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Title:
METHOD OF TREATMENT OF ANDROGEN-MEDIATED CANCERS
Document Type and Number:
WIPO Patent Application WO/2012/018759
Kind Code:
A2
Abstract:
Provided herein are methods for treating androgen-mediated carcinomas. The methods include administering a therapeutically effective amount of a pharmaceutical product that includes at least one selective and reversible monoamine oxidase A inhibitor.

Inventors:
BRAND BARRY SCOTT (US)
BURCH DANIEL JOESPH (US)
KRISHNAN RANGA (US)
Application Number:
PCT/US2011/046191
Publication Date:
February 09, 2012
Filing Date:
August 02, 2011
Export Citation:
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Assignee:
CENERX BIOPHARMA INC (US)
BRAND BARRY SCOTT (US)
BURCH DANIEL JOESPH (US)
KRISHNAN RANGA (US)
International Classes:
A61K31/39; A61K31/353; A61K31/38; A61K31/382; A61P35/00
Domestic Patent References:
WO2010080977A22010-07-15
Foreign References:
US20080009542A12008-01-10
Other References:
LAWRENCE TRUE ET AL.: 'A molecular correlate to the Gleason grading system f or prostate adenocarcinoma.' PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITIED STATES OF AMERICA vol. 103, no. 29, 18 July 2006, pages 10991 - 10996
Attorney, Agent or Firm:
JENKINS, Mark D. (P.O. Box 7037Atlanta, GA, US)
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Claims:
CLAIMS

We claim:

1. A method of treating one or more androgen-mediated precancers, carcinomas, or metastatic carcinomas comprising administering a therapeutically effective amount of a pharmaceutical composition comprising 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide..

2. A method of slowing or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas in a mammal suffering from said condition comprising administering to said mammal a therapeutically effective amount of a pharmaceutical product comprising 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10- dioxide.

3. A pharmaceutical composition for treating, slowing, or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas comprising 3- fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide.

4. Use of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10, 10-dioxide in the manufacture of a pharmaceutical composition for treating, slowing, or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas.

5. The method, composition, or use of claims 1 - 4, wherein the pharmaceutical

composition comprises an admixture of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and a stabilizer.

6. The method, composition, or use of claim 5, wherein the 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide and stabilizer are a solid-form unilamellar matrix.

7. The method, composition, or use of claims 1 -4, wherein the pharmaceutical

composition comprises a mixture of substantially amorphous 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathin 10,10-dioxide as a therapeutically active ingredient and a stabilizer.

8. The method, composition, or use of any one of claims 1 - 7, wherein the pharmaceutical composition comprises at least one excipient.

9. The method, composition, or use of any one of claims 1 -8, wherein the androgen- mediated carcinoma is an adenocarcinoma.

10. The method, composition, or use of claim 9, wherein the adenocarcinoma arises in the colon, lung, breast, esophagus, pancreas, stomach, small intestine, caecum, gallbladder, sweat glands, kidney, liver, rectum, cervix, ovary, endometrium, urachus, vagina, testicle, prostate, or a combination thereof.

11. The method, composition, or use of claim 9, wherein the adenocarcinoma is prostatic cancer.

12. The method, composition, or use of any one of claims 1 - 11 , wherein the

pharmaceutical product is administered orally, rectally, vaginally, intraurethrally, intraocularly, intranasally, intraauricularly, topically, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, or intrasternally.

Description:
METHOD OF TREATMENT OF ANDROGEN-MEDIATED CANCERS

FIELD OF THE INVENTION

The present invention relates generally to methods of treating androgen-mediated cancers and, more specifically, to methods of treating androgen-mediated adenocarcinomas by administering at least one monoamine oxidase A inhibitor to a patient in need thereof.

BACKGROUND

Androgen-mediated carcinoma, such as prostatic cancer, is one of the most common cancers in men. The normal development and maintenance of the prostate is dependent on androgen acting through the androgen receptor which plays a vital role in the development and progression of prostate cancer. Expression of the androgen receptor continues throughout prostate cancer progression while mutation of the androgen receptor is believed to contribute to the progression of prostatic cancer by allowing androgen receptor transcriptional activation in response to anti-androgens or other endogenous hormones. Prostatic cancer progression has also been associated with increased growth factor production and an altered response to growth factors by prostate cancer cells. The kinase signal transduction cascades initiated by mitogenic growth factors modulate the transcriptional activity of the androgen receptor. The inhibition of androgen receptor activity is believed to delay prostate cancer progression.

Prompt detection and treatment via prostate-specific antigen testing remain vital means of reducing mortality caused by prostatic cancer. While surgery is one option to limit mortality, such cancers can metastasize to other parts of the body before detection and surgery. In some cases, prostate-specific antigen concentrations can be reduced by radiation treatment.

Radiation therapy has also been widely used as an alternative to radical prostatectomy. For treatment of patients with locally advanced cancers, hormonal therapy such as androgen- deprivation therapy (ADT) before or following a prostatectomy, radiation or chemotherapy has been utilized.

Recent studies show elevated expression of monoamine oxidase A in androgen- mediated cancers such as prostatic cancer. Monoamine oxidase A has been found to be one of the most highly differentially overexpressed genes at the transcription level in poorly

differentiated primary prostate cancer cells suggesting that monoamine oxidase A plays a role in the progression of androgen-mediated cancers such as prostatic cancer. The monoamine oxidase A inhibitor, clorgyline, has been shown to exert anti-oncogenic and pro-differentiation effects in advanced prostatic cancer cells. Such monoamine oxidase A inhibitors, however, are not selective or reversible thereby potentially leading to accumulation or hypertensive crisis thereby requiring intense dietary restrictions.

SUMMARY

One aspect of the present invention includes a method of treating one or more androgen-mediated precancers, carcinomas, or metastatic carcinomas comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one selective monoamine oxidase-A inhibitor.

Another aspect of the present invention includes a method of slowing or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas in a mammal suffering from said condition comprising administering to said mammal a

therapeutically effective amount of a pharmaceutical product comprising at least one selective monoamine oxidase-A inhibitor.

Another aspect of the present invention includes a pharmaceutical composition for treating, slowing, or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas comprising at least one selective monoamine oxidase-A inhibitor.

Another aspect of the present invention includes a use of at least one selective monoamine oxidase-A inhibitor in the manufacture of a pharmaceutical composition for treating, slowing, or arresting growth of one or more androgen-mediated precancers, carcinomas or metastatic carcinomas.

In one embodiment of the methods, composition, or use, the at least one selective monoamine oxidase-A inhibitor is selected from the group consisting of moclobemide, brofaromine, bazinaprine, caroxazone, clorgiline, metralindole, minaprine, befloxatone, toloxatone, pirlindole, amiflamine, befol, cimoxatone, esuprone, sercloremine, tetrindole, and a combination thereof. In one embodiment, the at least one selective monoamine oxidase-A inhibitor is 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10, 10-dioxide. In one embodiment, the at least one selective monoamine oxidase-A inhibitor is reversible. In one embodiment, the at least one selective and reversible monoamine oxidase-A inhibitor is selected from the group consisting of moclobemide, brofaromine, caroxazone, metralindole, minaprine, befloxatone, toloxatone, pirlindole, amiflamine, befol, cimoxatone, esuprone, sercloremine, tetrindole, and a combination thereof. The at least one selective and reversible monoamine oxidase-A inhibitor is 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide according to one embodiment. In one embodiment, the pharmaceutical composition comprises an admixture of 3-fluoro- 7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and a stabilizer. In one embodiment, the 3- fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and stabilizer are a solid-form unilamellar matrix. In another embodiment, the pharmaceutical composition comprises a mixture of substantially amorphous 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathin 10,10-dioxide as a therapeutically active ingredient and a stabilizer. The pharmaceutical composition comprises at least one excipient according to one embodiment.

In one embodiment of the methods, composition, or use, the androgen-mediated carcinoma is an adenocarcinoma. In one embodiment, the adenocarcinoma arises in the colon, lung, breast, esophagus, pancreas, stomach, small intestine, caecum, gallbladder, sweat glands, kidney, liver, rectum, cervix, ovary, endometrium, urachus, vagina, testicle, prostate, or a combination thereof. The adenocarcinoma is prostatic cancer according to one embodiment. In one embodiment, the pharmaceutical product is administered orally, rectally, vaginally, intraurethrally, intraocularly, intranasally, intraauricularly, topically, subcutaneously,

intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, or intrasternally.

Combinations of aspects and embodiments form further embodiments of the present invention.

DETAILED DESCRIPTION

Provided herein are methods for treating, preventing, eradicating, slowing the growth of, or ameliorating androgen-mediated precancers, carcinomas or metastatic carcinomas. In one embodiment, the methods include administering a therapeutically effective amount of a pharmaceutical product that includes at least one monoamine oxidase A inhibitor. As used herein, the therapeutically effective amount is an amount effective to achieve the intended purpose. The therapeutically effective amount can depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as tumor markers, weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

Typically, patients taking monoamine oxidase A inhibitors are required to observe strict dietary limitations to avoid potentially serious cardiovascular side effects that can be triggered by eating tyramine-rich foods. In a preferred embodiment, the at least one monoamine oxidase A inhibitor is selective for monoamine oxidase A, which leaves monoamine oxidase B unaffected and available to metabolize excessive levels of tyramine, thus avoiding serious cardiovascular risks. In one embodiment, the selective monoamine oxidase A inhibitor includes moclobemide, brofaromine, bazinaprine, caroxazone, clorgiline, metralindole, minaprine, befloxatone, toloxatone, pirlindole, amiflamine, befol, cimoxatone, esuprone, sercloremine, tetrindole, TriRima™, and a combination thereof.

In yet another preferred embodiment, the at least one monoamine oxidase A inhibitor is reversible, which allows monoamine oxidase A to be freed up to metabolize tyramine should levels become too high. Most monoamine oxidase inhibitors are irreversible and can bind both monoamine oxidase A and monoamine oxidase B for up to two weeks leading to the "cheese effect" in the digestive system. In a particularly preferred embodiment, the at least one monoamine oxidase A inhibitor is both selective and reversible thereby allowing patients to realize the efficacy benefits without restrictive diets or tyramine reactions. In one embodiment, the selective and reversible monoamine oxidase A inhibitor includes moclobemide, brofaromine, caroxazone, metralindole, minaprine, befloxatone, toloxatone, pirlindole, amiflamine, befol, cimoxatone, esuprone, sercloremine, tetrindole, TriRima™, and a combination thereof. In a preferred embodiment, the selective and reversible monoamine oxidase A inhibitor is 3-fluoro-7- (2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide (also referred to as TriRima™, CX-157 or, as used herein, the active agent) which acts as an active pharmaceutical ingredient and has the structure:

3-fluoro-7-(2,2,2-trifluoroethoxy) phenoxathiin-10, 10-dioxide

CX-157 is a potent and specific monoamine oxidase A (MAO-A) inhibitor which is described in U.S. Patent No. 6,110,961, U.S Patent Publication No. 2008/0009542, U.S. Serial Nos. 61/143,764, and 61/143,767, the entireties of which are incorporated herein by reference. CX-157 is readily soluble in a variety of organic solvents but shows only sparing solubility in water.

As described in more detail herein, in one embodiment amorphous CX-157 is produced through the Form A polymorph, this polymorph being described in U.S. Publication No.

2008/0009542, herein incorporated by reference in its entirety. Without being bound by any theory, starting with the "high melt" Form A is believed to enhance the final stability of the amorphous material.

In one embodiment, the pharmaceutical products provided herein can be used to treat androgen-medicated carcinomas. Without being bound by any theory, the inventors believe that the pharmaceutical products provided herein: (a) inhibit the expression of monoamine oxidase A which is believed to promote the growth of cancer cells; (b) counteract oncogenic pathways; and (c) promote cell differentiation, thereby providing a therapeutic treatment of androgen-medicated carcinomas. In a preferred embodiment, the pharmaceutical products provided herein can be used to treat carcinomas that begin in cells that line certain internal organs and have gland-like or secretory properties (i.e., adenocarcinomas). Exemplary adenocarcinomas include, but are limited to, those arising in the colon, lung, breast, esophagus, pancreas, stomach, small intestine, caecum, gallbladder, sweat glands, kidney, liver and rectum as well as

adenocarcinomas arising in the urogenital areas such as, for example, the cervix, ovary, endometrium, urachus, vagina, testicle or prostate. In a particularly preferred embodiment, the pharmaceutical products provided herein can be used to treat prostatic carcinoma cells. In one embodiment, the prostatic carcinoma cells have an observed Gleason score of between 2 and 10 based on the primary and secondary grade.

Stabilizer

Stabilizers provided herein can be mixed with CX-157 to form a pharmaceutical product that is suitable for further formulation methods (e.g., tableting). While not wishing to be limited to the following explanation, it is believed that the interaction between CX-157 and the stabilizer forms a stable solid, which, under standard long-term storage conditions remains

morphologically unchanged such that the morphology of the CX-157 in the solid formulation is substantially not changed over time. Typically the stabilizer is suitable for oral formulations.

Exemplary stabilizers used in accordance with the teachings herein include, but are not limited to, copovidone (copolymer of vinylpyrrolidone and vinyl acetate), povidone

(poly(vinylpyrrolidone)), HPMCAS-M (hydroxypropyl methylcellulose acetate succinate), hydrogenated phosphatidylcholine (Phospholipon ® 90H), and Eudragit ® L100-55 (copolymer of methacrylic acid and ethyl acrylate).

In some embodiments, the stabilizer is readily soluble in at least one solvent in which CX- 157 also is soluble. In one embodiment, CX-157 and the stabilizer are both dissolved in a solvent, and the solvent is then removed (as described more fully below) to form the

pharmaceutical product in which the CX-157 and stabilizer are admixed. Typically, the solubilities of stabilizer and CX-157 in the selected solvent are appropriate for formulation methods. Typically, the solvent is an organic solvent such as acetone, ethanol, methanol, methylene chloride, and mixtures thereof.

In some embodiments, the melting point of the stabilizer is sufficiently higher than typical ambient or room temperatures such that the stabilizer remains in solid form at typical ambient or room temperatures. As provided herein, in some embodiments this characteristic can permit the stabilizer to maintain the resultant pharmaceutical product in solid form upon admixture with CX- 157. As a result, both the pharmaceutical product itself and the CX-157 admixed therein remain substantially morphologically unchanged, even after long-term storage

In some embodiments, the stabilizer has limited or no aqueous solubility. In such embodiments, when the pharmaceutical product is stored, contact between the pharmaceutical product and water vapor does not result in dissolution of the stabilizer such that CX-157 is then susceptible to morphological reorganization.

In other embodiments, the stabilizer is readily soluble under aqueous conditions. In such embodiments, when the pharmaceutical product is administered, contact between a CX- 157/stabilizer formulation results in efficient dissolution of the stabilizer and CX-157 such that CX-157 is more readily available in the gastrointestinal tract for absorption into the bloodstream. Other Compounds that can be Mixed in Formulation

Additional compounds can be combined with CX-157 and stabilizer in the

pharmaceutical product provided that the formulation and storage properties of the

pharmaceutical product remain acceptable in accordance with the guidance provided herein. Examples of suitable additional compounds include any pharmaceutically acceptable excipient such as, for example, vegetable gums, waxes, hydroxypropylmethylcellulose,

hydroxypropylcellulose and polyvinylpyrrolidone, carboxymethylcellulose, acacia, gelatin, acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypryopl cellulose (L-HPC), magnesium stearate, maltodextrin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium carboxymethylcellulose, polyvinyl acetate phthalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, xylitol; and inert substances such as talc, for example, kaolin, and titanium dioxide, lubricants such as magnesium stearate, finely divided silicon dioxide, crospovidone, and non-reducing sugars. Typically any such additional compounds are suitable for oral formulations. Method of Preparing Formulation

A pharmaceutical product comprising 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide can be synthesized by:

i) dissolving about 2 parts by weight or less of the 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide and 3 parts by weight of a stabilizer in an organic solvent; and

ii) removing the organic solvent.

In one embodiment, a pharmaceutical product comprising 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide can be synthesized by the further steps of:

iii) adding an aqueous liquid and mixing the resultant suspension; and

iv) when iii) is performed, subsequently removing the aqueous liquid.

Dissolution in Organic Solvent

The organic solvent used in step i) is any organic solvent or solvent mixture which does not affect the chemical nature of CX-157 or the stabilizer, in which both CX-157 and the stabilizer are soluble at sufficient concentrations, and which is able to be removed readily, e.g., by evaporation. Typically, the boiling point of the solvent is between, or between about 20°C and 180°C. Typically, the organic solvent used has low toxicity such that it is an acceptable solvent for pharmaceutical formulations. Particular solvents are alcohols such as methanol, ethanol, 2- methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, ketones such as acetone, methylethyl ketone, methylisobutyl ketone, methyltert-butyl ketone, and other solvents such as acetic acid, anisole, butyl acetate, terr-butylmethyl ether, cumene, dimethylsufoxide, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, ispropyl acetate, methyl acetate and combinations thereof.

The concentration of CX-157 dissolved in the organic solvent can be any amount that provides the desired solid formulation results upon removing the organic solvent from the CX- 157/stabilizer solution. Typically, the concentration of CX-157 in the organic solvent is from about 1 mg/mL to about 100 mg/mL.

The concentration of stabilizer dissolved in the organic solvent can be any amount that provides the desired ratio of CX-157 to stabilizer while providing the desired results upon removing the organic solvent from the CX-157/stabilizer solution. Typically, the concentration of stabilizer is from about 1 mg/mL to about 100 mg/mL. One example of CX-157 and stabilizer concentrations is CX-157 at 25 mg/mL and stabilizer at 75 mg/mL, where the stabilizer is copovidone, povidone or HPMCAS-M. Another example of CX-157 and stabilizer concentrations is CX-157 at 35 mg/mL and stabilizer at 65 mg/mL, where the stabilizer is copovidone or povidone. Another example of CX-157 and stabilizer concentrations is CX-157 at 40 mg/mL and stabilizer at 60 mg/mL, where the stabilizer is copovidone.

The dissolving can be conducted at any temperature which does not affect the chemical nature of CX-157 or the stabilizer. The dissolving can be conducted at temperatures above room temperature, such as at 50-70°C or 55-60°C, optionally followed by cooling. Alternatively, the dissolving can be conducted at room temperature, such as 20-25°C. Dissolving also can be facilitated by any of a variety of mixing methods such as stirring, ultrasound, and use of a bead beater. Those skilled in the art can readily determine a suitable dissolving process according to the solvent to be used, chemical stability of CX-157 and the stabilizer, and desired time frame for conducting the dissolution step.

Removal of Organic Solvent

The organic solvent removal step ii) can be carried out by any of a variety of methods known in the art for solvent removal. For example, the organic solvent can be removed by rotary evaporation or by spray drying. Optimal conditions for conducting the solvent removal can readily be determined by those skilled in the art according to the solvent used, stability of CX-157 and the stabilizer, and desired time frame for conducting the dissolution step. For example, spray drying methods can be performed by spraying in a spray dryer under the conditions: drying air flow rate 70-100 kg/h, inlet temperature 85-125°C, outlet temperature 45-60°C, atomization pressure 0.5-1.5 bar. As a more specific example, spray drying methods can be performed by spraying in a spray dryer under the conditions: drying air flow rate 75-90 kg/h, inlet temperature 90-120°C, outlet temperature 49-56°C, atomization pressure 0.7-1.3 bar. For example, spray drying methods can be performed by spraying in a spray dryer under the conditions: drying air flow rate 80 kg/h, inlet temperature 95°C, outlet temperature 52°C, atomization pressure 1.0 bar.

The further steps for solid drying can be any traditional method known in the art, such as vacuum oven drying. For example, vacuum oven drying can be conducted at 40°C and about 12-14 mTorr. As will be appreciated by those skilled in the art, the conditions for solvent removal can be modified according to the solvent to be used, chemical stability of CX-157 and the stabilizer, and desired time frame for conducting the solvent removal step. The resultant solid has substantially all of the organic solvent removed.

Optional Aqueous Step

In some embodiments, the solid can be further treated by contacting the solid with an aqueous liquid. The aqueous liquid can serve to reduce and homogenize the particle size of the solid formed in step ii), referenced herein. The aqueous liquid used in optional step iii) can be an aqueous solution or water itself, particularly de-ionized water. The aqueous liquid contacting step can be performed at any temperature which does not adversely affect the chemical and morphological stability of the solid, and particularly the CX-157 within the solid. In particular, the aqueous liquid contacting step is performed under conditions in which the solid formed in step ii) does not dissolve or change morphologically. For example, the aqueous liquid contacting step can be conducted at room temperature. The particle size reduction and homogenization can be facilitated by any known method, including, for example, using a beadbeater.

Aqueous Drying Step

In embodiments that include treatment of the solid by contacting the solid with an aqueous liquid, the aqueous liquid can then be subsequently removed. Any of a variety of known methods for removing aqueous liquids can be used. For example, the aqueous liquid can be removed by lyophilization. The resultant solid has substantially all of the aqueous liquid removed.

Formulation Product

In a preferred embodiment, the pharmaceutical product contains CX-157 and the stabilizer admixed throughout a solid-form unilamellar matrix. The amount of stabilizer present in the pharmaceutical product is at a sufficiently low amount as to permit formation of single unit dosages of a size and a number per daily administration that is acceptable in the art. In some embodiments, the weight percentage of CX-157 in the combination of CX-157 and stabilizer is no more than or no more than about 40%, 35%, 33%, 30%, 25%, 20%, 15% or 10% (e.g., no more than 40 parts by weight CX-157 per 100 parts of combined weight of CX-157 and stabilizer), where "about" in the present context provides for a variability of no more than 1/10 th of the indicated value (e.g., 40% + 4%). Typically the pharmaceutical product is formulated for oral delivery.

When two or more stabilizers are used in the pharmaceutical product, the

aforementioned amount of stabilizer refers to the combined amount of all stabilizers in the pharmaceutical product. In some embodiments, the solid-form unilamellar matrix of the pharmaceutical contains no additional components beyond CX-157 and the stabilizer.

In some embodiments, the pharmaceutical product efficiently dissolves in aqueous solutions comparable to a fluid found in the gastrointestinal tract. In particular, the

pharmaceutical product dissolves more readily under such conditions compared to a selected crystalline form of CX-157. In such instances, the pharmaceutical product disperses more readily than a selected crystalline form of CX-157, and the CX-157 of the pharmaceutical product is more readily available in the gastrointestinal tract for absorption into the bloodstream than when CX-157 is present in the selected crystalline form of CX-157. An example of a selected crystal form of CX-157 is crystalline CX-157 having a melting point at about 169-175°C, as described in U.S. Serial No. 11/ 773,892, which is herein incorporated by reference. The AUC measurement can be reported at any of a variety of time points. The conditions under which the AUC measurements can be performed can be any method established in the art as providing a reliable model for bioavailability of a pharmaceutical product.

In some embodiments, the pharmaceutical product has limited or no aqueous solubility. As a result, when the pharmaceutical product is stored, contact between the pharmaceutical product and water does not result in dissolution of the pharmaceutical product such that CX-157 is then susceptible to morphological reorganization.

In some embodiments, the melting point of the pharmaceutical product is sufficiently higher than typical ambient or room temperatures that the pharmaceutical product remains in solid form at these temperatures. This characteristic permits the pharmaceutical product to remain in solid form throughout its shelf storage. As a result, both the pharmaceutical product itself and the CX-157 admixed therein remain substantially morphologically unchanged, even after long-term storage.

Use of the term "substantially morphologically unchanged," as it applies to the pharmaceutical product or CX-157 refers to the condition in which the morphological nature of the solid does not change above a tolerated amount over a given storage period. For example, the morphological nature of the solid does not change above a tolerated amount. The storage conditions under which the morphology is substantially unchanged can include moisture in the ambient environment.

The tolerated amount of morphological change of the pharmaceutical product or CX-157 refers to the maximum amount of pharmaceutical product or CX-157 that can change morphology, such as, change from amorphous to any crystalline form, change from one crystalline form (including co-crystalline form) to a different crystalline form (including co- crystalline form), or change from solid to liquid or solute form. Morphological change can be measured by any of a variety of known methods, including, for example, differential scanning calorimetry and powder x-ray diffraction.

In some embodiments, the CX-157 in the pharmaceutical product is substantially noncrystalline. As provided herein, typically pharmaceutical formulation methodologies avoid formation of non-crystalline or amorphous forms of an active pharmaceutical ingredient because such forms are considered unstable during storage. In contrast to the general thinking in the art, this embodiment of the pharmaceutical product provided herein is able to maintain a noncrystalline form that is stable over time and is suitable for storage. Crystal forms of CX-157 are known in the art, as taught in U.S. Serial No. 11/773,892, which is incorporated herein by reference. Crystallinity of CX-157 can be measured by any of a variety of known methods, including, for example, differential scanning calorimetry and powder x-ray diffraction.

In some embodiments, the pharmaceutical product contains substantially no liposomes in the solid-form unilamellar matrix containing the stabilizer and CX-157. Although some stabilizers known in the art can be used to prepare liposomes that contain active pharmaceutical ingredients, it is believed that at least some of the methods and stabilizers provided herein for forming the pharmaceutical product yield combinations of stabilizer and CX-157 which are not in liposome form. Liposomes are vesicular structures of aligned hydrophobic and hydrophilic groups of molecules, and can often have dynamic, liquid- or gel-like structures at room temperature. In contrast, the pharmaceutical products provided herein have melting points well above room temperature and remain morphologically stable under standard storage conditions, permitting the CX-157 contained therein to also maintain good morphological stability over time. Any of the methods for identifying and characterizing liposomes known in the art can be used to assess the amount of liposomes present in the pharmaceutical product.

Typically, the pharmaceutical product contains substantially no organic solvent.

Typically, the pharmaceutical product contains substantially no aqueous liquid.

Dosage Form

The instant pharmaceutical products may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or as a drip, spray, suppository, salve, or ointment; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, or intrasternally, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation; (e) administration topically; as deemed appropriate by those of skill in the art for bringing the pharmaceutical products of the invention into contact with living tissue; as well as (f) administration locally (e.g., intraprostatic injection) thereby delivering the pharmaceutical products of the invention into or near the precancerous or cancerous cells or tumor. Also provided herein are unit dosages containing the pharmaceutical product. In a preferred embodiment, a unit dosage provided herein is a discrete vessel containing the pharmaceutical product, including, but not limited to, an injection, a tablet, pill, dragee, capsule, caplet, gelcap, or suppository, typically formulated for oral or other gastro-intestinal tract- mediated ingestion by a subject to be treated.

In some embodiments, the amount of CX-157 in a unit dosage is at least, at least about, more than, or more than about 5 milligrams. In another embodiment, the amount of CX-157 in a unit dosage is at least, at least about, more than, or more than about 100 milligrams. In a preferred embodiment, the amount of CX-157 in a unit dosage is at least, at least about, more than, or more than about 200 milligrams. In a particularly preferred embodiment, the amount of CX-157 in a unit dosage is at least, at least about, more than, or more than about 250 milligrams, or a range from, between, from about, or between about any of the aforementioned values.

In some embodiments, the amount of CX-157 in a unit dosage is the amount required to constitute or constitute about 1/10*, 1/9*, 1/8*, 1/7*, 1/6*. 1/5*, 1/4*, 1/3"*, one half, or a full daily dose of CX-157, or a range from, between, from about, or between about any of the aforementioned values. That is, typically the number of unit dosages required for delivery of a daily dose to a subject is 10 or less, 5 or less, 4 or less, 3 or less (TID), 2 or less (BID), or one daily (QD). In a preferred embodiment, the number of unit dosages required for delivery of a daily dose to a subject is 2 or less (BID).

The unit dosages can contain any of a variety of additional coatings known in the art, particularly oral formulation coatings. Such additional coatings for oral formulations include, but are not limited to, lubricant coating, enteric coating, sustained release coating, or controlled release coating. Examples of various coatings containing CX-157 are provided in

PCT/US10/20468 and PCT/US10/20459, the entireties of which are incorporated herein by reference.

The unit dosage is formed according to any of a variety of methods known in the art, such as tableting methods. As provided herein, the pharmaceutical product shows good compressibility for core formation, thus facilitating tableting and other such methodologies. Typically, the pharmaceutical product is sieved, e.g., using a 120 mesh and then further treated in tableting or other unit dosage formation methods.

Oral Dosage Formulations

Oral dosage formulations containing CX-157 can be configured to: control location in the digestive system of release and absorption of CX-157; control the rate of release of CX-157; or both control location in the digestive system of release and absorption of CX-157 and control the rate of release of CX-157. Such oral dosage formulations can contain a core that contains CX- 157, and also at least one additional layer, such as an enteric coating layer, a sustained release layer, or both.

In some embodiments, such presentations comprise one or more of: (a) a traditional core containing CX-157 and one or more pharmaceutical excipients; (b) a sustained release layer containing CX-157 and one or more sustained release excipients; (c) a separating layer; (d) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; and (e) a finishing layer. In some embodiments, a sustained release layer is present. In some embodiments, an enteric layer is present. In some embodiments, both a sustained release layer and an enteric layer are present. In some such embodiments, the core comprises an inert bead on which the CX-157 is deposited as a layer comprising the one or more pharmaceutical excipients. In some embodiments, the product is a tablet or capsule or a core sheathed in an annular body. In some embodiments, such presentations contain about 5 milligrams to 500 milligrams of CX-157.

As used herein, all expressions of percentage, ratio, and proportion will be in weight units unless otherwise stated. Expressions of proportions of the enteric product will refer to the product in dried form, after the removal of the water in which many of the ingredients are dissolved or dispersed.

The term sugar refers to a sugar other than a reducing sugar. A reducing sugar is a carbohydrate that reduces Fehling's (or Benedict's) or Tollens' reagent. All monosaccharides are reducing sugars as are most disaccharides with the exception of sucrose. One common binding or filling agent is lactose which is particularly useful for tablets since lactose compresses well and is a cost-efficient diluent and binder. Lactose, however, is a reducing sugar that potentially interacts with the active ingredient at both at room temperature and under accelerated stability conditions (heat). Therefore, avoidance of lactose and other reducing sugars from formulations comprising the active ingredient may be important. As discussed below, sucrose is a particularly preferred sugar.

The Core

A particular core for the pellet is typically prepared by applying a layer containing active ingredient (CX-157) to an inert core. Such inert cores are conventionally used in pharmaceutical science, and are readily available. A particular core is one prepared from starch and sucrose, for use in confectionery as well as in pharmaceutical manufacturing. Cores of any pharmaceutically acceptable excipient, however, can be used, including, for example, microcrystalline cellulose, vegetable gums, or waxes. The primary characteristic of the inert core is to be inert, with regard both to the active ingredient and the other excipients in the pellet and with regard to the subject who will ultimately ingest the pellet.

The size of the cores depends on the desired size of the pellet to be manufactured. In general, pellets can be as small as 0.1 mm, or as large as 2 mm. Particular cores are from about 0.3 to about 0.8 mm, in order to provide finished pellets in the size range of from about 0.5 to about 1.5 mm in diameter. For instance, the cores can be of a reasonably narrow particle size distribution, in order to improve the uniformity of the various coatings to be added and the homogeneity of the final product. For example, the cores can be specified as being of particle size ranges such as from 18 to 20 U.S. mesh, from 20 to 25 U.S. mesh, from 25 to 30 U.S. mesh, or from 30 to 35 U.S. mesh to obtain acceptable size distributions of various absolute sizes.

The amount of cores to be used can vary according to the weights and thicknesses of the added layers. In general, the cores comprise from about 10 to about 70 percent of the product. More particularly, the charge of cores represents from about 15 to about 45 percent of the product.

When manufacture of the pellet begins with inert cores, the active ingredient can be coated on the cores to yield a final drug concentration of about 10 to about 25 percent of the product, in general. The amount of active ingredient depends on the desired dose of the drug and the quantity of pellets to be administered. The active ingredient can be present in at least, or at least about, more than, or more than about 10 milligrams. In a preferred embodiment, the active ingredient can be present in at least, or at least about, more than, or more than about 100 milligrams. In a particularly preferred embodiment, the active ingredient can be present in at least, or at least about, more than, or more than about 250 milligrams. The active ingredient can be present in up to, or up to about, less than, or less than about 1000 milligrams. In a preferred embodiment, the active ingredient can be present in up to, or up to about, less than, or less than about 500 milligrams. In a particularly preferred embodiment, active ingredient can be present in up to, or up to about, less than, or less than about 300 milligrams.

A convenient manner of coating the cores with active ingredient is the "powder coating" process where the cores are moistened with a sticky liquid or binder, active ingredient is added as a powder, and the mixture is dried. Such a process is regularly carried out in the practice of industrial pharmacy, and suitable equipment is known in the art. Such equipment can be used in several steps of the present process. This process can be conducted in conventional coating pans similar to those employed in sugar coating processes. This process can be used to prepare pellets.

Alternately, the present product can be made in fluidized bed equipment (using a rotary processor), or in rotating plate equipment such as the Freund CF-Granulator (Vector

Corporation, Marion, Iowa). The rotating plate equipment typically consists of a cylinder, the bottom of which is a rotatable plate. Motion of the mass of particles to be coated is provided by friction of the mass between the stationary wall of the cylinder and the rotating bottom. Warm air can be applied to dry the mass, and liquids can be sprayed on the mass and balanced against the drying rate as in the fluidized bed case.

In some embodiments, a powder coating is applied. In such embodiments, the mass of pellets can be maintained in a sticky state, and the powder to be adhered to them, active ingredient in this case, can be added continuously or periodically and adhered to the sticky pellets. When all of such active has been applied, the spray can be stopped and the mass allowed to dry in the air stream. It can be appropriate or convenient to add some inert powders to the active ingredient.

Additional solids can be added to the layer with active ingredient. These solids can be added to facilitate the coating process as needed to aid flow, reduce static charge, aid bulk buildup and form a smooth surface. Inert substances such as talc, kaolin, and titanium dioxide, lubricants such as magnesium stearate, finely divided silicon dioxide, crospovidone, and non- reducing sugars, e.g., sucrose, can be used. The amounts of such substances are in the range from about a few tenths of 1 % of the product up to about 20% of the product. Such solids are typically of fine particle size, e.g., less than 50 micrometers, to produce a smooth surface.

The active ingredient can be made to adhere to the cores by spraying a pharmaceutical excipient which is sticky and adherent when it is wet, and dries to a strong, coherent film. Those skilled in the art are aware of and conventionally use many such substances, most of them polymers. Particular such polymers include hydroxypropylmethylcellulose,

hydroxypropylcellulose and polyvinylpyrrolidone. Additional such substances include

methylcellulose, carboxymethylcellulose, acacia and gelatin, for example. The amount of the adhering excipient can be in the range from about 4% to about 12% of the product, and depends, in large part, on the amount of active to be adhered to the core.

The active ingredient can also be built up on the cores by spraying a slurry comprising active suspended in a solution of the excipients of the active layer, dissolved or suspended in sufficient water to make the slurry sprayable. Such a slurry can be milled through a machine adapted for grinding suspension in order to reduce the particle size of active. Grinding in suspension form can be desirable because it avoids dust generation and containment problems which arise in grinding dry powder drugs. A particular method for applying this suspension is the pharmaceutical fluidized bed coating device, such as the Wurster column, which consists of a vertical cylinder with an air-permeable bottom and an upward spraying nozzle close above the bottom, or a downward-spraying nozzle mounted above the product mass. The cylinder is charged with particles to be coated, a sufficient volume of air is drawn through the bottom of the cylinder to suspend the mass of particles, and the liquid to be applied is sprayed onto the mass. The temperature of the fluidizing air is balanced against the spray rate to maintain the mass of pellets or tablets at the desired level of moisture and stickiness while the coating is built up.

On the other hand, the core can comprise a monolithic particle in which the active ingredient is incorporated. Such cores can be prepared by the granulation techniques which are wide spread in pharmaceutical science, particularly in the preparation of granular material for compressed tablets. The cores can be prepared by mixing the active into a mass of

pharmaceutical excipients, moistening the mass with water or a solvent, drying, and breaking the mass into sized particles in the same size range as described above for the inert cores. This can be accomplished via the process of extrusion and marumerization.

The core for the pellet can also be prepared by mixing active with conventional pharmaceutical ingredients to obtain the desired concentration and forming the mixture into cores of the desired size by conventional procedures, including but not limited to the process of R. E. Sparks et al., U.S. Patent Nos. 5,019,302 and 5,100,592, incorporated by reference herein. Sustained Release

In some embodiments, the product is formulated so as to achieve plasma levels of CX- 157 ranging from about 40 ng/ml to about 80 ng/ml. Also provided are oral pharmaceutical dosage forms comprising CX-157 and adapted to retard release of CX-157 in the digestive tract.

Sustained-release pharmaceutical formulations can be configured in a variety of dosage forms such as, for example tablets and beads. Such dosage forms can contain a variety of fillers and excipients, such as retardant excipients (also referred to a release modifiers) and can be made in a variety of ways. Those skilled in the art can determine the appropriate

configuration by routine experimentation guided by the descriptions provided herein.

Sustained-release pharmaceutical formulations can contain fillers. Examples of suitable fillers include, but are not limited to, methylcellulose, including that sold under the tradename METHOCEL ® , hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), corn starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), or cross-linked PVP. Sustained-release pharmaceutical formulations can contain excipients. Examples of suitable excipients include, but are not limited to, acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypryopl cellulose (L-HPC), magnesium stearate, maltodextrin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium

carboxymethylcellulose, polyvinyl acetate phthalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, or xylitol.

The active ingredient can be present in at least, or at least about, more than, or more than about 10 milligrams. In a preferred embodiment, the active ingredient can be present in at least, or at least about, more than, or more than about 100 milligrams. In a particularly preferred embodiment, the active ingredient can be present in at least, or at least about, more than, or more than about 250 milligrams. The active ingredient can be present in up to, or up to about, less than, or less than about 1000 milligrams. In a preferred embodiment, the active ingredient can be present in up to, or up to about, less than, or less than about 500 milligrams. In a particularly preferred embodiment, active ingredient can be present in up to, or up to about, less than, or less than about 300 milligrams. Particularly preferred ranges include about 50 milligrams to about 500 milligrams, or from about 200 milligrams to about 300 milligrams.

In preferred embodiments, the sustained-release pharmaceutical formulation comprises an active ingredient, methylcellulose and microcrystalline cellulose. In some embodiments, the formulation comprises, for example, from about 30%, 40%, or 50%, to about 80% or 90% active ingredient by weight. In some embodiments, the formulation comprises about 0.1%, 0.5%, 1%, 3%, 5%, 10% or 20% active ingredient by weight. Preferably, the active ingredient is present at a percentage of about 55%, 60%, 65%, or 70% by weight. In other preferred embodiments, the formulation comprises about 95% active ingredient.

The balance of ingredients in the sustained-release active ingredient pharmaceutical formulation can be chosen, for example, from modified polysaccharides such as, for example, methylcellulose (MC) and microcrystalline cellulose (MCC). In some embodiments, the formulation comprises between about 3% to about 99.9% microcrystalline cellulose by weight. In certain embodiments, the formulation comprises about 3% MCC. In other embodiments, the formulation comprises about 5% MCC. In further embodiments, the formulation comprises about 10% MCC. In yet other embodiments, the formulation comprises about 30% MCC. In further embodiments, the formulation comprises about 50% MCC.

In some embodiments, the sustained-release pharmaceutical formulation comprises about 0% to about 40% MC. In certain embodiments, the formulation comprises about 3% MC. In other embodiments, the formulation comprises about 5% MC. In further embodiments, the formulation comprises about 10% MC. In yet other embodiments, the formulation comprises about 30% MC. In further embodiments, the formulation comprises about 40% MC. In some embodiments, the formulation comprises about 95% active ingredient and the remaining 5% is divided between MC and MCC.

The dissolution rate of the sustained-release pharmaceutical formulation determines how quickly active ingredient becomes available for absorption into the blood stream and therefore controls the bioavailability of active ingredient. Dissolution rate is dependent on the size and the composition of the dosage form. In some embodiments, the dissolution rate of the formulation can be by changed by altering the additional components of the formulation. Disintegrants, such as starch or corn starch, or crosslinked PVPs, can be used to increase solubility when desired. Solubilizers can also be used to increase the solubility of the formulations. In some

embodiments, alternative binders, such as, for example, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), PVP, gums, or xanthine can be used to increase the dissolution rate.

In some embodiments, the dissolution rate of the formulation can be decreased by adding components that make the formulation more hydrophobic. For example, addition of polymers such as ethylcelluloses, wax, or magnesium stearate decreases the dissolution rate.

In some embodiments, the dissolution rate of the sustained-release pharmaceutical formulation is formulated so as to control the plasma levels of active ingredient. For example, the sustained-release pharmaceutical formulation can be formulated so as to achieve plasma levels of active ingredient that are, for example, at least, or at least about, more than, or more than about, 5 ng/ml, 10 ng/ml, 15 ng/ml, 20 ng/ml, 25 ng/ml, 30 ng/ml, 40 ng/ml, 50 ng/ml, 60 ng/ml, 70 ng/ml, 80 ng/ml, 90 ng/ml, or 100 ng/ml. The sustained-release pharmaceutical formulation can be formulated so as to achieve plasma levels of active ingredient that are, for example, up to, or up to about, less than, or less than about, 25 ng/ml, 30 ng/ml, 40 ng/ml, 50 ng/ml, 60 ng/ml, 70 ng/ml, 80 ng/ml, 90 ng/ml, 100 ng/ml, 125 ng/ml, 150 ng/ml, 175 ng/ml, 200 ng/ml, 250 ng/ml, 300 ng/ml, 350 ng/ml, 400 ng/ml, 450 ng/ml, or 500 ng/ml. Particular ranges are from about 10 ng/ml to about 150 ng/ml, from about 20 ng/ml to about 100 ng/ml, or from about 40 ng/ml to about 80 ng/ml. In one embodiment, such ranges can be favorable for achieving therapeutic levels of active ingredient without causing sufficient inhibition of MAO inhibition in the digestive tract and liver so as to cause the so-called "cheese effect."

In some embodiments, the dissolution rate of the sustained-release pharmaceutical formulation is such that about 25% of the active ingredient in the dosage form is dissolved within the first hour, about 60% of the active ingredient is dissolved within the first 6 hours, about 80% of the active ingredient is dissolved within the first 9 hours, and substantially all of the active ingredient is dissolved within the first 12 hours. In other embodiments, the dissolution rate of the sustained-release pharmaceutical formulation is such that about 35% of the active ingredient in the dosage form is dissolved within the first hour, about 85% of the active ingredient is dissolved within the first 6 hours, and substantially all of the active ingredient is dissolved within the first 9 hours. In yet other embodiments, the dissolution rate of the sustained-release pharmaceutical formulation in the dosage form is such that about 45% of the active ingredient is dissolved within the first hour, and substantially all of the active ingredient is dissolved within the first 6 hours.

The dissolution rate of the formulation can also be slowed by coating the dosage form. Examples of coatings include sustained-release polymers.

The sustained-release pharmaceutical formulation can take about, for example, from 2, 4, 6, or 8 hours to about 15, 20, or 25 hours to dissolve. Preferably, the formulation has a dissolution rate of from about 3, 4, 5, or 6 to about 8, 9, or 10 hours.

In one embodiment, a sustained-release pharmaceutical formulation can be prepared by mixing active ingredient with an excipient or filler or a combination thereof to form a mixture, and forming a suitable dosage form (e.g., tablet, bead, etc.) from the mixture. In some

embodiments, the formulation can be prepared by further adding another excipient or filler or a combination thereof to the mixture prior to forming the dosage form. The filler and excipient are as described herein. In an embodiment, the active ingredient is mixed with the excipient or filler or a combination thereof to form a wet mixture. The wet mixture can then be formed into particles or beads, which can then be dried. The dried product can then be tableted or placed into a gelatin capsule for oral delivery.

In one embodiment, the sustained-release pharmaceutical formulation is in the form of beads. In some embodiments, the beads comprise active ingredient and a filler. In other embodiments, the beads further comprise an excipient. In some embodiments, the excipient or filler or a combination thereof are in polymeric form.

As used herein, "beads" can be, for example, spheres, pellets, microspheres, particles, microparticles, or granules. The beads can have any desired shape. The shape can be, for example, spherical, substantially spherical, rod-like, cylindrical, oval, elliptical, or granular. The size and shape of the bead can be modified, if desired, to alter dissolution rates. The beads can be coated or can be uncoated. The beads can be formed into a capsule for oral delivery, a tablet, or any other desired solid oral dosage form, with or without other ingredients.

In one embodiment, a pharmaceutical formulation comprises a bead that comprises sustained-release active ingredient and a filler. In some embodiments, the bead further comprises an excipient. In some embodiments, the filler is a polymer. In some embodiments the excipient is a polymer. In some embodiments, the filler is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), corn starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and cross-linked PVP. In some embodiments, the excipient is selected from the group consisting of acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypropyl cellulose (L-HPC), magnesium stearate, maltodextrin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium carboxymethylcellulose, polyvinyl acetate phathalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, and xylitol. In some embodiments the bead comprises active ingredient, methylcellulose and microcrystalline cellulose. In some embodiments, the bead comprises from about 0.1% to about 95% active ingredient by weight. In some embodiments, the bead comprises between about 3% to about 99.9% microcrystalline cellulose by weight. In some embodiments, the bead comprises about 0% to about 40% methylcellulose by weight.

Separating Layer

The separating layer between the active-containing core and the enteric layer is not required, but is a particular feature of the formulation. The functions of the separating layer, if desired, are to provide a smooth base for the application of the enteric layer, to prolong the resistance of the pellet to acid conditions, and/or to improve stability by inhibiting any interaction between the drug and the enteric polymer in the enteric layer.

The smoothing function of the separating layer is purely mechanical, the objective of which is to improve the coverage of the enteric layer and to avoid thin spots in the enteric layer, caused by bumps and irregularities on the core. Accordingly, the more smooth and free of irregularities the core can be made, the less material is needed in the separating layer, and the need for the smoothing characteristic of the separating layer can be avoided entirely when the active is of extremely fine particle size and the core is made as close as possible to truly spherical.

When a pharmaceutically acceptable non-reducing sugar is added to the separating layer, the pellet's resistance to acid conditions can be markedly increased. Accordingly, such a sugar can be included in the separating layer applied to the cores, either as a powdered mixture, or dissolved as part of the sprayed-on liquid. A sugar-containing separating layer can reduce the quantity of enteric polymer required to obtain a given level of acid resistance. Use of less enteric polymer can reduce both the materials cost and processing time, and also can reduce the amount of polymer available to react with active. The inhibition of any core/enteric layer interaction is mechanical. The separating layer physically keeps the components in the core and enteric layers from coming into direct contact with each other. In some cases, the separating layer can also act as a diffusional barrier to migrating core or enteric layer components dissolved in product moisture. The separating layer can also be used as a light barrier by opacifying it with agents such as titanium dioxide or iron oxides.

In general, the separating layer can include coherent or polymeric materials, and finely powdered solid excipients which constitute fillers. When a sugar is used in the separating layer, the sugar is applied in the form of an aqueous solution and constitutes part of or the whole of the coherent material which sticks the separating layer together. In addition to or instead of the sugar, a polymeric material can also be used in the separating layer. For example, substances such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, or hydroxypropylcellulose can be used in small amounts to increase the adherence and coherence of the separating layer.

A filler excipient also can be used in the separating layer to increase the smoothness and solidity of the layer. Substances such as finely powered talc or silicon dioxide are universally accepted as pharmaceutical excipients and can be added as is convenient in the circumstances to fill and smooth the separating layer.

In general, the amount of sugar in the separating layer can be in the range of from about 2% to about 10% of the product, when a sugar is used at all, and the amount of polymeric or other sticky material can be in the range of from about 0.1 to about 5%. The amount of filler, such as talc, can be in the range of from about 5 to about 15%, based on final product weight.

The separating layer can be applied by spraying aqueous solutions of the sugar or polymeric material, and dusting in the filler as has been described in the preparation of an active layer. The smoothness and homogeneity of the separating layer can be improved, however, if the filler is thoroughly dispersed as a suspension in the solution of sugar and or polymeric material, and the suspension is sprayed on the core and dried, using equipment as described above in the preparation of cores with active layers.

Enteric Layer

In some embodiments, the presentation comprises an enteric coating. Enteric pharmaceutical presentations of CX-157 can serve to protect the MAO receptors from binding to CX-157 in the stomach to thereby limit dangerous food reactions or decrease the requirement for strict dietary restrictions by virtue of reducing release of the active ingredient and thereby reducing the degree to which CX-157 blocks MAO receptors from binding dietary tyramine. In some embodiments, such presentations comprise CX-157 and are adapted to retard or inhibit the release of CX-157 in the stomach.

The enteric layer is comprised of an enteric polymer, which can be chosen for compatibility with the active ingredient. The polymer can be one having only a small number of carboxylic acid groups per unit weight or repeating unit of the polymer. A particular enteric polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), which product is defined as containing not less than 4% and not more than 28% of succinoyl groups, which are the only free carboxylic groups in the compound. See Japanese Standards of Pharmaceutical

Ingredients 1991, page 1216-21, Standard No. 19026. HPMCAS is available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan, under the trademark AQOAT. It is available in two particle size grades and three molecular weight ranges. For example, the L grade, having number average molecular weight of 93,000 can be used.

Enteric polymers can be applied as coatings from aqueous suspensions, from solutions in aqueous or organic solvents, or as a powder. One skilled in the art will be able to select from known solvents or methods or a combination thereof, as desired.

The enteric polymer can also be applied according to a method described by Shin-Etsu Chemical Co. Ltd. (Obara, et al., Poster PT6115, AAPS Annual Meeting, Seattle, Wash., Oct. 27-31 , 1996). In this method, when the enteric polymer is applied as a powder the enteric polymer is added directly in the solid state to the tablets or pellets while plasticizer is sprayed onto the tablets or pellets simultaneously. The deposit of solid enteric particles is then turned into a film by curing. The curing is done by spraying the coated tablets or pellets with a small amount of water and then heating the tablets or pellets for a short time. This method of enteric coating application can be performed employing the same type of equipment as described above in the preparation of cores with active ingredient layers.

When the enteric polymer is applied as an aqueous suspension, a problem in obtaining a uniform, coherent film often results. In instances in which this problem may arise, a fine particle grade can be used or the particles of polymer can be ground to an extremely small size before application. It is possible either to grind the dry polymer, as in an air-impaction mill or to prepare the suspension and grind the polymer in slurry form. Slurry grinding is generally preferable, particularly since it can be used also to grind the filler portion of the enteric layer in the same step. In some embodiments, it is advisable to reduce the average particle size of the enteric polymer to the range from about 1 micrometer to about 5 micrometers, particularly no larger than 3 micrometers.

When the enteric polymer is applied in the form of a suspension, the suspension is typically maintained homogeneous. Such precautions include maintaining the suspension in a gently stirred condition, but not stirring so vigorously as to create foam, and assuring that the suspension does not stand still in eddies in nozzle bodies, for example, or in over-large delivery tubing. Frequently, polymers in suspension form will agglomerate if the suspension becomes too warm, and the critical temperature can be as low as 30°C in individual cases. Since spray nozzles and tubing are exposed to hot air in the usual fluid bed type equipment, care must be taken to assure that the suspension is kept moving briskly through the equipment to cool the tubing and nozzle. When HPMCAS is used, in particular, it is advisable to cool the suspension below 20°C before application, to cool the tubing and nozzle by pumping a little cold water through the tubing and nozzle before beginning to pump the suspension, and to use supply tubing with as small a diameter as the spray rate will allow so that the suspension can be kept moving rapidly in the tubing.

In one embodiment, one can apply the enteric polymer as an aqueous solution whenever it is possible to do so. In the case of HPMCAS, dissolution of the polymer can be obtained by neutralizing the polymer, particularly with ammonia. Neutralization of the polymer can be obtained merely by adding ammonia, preferably in the form of aqueous ammonium hydroxide to a suspension of the polymer in water; complete neutralization results in complete dissolution of the polymer at about pH 5.7-5.9. Good results are also obtained when the polymer is partially neutralized by adding less than the equivalent amount of ammonia. In such case, the polymer which has not been neutralized remains in suspended form, suspended in a solution of neutralized polymer. The particle size of the polymer can be controlled when such a process is to be used. Use of neutralized polymer more readily provides a smooth, coherent enteric layer than when a suspended polymer is used, and use of partially neutralized polymer provides intermediate degrees of smoothness and coherency. Particularly when the enteric layer is applied over a very smooth separating layer, excellent results can be obtained from partially neutralized enteric polymer. The extent of neutralization can be varied over a range without adversely affecting results or ease of operation. For example, the extent of neutralization can range from about 25% to about 100% neutralization. Another particular condition is from about 45% to about 100% neutralization, and another condition is from about 65% to about 100%. Still another particular manner of neutralization is from about 25% to about 65% neutralized. It may be found, however, that the enteric polymer in the resulting product, after drying, is neutralized to a lesser extent than when applied. When neutralized or partially neutralized HPMCAS is applied, the HPMCAS in the final product can be from about 0% to about 25% neutralized, more particularly from about 0% to about 15% neutralized.

A plasticizer can be used with enteric polymers for improved results. In the case of HPMCAS, a particular plasticizer can be triethyl citrate, used in an amount up to about 15%-30% of the amount of enteric polymer in aqueous suspension application. When a neutralized HPMCAS is employed, either lower levels or no plasticizer can be required. Minor ingredients, such as antifoam, suspending agents when the polymer is in suspended form, and surfactants to assist in smoothing the film, are also commonly used. For example, silicone anti-foams, surfactants such as polysorbate 80, sodium lauryl sulfate and suspending agents such as carboxymethylcellulose and vegetable gums, can commonly be used at amounts in the general range up to 1 % of the product.

Usually, an enteric layer is filled with a powdered excipient such as talc, glyceryl monostearate or hydrated silicon dioxide to build up the thickness of the layer, to strengthen it, to reduce static charge, and to reduce particle cohesion. Amounts of such solids in the range of from about 1% to about 10% of the final product can be added to the enteric polymer mixture, while the amount of enteric polymer itself can be in the range from about 5% to about 25%, more particularly, from about 10% to about 20%.

Application of the enteric layer to the pellets follows the same general procedure previously discussed, using fluid bed type equipment with simultaneous spraying of enteric polymer solution or suspension and warm air drying. Temperature of the drying air and the temperature of the circulating mass of pellets are typically kept in the ranges advised by the manufacturer of the enteric polymer.

Provided herein are formulations engineered to initiate drug release in the middle to lower portions of the small intestine, with a delayed release time of greater than, for example, approximately 1 hour, 1.25 hours, 1.5 hours, 1.75 hours or 2 hours after dosing. Such pharmaceutical formulations are manufactured in such a way that the product passes

unchanged through the stomach of the patient, and dissolves and releases the active ingredient when it leaves the stomach and enters the middle and lower portions of the small intestine. Such formulations can be in tablet or pellet form, where the active ingredient is in the inner part of the tablet or pellet and is enclosed in a film or envelope (i.e., the "enteric coating"). The enteric coating is insoluble in acid environments, such as the stomach, but is soluble in near- neutral environments such as the small intestine. The instant enteric coating-containing formulations avoid much of the drug competition with dietary tyramine for MAO-A since dietary tyramine is rapidly absorbed and metabolized in the stomach and upper portion of the small intestine and the liver with an average T max of 1.25 hours. In this regard, human plasma pharmacokinetic data of tyramine, administered with food in a capsule, in an oral dose of 200 milligrams demonstrated a rapid absorption of tyramine with a T max achieved within 1.25 hours and non-detectable levels observed 3-4 hrs after dosing.

Finishing Layer

A finishing layer over the enteric layer is not necessary in every case, but can improve the elegance of the product and its handling, storage and machinability and can provide further benefits as well. The simplest finishing layer is simply a small amount, about less than 1% of an anti-static ingredient such as talc or silicon dioxide, simply dusted on the surface of the pellets. Another simple finishing layer is a small amount, about 1%, of a wax such as beeswax melted onto the circulating mass of pellets to further smooth the pellets, reduce static charge, prevent any tendency for pellets to stick together, and increase the hydrophobicity of the surface.

More complex finishing layers can constitute a final sprayed-on layer of ingredients. For example, a thin layer of polymeric material such as hydroxypropylmethylcellulose or

polyvinylpyrrolidone, in an amount such as from about 2% up to about 10%, can be applied. The polymeric material can also carry a suspension of an opacifier, a bulking agent such as talc, or a coloring material, particularly an opaque finely divided color agent such as red or yellow iron oxide. Such a layer quickly dissolves away in the stomach, leaving the enteric layer to protect the active ingredient, but provides an added measure of pharmaceutical elegance and protection from mechanical damage to the product.

Finishing layers to be applied to the present product are of essentially the same types commonly used in pharmaceutical science to smooth, seal and color enteric products, and can be formulated and applied in the usual manners.

The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLES EXAMPLE 1

Enteric-Coated Sustained Release Tablet Formulation

Enteric Capsules of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide (60 mg/capsule)

Materials

Core

Sucrose-starch nonpareils, 30-35 mesh 134.15 mg

Sustained Release Active layer

3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10, 10-dioxide 60 mg

Sucrose 25.72 mg

Hydroxypropylmethylcellulose 12.89 mg

Separating layer

Hydroxypropylmethylcellulose 9.45 mg

Sucrose 28.24 mg

Talc, 500 mesh 50.21 mg

Enteric layer

HPMCAS-LF 65.66 mg

Triethyl citrate 13.14 mg

Talc, 500 mesh 39.66 mg

Finishing Layer

Color mixture white (HPMC + titanium dioxide) 43.02 mg

HPMC 10.78 mg

Talc Trace

The active layer was built up by suspending 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide 25% w/w in a binder solution consisting of 6.4% w/w sucrose and 3.2% w/w hydroxypropylmethylcellulose (HPMC). The resulting suspension was then passed through a Coball Mill (Fryma Mashinen AG, Rheinfelden, Switzerland) Model MS-12 to reduce the particle size of the bulk drug. The milled suspension was applied to 1.5 kg of sucrose starch non-pareils in a fluid bed dryer fitted with a Wurster column. Upon completing the application of the desired quantity of active ingredient suspension, the core pellets were completely dried in the fluid bed dryer.

The separating layer which contains talc 12% w w, sucrose 6.75% w/w and

hydroxypropylmethylcellulose 2.25% w/w was then applied as an aqueous suspension to the active core pellets. Upon completing the application of the desired quantity of suspension, the pellets were completely dried in the fluid bed dryer. The enteric coating aqueous suspension contained hydroxypropylmethylcellulose acetate succinate type LF 6% w/w, talc 1.8% w/w, triethyl citrate 1.2% w/w which is fully neutralized by the addition of 0.47% w/w ammonium hydroxide. This enteric coating suspension was applied to the separation layer coated pellets. Upon completing the application of the desired quantity of enteric coating suspension, the pellets were completely dried in the fluid bed dryer and a small quantity of talc was added to reduce static charge.

A finishing layer was then applied which contains color mixture white (comprised of titanium dioxide and hydroxypropylmethylcellulose) 8% w/w and hydroxypropylmethylcellulose 2% w/w. Upon completing the application of the desired quantity of color coating suspension, the pellets were completely dried in the fluid bed dryer and a small quantity of talc was added to reduce static charge. The resulting pellets were assayed for active content and filled into capsules to provide 60 milligrams of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide.

PROPHETIC EXAMPLES PROPHETIC EXAMPLE 1

Experiments may be conducted to show that 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide slows the in vitro growth of advanced primary prostate cancer cells. Procedures are set forth in Flamand et al. (2010) Targeting Monoamine Oxidase A in Advanced Prostate Cancer. J. Cancer Res. Clin. Oncol. (Published online 04 March 2010), herein incorporated by reference with regard to such procedures.

Advanced primary prostate cancer cells may be cultured in Dulbecco's modified Eagle medium (DMEM, available from Invitrogen of Carlsbad, California) with 10% fetal bovine serum (FBS, available from Hyclone, Logan, Utah) over a ten day period both with and without 3-fluoro- 7-(2,2,2-trifluoroethoxy)phenoxathiin 10, 10-dioxide.

The population difference between control cells and cells treated with 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide may then be detected thereby showing a slowed proliferation of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide in vitro.

PROPHETIC EXAMPLE 2

Experiments may be conducted to show that 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide inhibits xenograft tumor growth. Procedures are set forth in Flamand et al. (2010) Targeting Monoamine Oxidase A in Advanced Prostate Cancer. J. Cancer Res. Clin. Oncol. (Published online 04 March 2010), herein incorporated by reference with regard to such procedures. Xenografts may be generated from advanced prostate cancer cells injected

subcutaneously into a population of immunodeficient male mice. The xenograft-bearing mice may be treated daily with 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide injections. Once tumors reach a grossly measurable size of 200-300 mm 3 , half of the mice population may be intraperitoneally injected with water (control) while the remaining half is injected with 3-fluoro- 7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide daily for up to 21 days.

The tumor volume, tumor volume doubling time and histopathology may be determined for each group.

PROPHETIC EXAMPLE 3

Experiments may be conducted to show that 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide induces changes in gene expression in xenografts. Procedures are set forth in Flamand et al. (2010) Targeting Monoamine Oxidase A in Advanced Prostate Cancer. J. Cancer Res. Clin. Oncol. (Published online 04 March 2010), herein incorporated by reference with regard to such procedures.

Xenografts from a group of xenograft-bearing mice may be harvested 24 hours after a single 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide injection into each mouse. The impact on genes that are upregulated in xenografts from mice treated with 3-fluoro-7-(2,2,2- trifluoroethoxy)phenoxathiin 10,10-dioxide can be evaluated thereby showing the effect on the transcriptional program of advanced prostate cancer cells.

Specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Since modifications will be apparent to those of skill in this art, it is intended that this invention be limited only by the scope of the appended claims.