The invention related to formulations of substituted benzaoxazoles
FIELD OF THE INVENTION
The present invention relates to solid dosage formulations that include ERB-selective Ikjands that contain benzoxazole (or benzothiazole or benzoimidazole), and processes for manufacture of said formulations, more particularly to novel formulations and processes for manufacture of formulations containing the ERB-setectrve Bgand, ERB-041.
BACKGROUND OF THE INVENTION
This invention relates to formulations for substituted benzoxazoles (or benzothiazotes or benzoimkJazotes), which are useful as estrogenfc agents.
The pteiotropic effects of estrogens in mammalian tissues have been well documented, and it is now appreciated that estrogens affect many organ systems [Mendelsohn and Karas, New England Journal of Medicine 340:1801-1811 (1999), Epperson, et at. Psychosomatic Medicine 61:676-697 (1999), Crandall, Journal of Women's Health & Gender Based Medicine 8:1155-1166 (1999), Monk and Brodaty. Dementia & Geriatric Cognitive Disorders 11:1-10 (2000), Hum and Macrae, Journal of Cerebral Blood Flow & Metabolism 20:631-652 (2000), Calvin, Maturitas 34:195-210 (2000), RnkJng, et at., Zetschrin fur Kardnfegfe 89:442-453 (2000). Biincat, Maturitas 35:107-117 (2000), AI-AzzawJ, Postgraduate Medical Journal 77:292-304 (2001)]. Estrogens can exert effects on tissues in several ways, and the most wefl characterized mechanism of action is their Interaction with estrogen receptors leading to alterations in gene transcription. Estrogen receptors are Ugand-activated transcription factors and belong to the nuclear hormone receptor superfamiy. Other members of this family include the progesterone, androgen, glucocorticoid and mineralocorticoid receptors. Upon binding Kgand, these receptors dimerize and can activate gene transcription either by directly binding to specific sequences on DMA (known as response elements) or by interacting with other transcription factors (such as AP1), which in turn bind directly to specific DMA sequences [Moggs and OrphankJes, EMBO Reports 2: 775-781 (2001), Hall, et al.. Journal of Biological Chemistry 276: 36869-36872 (2001), McDonnell, Principles of Molecular Regulation. 351-361 (2000)]. A class of 'coregulatory' proteins can also interact with the ligand-bound receptor and further modulate its transcriptional activity [McKenna, et al.,
Endocrine Reviews 20: 321-344 (1999)]. It has also been shown that estrogen receptors can suppress NFicB-mediated transcription in both a ligand-dependent and independent manner [Quaedackers, et al., Endocrinology 142:1156-1166 (2001). Bhat, et al., Journal of Steroid Biochemistry & Molecular Biology 67:233-240 (1998), Pelzer, et al., Biochemical & Biophysical Research Communications 286: 1153-7 (2001)].
Estrogen receptors can also be activated by phosphorylation. This phosphorylation is mediated by growth factors such as EGF and causes changes in gene transcription in the absence of Hgand [Moggs and Orphankles, EMBO Reports 2:775-781 (2001), Had, et al., Journal of Biological Chemistry 276:36869-36872 (2001)].
A toss wefl-charactenzed means by which estrogens can affect ceHs is through a so-called membrane receptor. The existence of such a receptor is controversial, but H has been weB documented that estrogens can eHdt very rapid non-genomic responses from cells. The molecular entity responsible for transducing these effects has not been definitively isolated, but there is evidence to suggest it is at least related to the nuclear forms of the estrogen receptors [Levin, Journal of Applied Physiology 91:1860-1867 (2001), Levin, Trends in Endocrinology & Metabolism 10:374-377 (1999)].
Two estrogen receptors have been discovered to date. The first estrogen receptor was cloned about 15 years ago and is now referred to as ERa [Green, et al., Nature 320:134-9 (1986)]. The second form of the estrogen receptor was found comparatively recently and is called ERB [Kuiper, et al.. Proceedings of the National Academy of Sciences of the United States of America 93:5925-5930 (1996)]. Early work on ERB focused on defining its affinity for a variety of figands and indeed, some differences with ERa were seen. The tissue distribution of ERp has been well mapped in the rodent and it is not coincident with ERa. Tissues such as the mouse and rat uterus express predominantly ERa, whereas the mouse and rat lung express predominantly ERB [Couse, et al., Endocrinology 138:4613-4621 (1997), Kuiper, et al., Endocrinology 138:863-870 (1997)]. Even within the same organ, the distribution of ERa and ERp can be compartmentalized. For example, in the mouse ovary, ERp is highly expressed in the granulosa cells and ERa is restricted to the thecal and stromal cells [Sar and Welsch, Endocrinology 140:963-971 (1999),
Fitzpatrick, et al.. Endocrinology 140:2581-2591 (1999)]. However, there are examples where the receptors are coexpressed and there is evidence from in vitro studies that ERa and ERp can form heterodimers [Cowley, et al., Journal of Biological Chemistry 272:19858-19862 (1997)].
A large number of compounds have been descrfoed that either mimic or block the activity of 17f}-estradiol. Compounds having roughly the same biological effects as 178-estradiol, the most potent endogenous estrogen, are referred to as "estrogen receptor agonists*. Those which, when given in combination with 178-estradiol, block its effects are caHed 'estrogen receptor antagonists'. In reality there is a continuum between estrogen receptor agonist and estrogen receptor antagonist activity and indeed some compounds behave as estrogen receptor agonists in some tissues and estrogen receptor antagonists in others. These compounds with mixed activity are called selective estrogen receptor modulators (SERMS) and are therapeuticaNy useful agents (e.g. EVISTA*) [McDonnell, Journal of the Society for Gynecologic Investigation 7: S10-S15 (2000), Goldstein, et al., Human Reproduction Update 6:212-224 (2000)]. The precise reason why the same compound can have cell-specific effects has not been elucidated, but the differences in receptor conformation and/or in the milieu of coregulatory proteins have been suggested.
It has been known for some time that estrogen receptors adopt different conformations when binding Ikjands. However, the consequence and subtlety of these changes has been only recently revealed. The three dimensional structures of ERa and ERp have been solved by co-crystallization with various Ikjands and t (early show the repositioning of helix 12 in the presence of an estrogen receptor antagonist that stericaBy hinders the protein sequences required for receptor-coregulatory protein interaction [Pike, et al., EMB018:4608-4618 (1999), Shiau, et al., Cell 95: 927-937 (1998)]. In addition, the technique of phage display has been used to identify peptides that Interact with estrogen receptors in the presence of different ligands [Paige, et al.. Proceedings of the National Academy of Sciences of the United States of America 96: 3999-4004 (1999)]. For example, a peptide was identified that distinguished between ERa bound to the full estrogen receptor agonists 17p-estradiol and diethylstilbesterol. A different peptide was shown to distinguish between clomiphene bound to ERa and ERp. These data indicate that each ligand potentially
places the receptor in a unique and unpredictable conformation that is likely to have distinct biological activities.
The preparation of exemplary ERp selective ligands, including 2-{3-fluoro-4-hydroxyphenyl)-7-vInyM.3-benzoxazol-5-ol (ERB-041), is described in U.S. Pat. No. 6,794,403, incorporated herein by reference in Rs entirety.
As mentioned above, estrogens affect a panoply of biological processes. In addition, where gender differences have been described (e.g., disease frequencies, responses to challenge, etc.), it is possible that the explanation involves the difference in estrogen levels between males and females.
Given the importance of these compounds as pharmaceutical agents, it can be seen that effective formulations for delivery of the compounds is of great import This invention is directed to these, as wed as other, important ends.
SUMMARY OF THE INVENTION
In some embodiments, the present invention provides pharmaceutical formulations comprising a pharmaceutically effective amount of an active pharmacological agent and a carrier or exdpient system, the carrier or exdpient system comprising:
a) a filter/diluent component comprising from about 10% to about 60% by
weight of the pharmaceutical formulation;
b) a surface modifying agent component comprising from about 1% to
about 20% by weight of the pharmaceutical formulation;
c) a glidant/disintegrarrt component comprising from about 0.01% to
about 10% by weight of the pharmaceutical formulation;
d) an optional second filler/diluent component comprising up to about
20% by weight of the pharmaceutical formulation; and
e) a lubricant component comprising up to about 10% by weight of the
pharmaceutical formulation;
wherein the active pharmacological agent has the Formula I:
(Figure Removed)
wherein
R! is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyt of 1-6 carbon atoms, sulfoxoallcyl of 1-6 carbon atoms, sulfonoalkyt of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocydic ring having 1 to 4 heteroatoms selected from O, N or S, -N02, -NR5R6, -N(R5)COR,. -CN. -CHFCN, -CF2CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl. trifluoroalkoxy, -CORs. -CO2Rs, -NOj, CONR5R6, NRsR, or N(R5)COR6;
R2 and R2. are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -CORs, -COzRe, -NO* CONRcR* NR$R« or
RS, Raa. and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, afcoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -CORs, -CC^Rs, -NO2, CONRsR«, NRsR« or
Rs, R« are each, independently hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms; XisO,S,orNR7;and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryt of 6-10 carbon atoms, -CORS, -C02RS or -SO2R5; or a pharmaceuticalty acceptable salt thereof.
In some embodiments, X is 0. In some further embodiments, R, is alkenyl of 2-3 carbon atoms, which is optionally substituted with hydroxyl, -CN, halogen, trifiuoroalkyl, trifluoroalkoxy, -COR5, -CO2R5, -NO2, CONR5R6, NRsRe or N(R5)COR6. In some embodiments, the active ingredient is 2-{3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
The term halogen refers to chioro, bromo, fluoro or kxto, preferably fluoro. The alkyl of 1-6 carbon atoms (used atone or as part of a group e.g. alkoxy) may be a straight or branched alky) e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl. The cydoalkyl of 3-8 carbon atoms may be saturated or unsaturated and includes the moieties cyclopropyl, cyclobutyl, cyctopenty) and cydohexyl. The trifiuoroalkyl of 1-6 carbon atoms (used alone or as part of a group) may suitably be trifluoromethyi. Sulfoxoalkyl of 1-6 carbon atoms refers to the group -SO-R wherein R is an alkyl of 1-6 carbon atoms as defined above. Aryl of 6-10 carbon atoms refers to a mono or poly cyclic aromatic group, e.g., phenyl or napthyl. The 5 to 6 membered heterocycBc ring having 1 to 4 heteroatoms selected from O, N or S is a saturated, partially unsaturated or aromatic ring, e.g., a furanvl, pyranyl, pyrkfinyl, pyrlmldinyl, pyrazinyt, morpholinyl, thkxnorpholinyl, imidazoiyi, oxazolyl, thioxazoryl, thienyl or piperidinyl ring. The alkynyl of 2-7 carbon atoms is a group having at least one triple bond, e.g., ethynyl. The alkenyl of 2-7 carbon atoms is a group having at least one double bond, e.g., vinyl. When the alkyl or alkenyl moieties are substituted they may be substituted with 1 or more substituents as defined above, e.g. by 1, 2 or 3 substituents which may be the same or different.
In some embodiments, the active pharmacological agent comprises up to about 88% by weight of the pharmaceutical formulation.
In some embodiments, the active pharmacological agent comprises from about 10% to about 50% by weight of the pharmaceutical formulation; the filler/diluent component comprises from about 30% to about 60% by weight of the pharmaceutical formulation; the surface modifying agent component comprises from about 1% to about 10% by weight of the pharmaceutical formulation; the glidant/disintegrant component comprises from about 0.01% to about 5% by weight
of the pharmaceutical formulation; the optional second filler/diluent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation; and the lubricant component comprises from about 0.01% to about 2% by weight of the pharmaceutical formulation.
In some further embodiments, the active pharmacological agent comprises from about 20% to about 40% by weight of the pharmaceutical formulation; the filler/diluent component comprises from about 40% to about 60% by weight of the pharmaceutical formulation; the surface modifying agent component comprises from about 3% to about 7% by weight of the pharmaceutical formulation; the glidant/dteintegrant component comprises from about 1% to about 2% by weight of the pharmaceutical formulation; the optional second filter/diluent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation; and the lubricant component comprises from about 0.01% to about 1% by weight of the pharmaceutical formulation.
In further embodiments, the active pharmacological agent comprises from about 25% to about 35% by weight of the pharmaceutical formulation; the filler/diluent component comprises from about 44% to about 53% by weight of the pharmaceutical formulation; the surface modifying agent component comprises from about 4% to about 6% by weight of the pharmaceutical formulation; the glidant/disintegrant component comprises from about 1% to about 2% by weight of the pharmaceutical formulation; the optional second filler/diluent component comprises from about 12% to about 18% by weight of the pharmaceutical formulation; and the lubricant component comprises from about 0.1% to about 1% by weight of the pharmaceutical formulation.
In some embodiments, the filter/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, mattodextrin, sorbRol, starch, xyTrtol, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, starch, a calcium phosphate, for example anhydrous dicalcium phosphate, sodium starch gtycdate, or metal aluminosilicate, for example, magnesium aluminometasilicate (Neusilin*). In some embodiments, the filler/diluent component comprises mannitol, for example, Pearlitol* 200D.
In some embodiments, the optional second filler/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose,
icrocrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, starch, a calcium phosphate, for example, anhydrous dicateium phosphate, sodium starch glycolate, or metal aluminosilicate, for example, magnesium aluminometasilicate (Neusilin*). In some embodiments, the optional second filler/diluent component comprises microcrystalline cellulose, for example, Avfcel* PH101.
In some embodiments, the surface modifying agent component comprises one or more of Poloxamer 188, metal alkyl sulfate, sodium lauryi sulfate, poryoxyethylene sorbitan fatty acid ester, polyethylene glycol, potyoxyethytene castor oil derivative, docusate sodium, quaternary ammonium amine compound, sugar esters of fatty acid or grycerides of fatty acid. In some embodiments, the surface modifying agent component comprises sodium lauryi sulfate.
In some embodiments, the gfidant/disintegrant component comprises one or more of croscarmellose sodium, modified cellulose, pregelatinized starch, sodium starch glycolate, crospovklone, starch, alginic acid, sodium alginate, day, ceHutose floe, ion exchange resin, effervescent systems based on food acids and an alkaline component, silca such as Aerosil* 200, talc, lactose, stearate, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium sifcate, silicon dioxide, or silicon dioxide aerogel. In some embodiments, the glidant/disintegrant component comprises silica, for example, Aerosil* 200.
In some embodiments, the lubricant component comprises one or more of metallic stearate, fatty acid ester, fatty acid, fatty alcohol, glyceryl behenate, mineral oi, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metallic lauryi sulfate, silica such as Aerosil* 200, and sodium chloride. In some embodiments, the lubricant component comprises magnesium stearate.
In some embodiments, the filter/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol or a metal aluminosQicate; the optional second filler/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol or a metal aluminosilicate; the surface modifying agent component comprises one or more of Poloxamer 186, metal alkyl sulfate, sodium lauryi sulfate, or polyethylene glycol; the glidant/disintegrant component comprises one or more of croscarmellose
sodium, modified cellulose, pregelatinized starch, sodium starch glycolate, crospovidone, starch, aiginic acid, sodium alginate, silica such as Aerosi 200, lactose, stearate, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate or silicon dioxide; and the lubricant component comprises one or more of metallic stearate, fatty acid ester, fatty acid, fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metallic lauryl sulfate, silica such as Aerosil* 200, or sodium chloride.
In some further embodiments, the filter/diluent component comprises mannitor, the optional second filler/diluent component comprises mterocr/stalHne cellulose; the surface modifying agent component comprises sodium lauryl sulfate; the gDdant/disintegrarrt component comprises silica; and the tubricant component comprises a metallic stearate. In some stifl further embodiments, the filtor/dBuent component comprises Pearfitol* 200SD; the optional second Wee/diluent component comprises Avicef PH101; the surface modifying agent component comprises sodium lauryl sulfate; the gfidant/disintegrant component comprises Aeros'il 200; and the lubricant component comprises magnesium stearate.
In some embodiments of the processes and formulations of the invention, the pharmaceutical formulation contains from about 1 mg to about 125 mg of active pharmacological agent, or from about 1 mg to about 3 mg of active pharmacological agent; or from about 3 mg to about 7 mg of active pharmacological agent; or from about 20 mg to about 30 mg of active pharmacological agent; or from about 40 mg to about 60 mg of active pharmacological agent; or from about 70 mg to about 80 mg of active pharmacological agent; or from about 90 mg to about 110 mg of active pharmacological agent
The present invention also provides processes for preparing a pharmaceutical formulation comprising a pharmaceuticalty effective amount of an active pharmacological agent and a carrier or excipient system, the carrier or excipient system comprising:
a) a filler/diluent component comprising from about 10% to about 60% by
weight of the pharmaceutical formulation;
b) a surface modifying agent component comprising from about 1% to
about 20% by weight of the pharmaceutical formulation;
c) a glidant/disintegrant component comprising from about 0.01% to
about 10% by weight of the pharmaceutical formulation;
d) an optional second filler/diluent component comprising up to about
20% by weight of the pharmaceutical formulation; and
e) a lubricant component comprising up to about 10% by weight of the
pharmaceutical formulation;
the process comprising:
i) blending the glidant/disintegrant component and the active pharmacological agent to form a first mixture;
ii) blending the first mixture with the second filler/diluent component to form a second mixture;
Hi) mixing the first fllter/dluent component and the surface modifying agent component together with the second mixture to form a third mixture; and
roalkaxy, -CORs, -COjRs. -NO* CONRjR,, NR,R« or N(Rs)CORe;
Ro, Ra.. and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, haiogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, -CN, halogen, trifluoroakyl, trifluoroalkoxy, -COR5, -CO2Rs, -NOZ, CONRsRg, NRjR, or
R5| Re are each, independently hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms; X is O, S, or N R7; and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5, -CO2R5 or -SO2R5; or a pharmaceutically acceptable salt thereof.
In some embodiments, X is 0. In some further embodiments, R7is atkenyl of 2-3 carbon atoms, which is optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyt, trifluoroalkoxy. -CORs, -COZR5, -NO2> CONRsRs, NR5R« or N^JCORs. In some preferred embodimerrts, the active ingredient is 2-(3-fluoro-4-hydroxypheny1}-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
Generally, the active pharmacological agent comprises up to about 86% by weight of the pharmaceutical formulation. In some embodiments, the active pharmacological agent can be present in an amount of from about 10% to about 50% by weight of the pharmaceutical formulation- from about 20% to about 40% by weight of the pharmaceutical formulation; or from about 25% to about 35% by weight of the pharmaceutical formulation. Preferably, the active pharmacological agent is 2-(3-fluoro-44ivdroxvpheiiy1)-7-vinyl-13-t)enzoxazo4-5-ol or a pharmaceuticaRy acceptable salt thereof.
Generally, the fitter/diluent is present in an amount of about 10% to about 60% by weight of the pharmaceutical formulation, about 30% to about 60% by weigh* of the pharmaceutical formulation, about 40% to about 60% by weight of the pharmaceutical formulation, or about 44% to about 53% by weight of the pharmaceutical fbrmulatieLh. The optional second finer/diluent component is generally present Hi an amount of up to about 20% by weight of the pharmaceutical formulation, from about 10% to about 20% by weight of the pharmaceutical formulation, or about 12% to about 18% by weight of the pharmaceutical formulation. In some embodiments, the filler/diluent component and the second fiNer/cffluent component include one or more agent that is useful as a filler or dBuent or a combination of such agents. Both the filler/diluent and the second filler/diluent can be selected from fillers and diluents known to be useful in the art, including for example, mannttol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, maltodextrin, sorbitol, starch, xylitol, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl celluloses, starches, calcium phosphates, for example, anhydrous dicalcium phosphate, sodium starch glycolates, and metal aluminosilicates, for
example, magnesium aluminometasiltcate (Neusilin*). One or more fillers and/or one or more diluents may be selected in each case. In some embodiments, the filler/diluent component comprises mannitol. for example, Peariitor* 200D, and the second filler/diluent comprises microcrystalline cellulose, for example, Avicel* PH101.
Generally, the surface modifying agent component is present in an amount of from about 1% to about 20% by weight of the pharmaceutical formulation; about 1% to about 10% by weight of the pharmaceutical formulation, about 3% to about 7% by weight of the pharmaceutical formulation, or about 4% to about 6% by weight of the pharmaceutical formulation. The surface modifying agent can be selected from surface modifying agents, known to be useful in the art, including, for example, surfactants, PoJoxamer 188, metal alkyl sulfates such as sodium teuryt suttate, pdyoxyethytene sorbHan fatty acid esters, polyethylene grycote, poryoxyethytene castor 08 derivatives, docusate sodium, quaternary ammonium amine compounds, sugar esters of fatty adds and grycerides of fatty acids. In some embodiments, the surface modifying agent component comprises sodium lauryt sulfate.
Generally, the gSdant/dislntegrant component is present in an amount from about 0.01 % to about 10% by weight of the pharmaceutical formulation, about 0.01 % to about 5% by weight of the pharmaceutical formulation, or about 1% to about 2% by weight of the pharmaceutical formulation. The gOdant/dJJuent can be selected from glidants and disintegrants known to be useful for pharmaceutical formulations. One or more glkJartts and/or one or more disintegrants may be selected. Examples of suitable glidant/disbitegrants include croscarmeflose sodium, modified cellulose, pregetetinized starch, sodium starch grycotate, crospovidone, starch, alginic acid, sodium alginate, days, cellulose floe, ion exchange resins, effervescent systems based on food adds and an alkaline carbonate component, silica such as Aerosif® 200, talc, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silicon dioxide, and silicon dioxide aerogels. In some embodiments, the glidant/diluent is a silica, for example, Aerosif* 200. The glidant/distntegrant component is preferably an agent that is useful both as a glidant and as a disintegrant or a combination of such agents.
The lubricant component is present in an amount of up to about 10% of the formulation, from about 0.01% to about 2% of the formulation, from about 0.01% to
about 1% of the formulation, or from aboutO.1% to about 1% of the formulation. The lubricant can be selected from the many lubricants useful in the pharmaceutical arts. Examples of suitable lubricants include metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, teucine, polyethylene glycols, metallic lauryl sulfates, silica such as Aerosil® 200, and sodium chloride. In some embodiments, the lubricant is magnesium stearate.
Additional suitable filter/diluents, surface modifying agents, glidant/dislntegrants and lubricants can be found in, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company. Easton, Pa., 1985, which is incorporated herein by reference in its entirety.
In some preferred embodiments, the formulation contains from about 1 mg to about 125 mg, or about 1 mg to about 3 mg, or about 3 mg to about 7 mg, or about 20 mg to about 30 mg, or about 40 mg to about 60 mg, or about 70 mg to about 80 mg, or about 90 mg to about 110 mg of active pharmacological agent
The present invention also provides processes for preparing a pharmaceutical formulation comprising a pharmaceutically effective amount of an active pharmacological agent and a carrier or excipient system, the carrier or excipient system comprising:
a) a filer/diluent component comprising from about 10% to about 60% by
weight of the pharmaceutical formulation;
b) a surface modifying agent component comprising from about 1% to
about 20% by weight rftneplwmaceutical formulation;
c) a gfidant/disintegrant component comprising from about 0.01% to
about 10% by weight of the pharmaceutical formulation;
d) an optional second filler/diluent component comprising up to about
20% by weight of the pharmaceutical formulation; and
. e) a lubricant component comprising up to about 10% by weight of the pharmaceutical formulation; the process comprising:
i) blending the glidant/disinfegrartt component and the active pharmacological agent to form a first mixture;
it) blending the first mixture with the second filler/diluent component to form a second mixture;
iii) mixing the first filler/diluent component and the surface modifying agent component together with the second mixture to form a third mixture; and
iv) mixing the lubricant component with the third mixture to form a final blend; wherein the active pharmacological agent is 2-(3-fluoro-4-hydroxyphenyi)-7-vinyt-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
In some embodiments, the processes further comprise encapsulating at least a portion of the final blend.
The present invention also provides products of the processes described herein.
It wil be understood that the weight percentages set forth for the filler/diluent component surface modifying agent component, dis'mtegrant component, optional second filler component, and lubricant component of the formulations disclosed herein are the percentages that each component wffl comprise of a final pharmaceutical formulation, without reference to any surface covering, such as a tablet coating or capsule. The remainder of the final formulation w» be comprised of the active pharmacological agents).
Oral formulations containing the present solid dispersions can comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions, and the ike. Capsules are preferred. Capsutes or tablets containing the present soid dispersion can also be combined with mixtures of other active compounds or inert filters/diluents such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystaffine and microcrystafline celluloses, flours, gelatins, gums, etc. In some preferred embodiments, the formulations are direct blend solid dispersions contained in capsules.
Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable fillers/diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryf sulfate, microcrystalfine cellulose, carboxymethytcellulose calcium,
polyvinylpyrrolidone, gelatin, algintc acid, acacia gum, xantnan gum, sodium citrate, complex silicates, calcium carbonate, giycine, dextrin, sucrose, sorbrtol, dfcalcium phosphate, calcium sulfate, lactose, kaolin, mannftol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations used herein may utilize standard delay or time release formulations or spansuies. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to after the suppositories melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
Film coatings useful with the present formulations are known in the art and generally consist of a polymer (usually a celluJosic type of polymer), a colorant and a ptesticteer. Additional ingredients such as wetting agents, sugars, flavors, oils and lubricants can be included in fflm coating formulations to impart certain characteristics to the fflm coat. The formulations and formulations herein may also be combined and processed as a solid, then placed in a capsule form such as a gelatin capsule.
As will be appreciated, some components of the formulations of the invention can possess multiple functions. For example, a given component can act as both a filler/diluent and a disirrtegrant In some such cases, the function of a given component can be considered singular even though its properties may allow multiple functionality.
'" The pharmaceutical formulations and excipient systems herein can also contain an antioxidant or a mixture of antioxidants such as ascorbic acid. Other antioxkJants that can be used include sodium ascorbate and ascorbyi palmitate, optionally in conjunction with an amount of ascorbic acid. An example range for the antioxklant{s) is from about up to about 15% by weight, e.g., from about 0.05% to about 15% by weight, from about 0.5% to about 15% by weight, or from about 0.5% to about 5% by weight. In some embodiments, the pharmaceutical formulations contain substantially no antioxidant.
Additional numerous various excipients, dosage forms, dispersing agents and the like that are suitable for use in connection with the solid dispersions of the invention are known in the art and described in, for example, Remington's
Pharmaceutical Sciences, 17th ed,, Mack Publishing Company. Easton, Pa., 1985, which is incorporated herein by reference in its entirety.
The materials, methods, and examples presented herein are intended to be illustrative, and are not intended to limit the scope of the invention.
EXAMPLES
EXAMPLE 1 PROCEDURE FOR PREPARATION OF CAPSULES CONTAINING ERB-041
Amounts of components are shown in the Table below.
1. Aerosil® 200 and ERB-041 are mixed together for 10 minutes using a
tumbling type blender at 30 rpm.
2. The prebtend from Step 1 is then passed through a 500 micron screen.
3. Avteef® PH101 is used to wash the internal surfaces of the screen and mixing
vessel, and is then passed through a 500 micron screen and blended with the
sieved pre-Wend from Step 2 for a further 10 minutes.
4. Pearlitol® 200SD and sodium lauryl sulfate are passed through a 500 micron
screen and mixed with the blend from Step 3 for 10 minutes.
5. Magnesium stearate is mixed with a portion of the blend from Step 4 and the
mixture passed through a 500 micron screen and blended with the bulk of the
blend from Step 4 for an additional one minute.
6. The final btend is then encapsulated into size 1 propyl hydroxymethyl
cellulose (HPMC) capsule shells.

The formulation of the capsules is shown in the Table below.
(Table Removed)
It is intended that each of the patents, applications, and printed publications, including books, mentioned in this patent document be hereby incorporated by reference in their entirety.
As those skilled in the art wM appreciate, numerous changes and modifications may be made to the embodiments of the Invention without departing from the spirit of the invention. It is intended that all such variations fad within the scope of the invention.
The present invention daims benefit of priority from provisional U.S. Patent Application Serial No. 60/632,448 filed December 2,2004, which is incorporated herein by reference hi its entirety.

WHAT IS CLAIMED IS:
1. A pharmaceutical formulation comprising a pharmaceuticalty effective amount of an active pharmacological agent and a carrier or excipient system, the carrier or excipient system comprising:
a) a filter/diluent component comprising from about 10% to about 60% by
weight of the pharmaceutical formulation;
b) a surface modifying agent component comprising from about 1% to
about 20% by weight of the pharmaceutical formulation;
c) a glJdant/disirrtegrant component comprising from about 0.01% to
about 10% by weight of the pharmaceutical formulation;
d) an optional second fflter/dluent component comprising up to about
20% by weight of the pharmaceutical formulation; and
e) a lubricant component comprising up to about 10% by weight of the
pharmaceutical formulation;
wherein the active pharmacological agent has the Formula I:

(Figure Removed)
wherein
Rt is hydrogen, hydroxyl, halogen, alkyf of 1-6 carbon atoms, trifluoroaOcyl of 1-6 carbon atoms, cydoalkyl of 3-8 carbon atoms, aDcoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyi of 1-6 carbon atoms, surfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocyctic ring having 1 to 4 heteroatoms selected from O, N or S, -NOZ, -NRsRe, -NfRsJCOR6, -CN, -CHFCN, -CF2CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyf or alkenyl moieties are opttonalry
substituted with hydroxyl, -CN, halogen, trifluoroalkyi, trifluoroalkoxy, -CORS, -CO2R5, -N02, CONRsRs, NR5R6 or N(R5)COR6;
R2 and R2, are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyi of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoroalkyi of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyi moieties are optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyi, trifluoroalkoxy, -COR5, -CO2R5, -NO2, CONR5R6, NR6R6 or
Rs. R». and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms,
alkenyi of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyi of 1-6 carbon atoms, or trifiuoroafcoxy of 1-6 carbon atoms; wherein the alkyl or alkenyi moieties are optionally substituted with hydroxyl, -CN, halogen, trifluofoalkyl, trifluoroalkoxy, -COR,, -CO2R5, -NO3, CONRsR,, NR5R« or
R5, R6 are each, independently hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms; X is O, S, or N R7; and
RT is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR6,
or a pharmaceuticalry acceptable saH thereof.
2. The pharmaceutical formulation of claim 1 wherein X is O.
3. The pharmaceutical formulation of claim 2, wherein R, is alkenyi of 2-3 carbon
atoms, which is optionally substituted with hydroxyl, -CN, halogen, trifluoroafcyl,
trifluoroalkoxy, -COR5. -CO2Rs, -NO2 CONRsR«, NRsRe or
4. The pharmaceutical formulation of darn 1 wherein the active ingredient is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical formulation of any one of claims 1 to 4 wherein the active
pharmacological agent comprises up to about 88% by weight of the pharmaceutical
formulation.
6. The pharmaceutical formulation of any one of claims 1 to 4 wherein:
the active pharmacological agent comprises from about 10% to about 50% by weight of the pharmaceutical formulation;
the filler/diluent component comprises from about 30% to about 60% by weight of the pharmaceutical formulation;
the surface modifying agent component comprises from about 1% to about 10% by weight of the pharmaceutical formulation;
the gBdant/disintegrant component comprises from about 0.01% to about 5% by weight of the pharmaceutical formulation;
the optional second filler/diluent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation; and
the lubricant component comprises from about 0.01% to about 2% by weight of the pharmaceutical formulation.
7. The pharmaceutical formulation of any one of claims 1 to 4 wherein:
the active pharmacological agent comprises from about 20% to about 40% by weight of the pharmaceutical formulation;
the fiHer/diluent component comprises from about 40% to about 60% by weight of the pharmaceutical formulation;
the surface modifying agent component comprises from about 3% to about 7% by weight of the pharmaceutical formulation;
the gBdant/disintegrant component comprises from about 1% to about 2% by weight of the pharmaceutical formulation;
the optional second filler/diluent component comprises from about 10% to about 20% by weight of the pharmaceutical formulation; and
the lubricant component comprises from about 0.01% to about 1% by weight of the pharmaceutical formulation.
8. The pharmaceutical formulation of any one of claims 1 to 4 wherein:
the active pharmacological agent comprises from about 25% to about 35% by weight of the pharmaceutical formulation;
the filler/diluent component comprises from about 44% to about 53% by weight of the pharmaceutical formulation;
the surface modifying agent component comprises from about 4% to about 6% by weight of the pharmaceutical formulation;
the glklant/disintegrant component comprises from about 1% to about 2% by weight of the pharmaceutical formulation;
the optional second frier/diluent component comprises from about 12% to about 18% by weight of the pharmaceutical formulation; and
the lubricant component comprises from about 0.1% to about 1% by weight of the pharmaceutical formulation
9. The pharmaceutical formulation of any one of claims 1 to 8 wherein the
fifler/dBuent component comprises one or more of mannrW, lactose, sucrose,
powdered cellulose, mfcrocrystalline cellulose, mattodextrin, sorbXol, starch, xylttol,
carboxymethyl ceButose, carboxyethyi celutose, hydroxyethyi ceButose, starch, a
calcium phosphate, anhydrous dicalcium phosphate, sodium starch grycolate, metal
aluminosifcate, or magnesium atuminometasKcate.
10. The pharmaceutical formulation of any one of claims 1 to 8 wherein the
fflter/dfluerrt component comprises mannitoi.
11. The pharmaceutical formulation of any one of claims 1 to 10 wherein the
optional second filer/diluent component, if present, comprises one or more of
mannitoi, lactose, sucrose, powdered cellulose, microcrystalline cellulose,
mattodextrin, sorbttol, starch, xylitol, carboxymethyl cellulose, carboxyethyi cellulose,
hydroxyethyi cellulose, starch, a calcium phosphate, anhydrous dfealcium
phosphate, sodium starch grycolate, metal aluminosificate, or magnesium
aluminometasilicate.
12. The pharmaceutical formulation of any one of claims 1 to 10 wherein the
optional second filler/diluent component, if present, comprises mterocrystalline
cellulose.
13. The pharmaceutical formulation of any one of claims 1 to 12 wherein the
surface modifying agent component comprises one or more of Poloxamer 188, metal
atkyt sulfate, sodium lauryl surfate, polvoxyethytene sorbitan fatty acid ester,
polyethylene glycol, polyoxyethylene castor oil derivative, docusate sodium,
quaternary ammonium amine compound, sugar esters of fatty add or glycerides of
fatty acid.
14. The pharmaceutical formulation of any one of claims 1 to 12 wherein the
surface modifying agent component comprises sodium lauryl sulfate.
15. The pharmaceutical formulation of any one of daims 1 to 14 wherein the
gltdanf dislntegrarrt component comprises one or more of croscarmeflose sodium,
modified cellulose, pregetetinized starch, sodium starch glycolate, crospovidone,
starch, alglnic acid, sodium alginate, day, cellulose floe, ton exchange resin,
effervescent systems based on food acids and an alkaline carbonate component,
talc, lactose, stearate, dibasic calcium phosphate, magnesium carbonate,
magnesium oxide, calcium silicate, silica, silicon dioxide, or silicon dioxide aerogel.
16. The pharmaceutical formulation of any one of claims 1 to 14 wherein the
glidant/disintegrant component comprises sifica.
17. The pharmaceutical formulation of any one of claims 1 to 16 wherein the
lubricant component comprises one or more of metallic stearates, fatty acid esters,
fatty acids, fatty alcohols, gryceryl behenate, mineral oil, paraffins, hvdrogenated
vegetable oils, teucine, polyethylene grycds, metallic lauryl surfates, silica or sodium
chloride.
18. The pharmaceutical formulation of any one of claims 1 to 16 wherein the
lubricant component comprises magnesium stearate.
19. The pharmaceutical formulation of any one of claims 1 to 8 wherein:
the filler/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, mattodextrin, sorbitot, starch, xyfitol or a metal aluminosilicate;
the optional second filler/diluent component comprises one or more of mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose, maltodextrin, sorbrtol, starch, xylrtol or a metal aluminosilicate;
the surface modifying agent component comprises one or more of Pokwamer 188. metal alkyl sulfate, soc