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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This invention relates to vitamin D compounds, and more particularly to 2-methylene-19,21-dinor-1 ⁇ -hydroxy-bishomopregnacalciferol and to pharmaceutical formulations that include this compound.
• the invention also relates to the use of 2-methylene-19,21-dinor-1 ⁇ -hydroxy ⁇ bishomopregnacalciferol or salts thereof in the preparation of medicaments for use in treating various diseases.
• the natural hormone, 1 ⁇ ,25-dihydroxyvitamin D 3 also referred to as l ⁇ -dihydroxycholecalciferol and calcitriol
• its analog in the ergosterol series i.e. 1 ⁇ ,25-dihydroxyvitamin D 2
• l ⁇ -dihydroxycholecalciferol and calcitriol l ⁇ -dihydroxycholecalciferol and calcitriol
• Another class of vitamin D analogs i.e. the so called 19-nor- vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms.
• Biological testing of such 19-nor-analogs revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity.
• these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders.
• the invention provides 2-methylene-19,21 -dinor-1 ⁇ -hydroxy- bishomopregnacalciferol and related compounds, pharmaceutical formulations that include 2-methylene-19,21 -dinor-1 ⁇ -hydroxy-bishomopregnacalciferol, and Atty. Docket No. 032026-0906
• the invention provides a compound having the formula I shown below
• X 1 and X 2 may be the same or different and are independently selected from H or hydroxy-protecting groups.
• X 1 and X 2 are both hydroxy protecting groups such as silyl groups.
• X 1 and X 2 are both t-butyldimethylsilyl groups.
• X 1 and X 2 are both H such that the compound is 2-methylene-19,21-dinor-1 ⁇ -hydroxy- bishomopregnacalciferol having the formula IA as shown below:
• the compound of formula IA is a compound of formula IB and has the structure shown below:
• the above compound exhibits a desired, and highly advantageous, pattern of biological activity.
• This compound is characterized by relatively high binding to vitamin D receptors, but very low intestinal calcium transport activity, as compared to that of 1 ⁇ ,25-dihydroxyvitamin D 3 , and has very low ability to Atty. Docket No. 032026-0906
• this compound can be characterized as having little, if any, calcemic activity. Thus, it may be useful as a therapy for suppression of secondary hyperparathyroidism of renal osteodystrophy.
• the compound of the invention is also especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g. in autoimmune diseases, including multiple sclerosis, lupus, diabetes mellitus, host versus graft reaction, and rejection of organ transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease, ulcerative colitis and Crohn's disease. Acne, alopecia and hypertension are other conditions which may be treated with the compound of the invention.
• autoimmune diseases including multiple sclerosis, lupus, diabetes mellitus, host versus graft reaction, and rejection of organ transplants
• inflammatory diseases such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease, ulcerative colitis and Crohn's disease.
• Acne, alopecia and hypertension are other conditions which may be treated with the compound of the
• the above compound is also characterized by relatively high cell differentiation activity.
• this compound also provides a therapeutic agent for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer and prostate cancer.
• this compound provides a therapeutic agent for the treatment of various skin conditions including wrinkles, lack of adequate dermal hydration, i.e. dry skin, lack of adequate skin firmness, i.e. slack skin, and insufficient sebum secretion. Use of this compound thus not only results in moisturizing of skin but also improves the barrier function of skin.
• the compounds of the invention may be used to prepare pharmaceutical formulations or medicaments that include a compound of the invention in combination with a pharmaceutically acceptable carrier. Such pharmaceutical formulations and medicaments may be used to treat various biological disorders such as those described herein. Methods for treating such disorders typically include administering an effective amount of the compound or an appropriate amount of a pharmaceutical formulation or a medicament that includes the compound to a subject suffering from the biological disorder.
• a pharmaceutical formulation or a medicament that includes the compound to a subject suffering from the biological disorder.
• the subject is a mammal.
• the mammal is selected from a rodent, a primate, a bovine, an equine, a canine, a feline, an ursine, a porcine, a rabbit, or a guinea pig.
• the mammal is a rat or is a mouse.
• the subject is a primate such as, in some embodiments, a human.
• the compound may be present in a composition to treat the above- noted diseases and disorders in an amount from about 0.01 ⁇ g/gm to about 1 mg/gm of the composition, preferably from about 0.1 ⁇ g/gm to about 500 ⁇ g/gm of the composition, and may be administered topically, transdermal ⁇ , orally, or parenterally in dosages of from about 0.01 ⁇ g/day to about 1 mg/day, preferably from about 0.1 ⁇ g/day to about 500 ⁇ g/day.
• Figures 1 -7 illustrate various biological activities of 2-methylene-
• 19,21-dinor-i ⁇ -hydroxy-bishomopregnacalciferol referred to as "19,21-dinor” in the Figures
• those of the native hormone 1 ⁇ ,25-dihydroxyvitamin D 3 referred to as "1 ,25(OH) 2 D 3 " in the Figures.
• Figure 1 is a graph comparing the relative activity of 19,21-dinor and 1 ,25(OH) 2 D 3 to compete for binding with [ 3 H]-1 ,25-(OH) 2 -D 3 to the full-length recombinant rat vitamin D receptor.
• Figure 2 is a graph comparing the percent HL-60 cell differentiation as a function of the concentration of 19,21-dinor with that of 1 ,25(OH) 2 D 3 .
• Figure 3 is a graph comparing the in vitro transcription activity of
• Figure 4 is a bar graph comparing the bone calcium mobilization activity of 19,21-dinor with that of 1 ,25(OH) 2 D 3 .
• Figure 5 is a bar graph comparing the intestinal calcium transport activity of 19,21 -dinor with that of 1 ,25(OH) 2 D 3 .
• Figure 6 is a bar graph comparing the serum calcium levels in adult rats after administration of 19,21 -dinor and 1 ,25(OH) 2 D 3 .
• Figure 7 is a bar graph comparing the percent parathyroid hormone
• Preparation of 2-methylene-19,21 -dinor-1 ⁇ -hydroxy- bishomopregnacalciferol can be accomplished by condensing an appropriate bicyclic Windaus-Grundmann type ketone (II) with the allylic phosphine oxide followed by deprotection (removal of the Y 1 and Y 2 groups).
• II bicyclic Windaus-Grundmann type ketone
• Yi and Y 2 are preferably hydroxy-protecting groups such as silyl protecting groups.
• the t-butyldimethylsilyl (TBDMS) group is an example of a particularly useful hydroxy-protecting group.
• Phosphine oxide III is a convenient reagent that can be used to prepare a large number of 19-nor vitamin D compounds and may be prepared according to the procedures described by Sicinski et al., J. Med. Chem., 41, 4662 (1998), DeLuca et al., U.S. Patent No. 5,843,928; Perlman et al., Tetrahedron Lett. 32, 7663 (1991 ); and DeLuca et al., U.S. Patent No. 5,086,191.
• Scheme I shows the general procedure for synthesizing phosphine oxide III as outlined in U.S. Patent No.
• phosphonium compounds may be used in place of the MePh 3 P + Br used to convert ketone B to alkene C.
• examples of such compounds include EtPh 3 P + Br " , PrPh 3 P + Br " , and compounds generally prepared by reaction of triphenylphosphine with an alkyl halide, an alkenyl halide, a protected- hydroxyalkyl halide, and a protected hydroxyalkenyl halide. Alkenes prepared using this procedure may then be carried through to prepare a phosphine oxide in an analogous manner to that used to prepare phosphine oxide H in Scheme I.
• an alkene analogous to compound C of Scheme I may be reduced with (Ph 3 P) 3 RhCI and H 2 to provide other vitamin D analogs.
• (Ph 3 P) 3 RhCI and H 2 may be reduced with (Ph 3 P) 3 RhCI and H 2 to provide other vitamin D analogs.
• Hydraindanones of structure Il can prepared by known methods or adapted methods as will be readily apparent to one of skill in the art and described herein. Specific examples of some important bicyclic ketones used to synthesize vitamin D analogs are those described in Mincione et al., Synth. Commun 19, 723, (1989); and Peterson et al., J. Org. Chem. 51, 1948, (1986).
• hydroxy-protecting group signifies any group commonly used for the temporary protection of the hydroxy (-OH) functional group, such as, but not limited to, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups.
• Alkoxycarbonyl protecting groups are alkyl-O-CO- groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl.
• acyl signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group.
• Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl.
• Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
• aryl specifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.
• An extensive list of protecting groups for the hydroxy functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.
• a "protected hydroxy” group is a hydroxy group derivatized or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functional groups, e.g., the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined. Atty. Docket No. 032026-0906
• BL21 (DE3) Codon Plus RIL cells and purified to homogeneity using two different column chromatography systems.
• the first system was a nickel affinity resin that utilizes the C-terminal histidine tag on this protein.
• the protein that was eluted from this resin was further purified using ion exchange chromatography (S-Sepharose Fast Flow). Aliquots of the purified protein were quick frozen in liquid nitrogen and stored at -80 0 C until use.
• the protein was diluted in TEDK 50 (50 mM Tris, 1.5 mM EDTA, pH 7.4, 5 mM DTT, 150 mM KCI) with 0.1% Chaps detergent.
• the receptor protein and ligand concentration was optimized such that no more than 20% of the added radiolabeled ligand was bound to the receptor.
• Radiolabeled and unlabeled ligands were added to 100 mcl of the diluted protein at a final ethanol concentration of ⁇ 10%, mixed and incubated overnight on ice to reach binding equilibrium. The following day, 100 mcl of hydroxylapatite slurry (50%) was added to each tube and mixed at 10-minute intervals for 30 minutes. The hydroxylapaptite was collected by centrifugation and then washed three times with Tris-EDTA buffer (50 mM Tris, 1.5 mM EDTA, pH 7.4) containing 0.5% Titron X-100.
• Tris-EDTA buffer 50 mM Tris, 1.5 mM EDTA, pH 7.4
• the pellets were transferred to scintillation vials containing 4 ml of Biosafe Il scintillation cocktail, mixed and placed in a scintillation counter. Total binding was determined from the tubes containing only radiolabeled ligand.
• HL60 Human promyelocytic leukemia
• HL60 cells were plated at 1.2 x 10 5 cells/ml. Eighteen hours after plating, cells in duplicate were treated with drug. Four days later, the cells were harvested and a nitro blue tetrazolium reduction assay was performed (Collins et a/., 1979; J. Exp. Med. 149:969-974). The percentage of differentiated cells was determined by counting a total of 200 cells and recording the number that Atty. Docket No. 032026-0906
• Animals were housed in suspended, stainless steel, wire-bottom cages. Each cage contained one animal.
• the animal rooms were maintained at a temperature of 68 to 72°F and a relative humidity of 25 to 75%. The holding rooms were set to provide 12 hours of light per day.
• Water and a purified rodent diet (Suda et al., Purified Rodent Diet-Diet 11) containing 0.47% and 0.3% phosphorus and fat soluble vitamins A, D, E and K were provided ad libitum.
• the negative control material was prepared by volumetrically measuring ethanol ( ⁇ 5%) and propylene glycol, mixing, and then placing in storage at 2 to 8 0 C.
• 2-Methylene-19,21-dinor-1 ⁇ -hydroxy-bishomopregnacalciferol binds to the recombinant vitamin D receptor, but is about 5 times less active than is 1 ⁇ ,25-dihydroxyvitamin D 3 in this respect (see Figure 1). Furthermore, it is active in stimulating transcription of a reporter gene stably transfected in Ros17/2.8 (bone) cells, indicating significant biological activity (see Figure 3). However, it is about 15 times less active than 1 ⁇ ,25-dihydroxyvitamin D 3 in inducing differentiation of HL-60 cells (see Figure 2). It has no calcemic activity when measured either by intestinal calcium transport or bone calcium mobilization even when given at 100 times the dose of 1 ⁇ ,25-dihydroxyvitamin Atty. Docket No. 032026-0906
• D 3 (see Figures 4 and 5). However, it does possess significant activity in suppressing parathyroid hormone levels in normal rats (see Figure 7).
• This compound should find its uses in the treatment of autoimmune diseases such as multiple sclerosis, type I diabetes, rheumatoid arthritis, lupus, and other similar degenerative diseases. It should also have significant activity in treating malignant growth such as colorectal, breast and prostate cancers. All of these activities should be evident in the absence of raising serum calcium concentrations (see Figure 6). This compound should also be useful in treating secondary hyperparathyroidism found in patients who have lost kidney function such as those on hemodialysis or peritoneal dialysis.
• the compounds of the invention are also useful in preventing or treating obesity, inhibiting adipocyte differentiations, inhibiting SCD-1 gene transcription, and/or reducing body fat in animal subjects. Therefore, in some embodiments, a method of preventing or treating obesity, inhibiting adipocyte differentiations, inhibiting SCD-1 gene transcription, and or reducing body fat in animal subject includes administering to the animal subject, an effective amount of the compound or a pharmaceutical composition that includes the compound. Administration of the compound or the pharmaceutical composition to the subject inhibits adipocyte differentiation, inhibits gene transcription, and/or reduces body fat in the animal subject.
• the compounds defined by formula I, formula IA, and formula IB may be formulated for pharmaceutical applications as a solution in innocuous solvents, or as an emulsion, suspension or dispersion in suitable solvents or carriers, or as pills, tablets or capsules, together with solid carriers, according to conventional methods known in the art. Any such formulations may also contain other pharmaceutically acceptable and non-toxic excipients such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, Atty. Docket No. 032026-0906
• the compounds may be administered orally, topically, parenterally, or transdermally.
• the compounds are advantageously administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal, or in the form of creams, ointments, patches, or similar vehicles suitable for transdermal applications.
• doses of from 0.001 ⁇ g to about 1 mg per day of the compound are appropriate for treatment purposes.
• an appropriate and effective dose may range from 0.01 ⁇ g to 1 mg per day of the compound.
• an appropriate and effective dose may range from 0.1 ⁇ g to 500 ⁇ g per day of the compound.
• Such doses will be adjusted according to the type of disease or condition to be treated, the severity of the disease or condition, and the response of the subject as is well understood in the art.
• the compound may be suitably administered alone, or together with another active vitamin D compound.
• compositions for use in the invention include an effective amount of 2-methylene-19,21-dinor-1 ⁇ -hydroxy-bishomopregnacalciferol as the active ingredient, and a suitable carrier.
• An effective amount of the compound for use in accordance with some embodiments of the invention will generally be a dosage amount such as those described herein, and may be administered topically, transdermally, orally, nasally, rectally, or parenterally.
• the compounds of formula IA and IB may be advantageously administered in amounts sufficient to effect the differentiation of promyelocytes to normal macrophages. Dosages as described above are suitable, it being understood that the amounts given are to be adjusted in accordance with the severity of the disease, and the condition and response of the subject as is well understood in the art. Atty. Docket No. 032026-0906
• the compound may be formulated as creams, lotions, ointments, aerosols, suppositories, topical patches, pills, capsules or tablets, or in liquid form as solutions, emulsions, dispersions, or suspensions in pharmaceutically innocuous and acceptable solvent or oils, and such preparations may contain, in addition, other pharmaceutically innocuous or beneficial components, such as stabilizers, antioxidants, emulsifiers, coloring agents, binders or taste-modifying agents.
• other pharmaceutically innocuous or beneficial components such as stabilizers, antioxidants, emulsifiers, coloring agents, binders or taste-modifying agents.
• the formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients.
• the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
• Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
• Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema.
• Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
• Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or as sprays.
• liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or as sprays.
• a nebulizer or an atomizer can be used for nasal administration, inhalation of powder, self-propelling or spray formulations.
• a nebulizer or an atomizer can be used for nasal administration, inhalation of powder, self-propelling or spray formulations.
• the formulations, when dispensed, preferably have a particle size in the range of 10 to 100 microns.
• formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.
• dosage unit is meant a unitary, i.e., a single dose which is capable of being administered to a patient as a physically and chemically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

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