claim 10, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is 375 mg. The composition of claim 4, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 35% to about 60% by weight. The composition of claim 12, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 40% to about 55% by weight. The composition of claim 13 wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 50% to about 55% by weight. The composition of claim 14, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from about 52% by weight to about 54% by weight. The composition of claim 15, wherein the amount of the difluoromethylornithine hydrochloride monohydrate racemate is from 52% by weight to 54% by weight. The composition of any one of claims 2 to 16, wherein the amount of sulindac is from about 10 mg to about 250 mg. The composition of claim 17, wherein the amount of sulindac is from about 50 mg to about 100 mg. The composition of claim 18, wherein the amount of sulindac is from about 70 mg to about 80 mg. The composition of claim 19, wherein the amount of sulindac is about 75 mg. The composition of claim 20, wherein the amount of sulindac is 75 mg. The composition of any one of claims 2 to 16, wherein the amount of sulindac is from about 5% by weight to about 20% by weight. The composition of claim 22, wherein the amount of sulindac is from about 8% by weight to about 15% by weight. The composition of claim 23, wherein the amount of sulindac is from about 10% to about 12% by weight. The composition of claim 24, wherein the amount of sulindac is from 10% to 11% by weight. The composition of any one of claims 2 to 25, further comprising an excipient. The composition of claim 26, wherein the excipient is starch, colloidal cerium oxide or deuterated microcrystalline cellulose. The composition of claim 26, wherein the excipient is colloidal ceria. The composition of claim 28, wherein the composition further comprises a second excipient. The composition of claim 29, wherein the second excipient is deuterated microcrystalline cellulose. The composition of any one of claims 2 to 30, further comprising a lubricant. The composition of claim 31, wherein the lubricant is magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, aluminum stearate, polyethylene glycol, boric acid or sodium benzoate. The composition of claim 32, wherein the lubricant is magnesium stearate. The composition of claim 33, wherein the amount of magnesium stearate is from about 0.25 wt% to about 2 wt%. The composition of claim 34, wherein the amount of magnesium stearate is from about 0.75% by weight to about 2% by weight. The composition of claim 35, wherein the amount of magnesium stearate is from about 1% to about 1.5% by weight. The composition of claim 36, wherein the amount of magnesium stearate is about 1.1% by weight. The composition of claim 36, wherein the amount of magnesium stearate is about 1.5% by weight. The composition of any one of claims 2 to 38, wherein the composition is in the form of a capsule, a lozenge, a micro-tablet, a granule, a pellet, a solution, a gel, a cream, a foam or a patch. The composition of claim 39, wherein the composition is in the form of a tablet. The composition of claim 40, wherein the lozenge has a weight of from about 650 mg to about 1,000 mg. The composition of claim 41, wherein the lozenge has a weight of from about 675 mg to about 725 mg. The composition of claim 42, wherein the lozenge has a weight of about 700 mg. The composition of claim 40, wherein the tablet further comprises a coating. The composition of claim 44, wherein the coating is a modified release coating or an enteric coating. The composition of claim 45, wherein the coating is further defined as a pH reactive coating. The composition of claim 45, wherein the coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate) phthalate (PVAP) , hydroxypropyl methylcellulose 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, or succinic acid hydroxypropyl methylcellulose (HPMCAS). The composition of claim 44, wherein the coating masks the taste of difluoromethylornithine. The composition of claim 49, wherein the coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow. The composition of any one of claims 44 to 49, wherein the amount of coating is from about 1% to about 5% by weight. The composition of claim 50, wherein the amount of the coating is from about 2% to about 4% by weight. The composition of claim 51, wherein the amount of the coating is about 3% by weight. The composition of any one of claims 44 to 49, wherein the amount of the coating is from about 5 mg to about 30 mg. The composition of claim 53, wherein the amount of the coating is from about 15 mg to about 25 mg. The composition of claim 54, wherein the amount of the coating is about 21 mg. The composition of claim 44, wherein the lozenge has a weight of from about 675 mg to about 750 mg. The composition of claim 56, wherein the lozenge has a weight of from about 700 mg to about 725 mg. The composition of claim 57, wherein the lozenge has a weight of about 721 mg. A method of preventing and/or treating a disease or condition in a patient in need thereof, comprising administering to the patient a composition according to any one of claims 2 to 58. The method of claim 59, further comprising administering to the patient a second composition according to any one of claims 2 to 58, wherein the first and second compositions comprise the same fixed dose combination. The method of claim 60, wherein the first and the second administration are performed simultaneously. The method of claim 61, wherein the second administration follows the first vote at intervals of 1 second to 1 hour. The method of any one of claims 60 to 62, wherein the first and second compositions are formulated as a tablet and contain the same amount of difluoromethylornithine and sulindac. The method of any one of claims 59 to 63, wherein the disease is cancer. The method of claim 64, wherein 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. The method of claim 65, wherein the colon cancer is a familial adenomatous polyposis. The method of claim 64, wherein the cancer is a neuroblastoma. The method of claim 59, wherein the condition is a skin disease. The method of claim 68, wherein the skin disorder is facial hirsutism. The method of claim 59, wherein the composition is administered orally, intraarterially, intravenously or topically. The method of claim 59, wherein the composition is administered orally. The method of claim 59, wherein the composition is administered every 12 hours. The method of claim 59, wherein the composition is administered every 24 hours. The method of claim 59, wherein the composition is administered at least a second time. A method of preparing a tablet of any one of claims 40 to 58 comprising: (a) premixing sulindac with an excipient to form a first mixture; (b) combining the first mixture with Mixing a second mixture of fluoromethylornithine and an excipient to form a blend; (c) sieving the blend to form a granulated blend; (d) adding a lubricant to the granulated blend To obtain a final blend; and (e) applying a compressive force to the final blend to form the tablet. The method of claim 75, further comprising mixing the granulated blend prior to step (d) and mixing the final blend prior to step (e). The method of claim 75, wherein there are two excipients in the first mixture, wherein the first excipient is colloidal ceria and the second excipient is deuterated microcrystalline cellulose. The method of claim 75 or 77, wherein the excipient of the second mixture is deuterated microcrystalline cellulose. The method of claim 75, wherein the premixing is carried out in a polyethylene coated container. The method of claim 75 or 76, wherein the mixing is carried out in a diffusion blender. The method of any one of claims 75 to 77, wherein the lubricant is magnesium stearate. The method of claim 81, wherein prior to step (d), the magnesium stearate is sieved through a screen. The method of claim 82, wherein the screen is a 500 μm screen. The method of claim 75, wherein the sifting comprises applying the blend to a rotation corrector. The method of claim 84, wherein the rotation corrector comprises a 1.0 mm screen. The method of claim 75, further comprising a pre-compression step after step (d) and prior to step (e), wherein the blend is compressed with a force lower than the force of step (e) to form a pre-compression blend. The compound, in addition, wherein the compressive force of step (e) is applied to the pre-compressed blend to form the tablet. The method of claim 86, wherein the pre-compression step prevents the tablet from capping. The method of claim 81, wherein the compressive force of the pre-compression step is applied from about 5% to about 15% of the compressive force applied in step (e). The method of any one of clauses 86 to 88, wherein the pre-compression step has a compressive force of 2.5 kN to 3.5 kN. The method of claim 89, wherein the pre-compression step has a compressive force of about 3 kN. The method of claim 75, wherein the compressive force of step (e) is from 20 kN to 35 kN. The method of claim 91, wherein the compressive force of step (e) is about 25 kN. The method of claim 75, further comprising coating the tablet. The method of claim 93, wherein the coating comprises hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, and iron oxide yellow.