USOO6423719B1 (12) United States Patent (10) Patent No.: US 6,423,719 B1 Lawyer (45) Date of Patent: Jul. 23, 2002

(54) METHOD FOR TREATING BENIGN Hasan et al., “Antagonism of coronary artery relaxation by PROSTATE HYPERPLASA adenosine AA-receptor antagonist ZM241385,” J Cardio vasc Pharmacol. 2000 Feb.; 35(2):322–5. (75) Inventor: Carl H. Lawyer, Mequon, WI (US) Kotera et al., “Immunohistochemical localization of c(GMP binding c(GMP-specific phosphodiesterase (PDE5) in rat (73) Assignee: Upsher-Smith Laboratories, Inc., tissues,” J Histochem Cytochem. 2000 May;48(5):685–93. Minneapolis, MN (US) Landells et al., “The role of adenosine receptors in the action of theophylline on human peripheral blood mononuclear (*) Notice: Subject to any disclaimer, the term of this cells from healthy and asthmatic Subjects.” BrJ Pharmacol, patent is extended or adjusted under 35 2000 Mar.; 129(6):1140–4. U.S.C. 154(b) by 0 days. Lew et al., “Examination of adenosine receptor-mediated relaxation of the pig coronary artery,” Clin Exp Pharmacol (21) Appl. No.: 09/505,220 Physiol, 1999 May–Jun.; 26(5–6):438–43.* Li et al., “Adenosine A receptors increase arterial endot (22) Filed: Feb. 16, 2000 helial cell nitric oxide,” J Surg Res, 1998 Dec.; Related U.S. Application Data 80(2):357-64.* (60) Provisional application No. 60/120,099, filed on Feb. 16, Li et al., “Adenosine enhances nitric oxide production by 1999. vascular endothelial cells,” Am J Physiol, 1995 Aug.; 269(2 Pt 1):C519-23.* (51) Int. Cl...... A61K 31/52 Olanrewaju et al., “Adenosine A and A receptors in cultured human and porcine coronary artery endothelial (52) U.S. Cl...... 514/263; 514/8; 514/12; cells,” Am J Physiol Heart Circ Physiol, 2000 Aug.; 279(2):H650–6.* 514/15; 514/264; 514/265; 514/922 Rump et al., “Adenosine mediates nitric-oxide-independent renal vasodilation by activation of AA receptors,” J Hyper (58) Field of Search ...... 514/8, 12, 15, tens. 1999 Dec.; 17(12 Pt. 2):1987–93.* 514/263,264, 265,922 Schmeichel et al., “Methylxanthine bronchodilators poten (56) References Cited tiate multiple human neutrophil functions,” J Immunol. 1987 Mar; 138(6):1896–903.* U.S. PATENT DOCUMENTS Schmidt et al. “The Effect of Selective and Non-selective 2,575,344 A 11/1951 Jones et al. Phosphodiesterase Inhibitors on Allergen- and Leukotriene 4,031,218 A 6/1977 El-Antably C(4)-Induced Contractions in Passively Sensitized Human 4,187,308 A 2/1980 Franzone et al. Airways.” Br J Pharmacol. 2000 Dec.;131(8): 1607–18.* 4,341,783 A 7/1982 Scheindlin ShneyvayS et al., “Induction of apoptosis in cardiac myo 4,581,359 A 4/1986 Ayres cytes by an A. adenosine receptor agonist, Exp Cell ReS. 5,171,217 A 12/1992 March et al...... 604/53 1998 Sep.; 243(2):383-97.* 5,753,641 A 5/1998 Gormley et al. ShneyvayS et al., “Induction of apoptosis in rat cardiocytes 5,891,904. A 4/1999 Stief et al. by A. adenosine receptor activation and its Suppression by OTHER PUBLICATIONS isoproterenol.” Exp Cell Res. 2000 May; 257(1):111-26.* Chemical Abstracts 121:50051, “Ocular hypotension (List continued on next page.) induced by topical dopaminergic drugs and phosdiesterase inhibitors” (1994).* Primary Examiner Frederick Krass Kukovetz et al., “Overadditive Synergism Between Theo (74) Attorney, Agent, or Firm- Mueting, Raasch & phylline, Diprophylline and Proxyphylline in Tracheal Gebhardt, PA. Smooth Muscle Relaxation, Arzneimittelforschung, (57) ABSTRACT 33(10): 1450–1454 (1983). Brambilla et al., “Activation of the A. adenosine receptor A method of treating and/or preventing renal dysfunction in affects cell cycle progression and cell growth,” Naunyn a patient, Such as renal colic or contrast nephropathy by Schmiedeberg's Arch Pharmacol, 2OOO Mar.; administering to a patient, a compound of the formula: 361(3):225–34. Brodie et al., “Activation of the AA adenosine receptor O i inhibits nitric oxide production in glial cells,” FEBS Lett. R1 1998 Jun.; 429(1):139–42. NN N Conti et al., “The Molecular Biology of Cyclic Nucleotide Phosphodiesterases,” Prog Nucleic Acid Res Mol Biol. 1. X-R, O N 1999;63:1-38. Conti, "Phosphodiesterases and cyclic nucleotide Signaling R2 in endocrine cells,” Mol Endocrinol. 2OOO Sep.;14(9): 1317-27. Granovsky et al., “Identification of the gamma Subunit-int is described herein. Administration of dyphylline in a Sus eracting residues on photoreceptor cGMP phosphodi tained release oral dosage form is preferred. esterase, PDE6.O., J Biol Chem. 2000 Dec. 29:275(52):41258–62. 21 Claims, No Drawings US 6,423,719 B1 Page 2

OTHER PUBLICATIONS Acara et al., “Probenecid inhibition of the renal excretion of This Week in Science: from Science. Jun. 9, 2000; dyphylline in chicken, rat and man,” J. Pharm. Pharmacol., 288(5472): 1701.* 39(7):526-530 (1987). Walker et al., “Adenosine A receptor activation delayS Becker et al., “The effect of the specific phosphodi apoptosis in human neutrophils,” J Immunol, 1997 Mar.; esterase-IV-inhibitor rollipram on the ureteral peristalsis of 158(6):2926–31.* the rabbit in vitro and in vivo,” J. Urol., 160(3Pt. 1): 920–925 Xu et al., “Atomic Structure of PDE4: Insights into Phos (1998). phodiesterase Mechanism and Specificity,” Science. Jun. 9, Drescher et al., “Alpha-1 receptor mediated Smooth muscle 2000; 288:822-1825.* regulation in benign prostatic hyperplasia,” Scand. J. Urol. Yasui et al., “Effects of theophylline on human eosinophil Nephrol. Suppl., 157:33–40 (1994). functions: comparative Study with neutrophil functions,” J Drescher et al., “Smooth Muscle Contractility in Prostatic Leukoc Biol. 2000 Aug.; 68(2):194–200.* Hyperplasia: Role of Cyclic Adenosine Monophosphate,” Yasui et al., “Theophylline induces neutrophil apoptosis Prostate, 25(2):76–80 (1994). through adenosine A receptor antagonism,” J. Leukoc Biol. 2000 Apr.; 67(4):529–35.* Drescher et al., letter to Editor (regarding “Nephrotoxicity Andersson, “The Concept of Uroselectivity,” Eur: Urol., from contrast media: attenuation with theophylline,” which 33(Suppl. 2):7-11 (1998). appeared in Radiology, 195(1):17-22 (1995)), Radiology, Bang et al., “Cyclic AMP induces transforming growth 197(2):547-548 (1995). factor B2 gene expression and growth arrest in the human Drescher, “Ca" and Cyclic Adenosine Monophosphate androgen-independent prostate carcinoma cell line PC-3.” Involvement in Radiographic Contrast Medium-induced Proc. Natl. Acad. Sci. USA, 89(8):3556-3560 (1992). Renal Vasoconstriction.” J. Vasc. Interv. Radiol, Barza, “Anatomical Barriers for Antimicrobial Agents,” Eur: 6(5):813–818 (1995). J. Clin. Microbiol. Infect. Dis., 12(Suppl. 1):S31-S35 Erley et al., “Adenosine antagonist theophylline prevents the (1993). reduction of glomerular filtration rate after contrast media Boatman et al., “Pharmacological Evaluation of Ureteral application,” Kidney Int., 45(5):1425-1431 (1994). Smooth Muscle, A Technique for Monitoring Ureteral Peri Gladstone et al., “The use of theophylline ethylene diamine stalsis.” Invest. Urol, 4(6):509-520 (1967). (aminophylline) for the relief of biliary collic: a preliminary Coe et al., “The Pathogenesis and Treatment of Kidney report,” J. Am. Med. Assoc., 126(17): 1084-1085 (1944). Stones,” N. Engl. J. Med., 327(16):1141-1152 (1992). Edelstein et al., “Chapter 8: Etiology, Pathogenesis, and Katholiet al., “Nephrotoxicity from Contrast Media: Attenu Management of Renal Failure.” Campbell's Urology, 7" ation with Theophylline,” Radiology, 195(1):17–22 (1995). edition, Walsh et al., eds., W.B. Saunders Co., Philadelphia, King et al., “Purinergic Modulation of Rat Urinary Bladder Title page, publication page, table of contents, and pp. Detrusor Smooth Muscle,” Gen. Pharmacol., 315–341 (1998). 29(4):597–604 (1997). Fair et al., “The pH of Prostatic Fluid: A Reappraisal and Kolonko et al., “The nonselective adenosine antagonist Therapeutic Implications,” J. Urol., 120(6):695-698 (1978). theophylline does prevent renal dysfunction induced by Fang et al., “P-Purinergic Receptor Agonists Inhibit the radiographic contrast agents,” J. Nephrology, 11(3):151-156 Growth of Androgen-independent Prostate Carcinoma (1998). Cells,” J. Clin. Invest., 89(1):191-196 (1992). Lawyer et al., “Utilization of intravenous dihydroxypropyl Kawabe et al., “Use of an O. 1-Blocker, YM617, in the theophylline (dyphylline) in an aminophylline-Sensitive Treatment of Benign Prostatic Hypertrophy,” J. Urol., patient, and its pharmacokinetic comparison with theophyl 144(4):908–912 (1990). Kerttula et al., “Theophylline infusion modulates prostag line,” J. Allergy Clin. Immunol., 65(5):353–357 (1980). landin and leukotriene production in man,” ProStaglandins May et al., “Effect of probenecid on dyphylline elimination,” Leukot. Essent. Fatty Acids, 57(6):555-560 (1997). Clin. Pharmacol Therapeut., 33(6):822–825 (1983). Leoniet al., “the Effects of Isoproterenol and Aminophylline Morcos et al., “Nephrotoxicity from Contrast Media: on Detrusor Muscle Contractility in an Organ Bath Appa Attenuation with Theophylline,” letter to Editor (regarding ratus.” Invest. Urol., 10(6):458–463 (1973). “Nephrotoxicity from contrast media: attenuation with theo Martin et al., “Relationship Between the Effects of Alfuzosin phylline,” which appeared in Radiology, 195(1):17-22 on Rat Urethral and Blood Pressures and its Tissue Con (1995)), Radiology, 197(2):546–547 (1995). centrations,” Life Sci., 63(3):169-176 (1998). Morcos et al., “Contrast Media-induced Nephrotoxicity: A Martin et al., “Functional Uroselectivity.” Eur: Urol., New Insight,” Clin. Radiol., 52(8):573–574 (1997). 33(Suppl. 2):12-18 (1998). Nadai et al., “Pharmacokinetics and the Effect of Probenecid Nolan, “Theophylline option for attenuating contrast medi on the Renal Excretion Mechanism of Diprophylline,” J. a-induced nephrotoxicity in patients on metformin, Am. J. Pharm. Sci., 81 (10): 1024–1027 (1992). Health-Syst. Pharm., 54(5):587–588 (1997). Oesterling, “Benign Prostatic Hyperplasia-Medical and OSSwald et al., “Therapeutic use of theophylline to antago Minimally Invasive Treatment Options,” N. Engl. J. Med., nize renal effects of adenosine,” Clin. Nephrol, 43(Suppl. 332(2):99-109 (1995). 1):S33-S37 (1995). Simons et al., “Urinary Excretion of Dyphylline in Quasny, "Metformin, contrast media, and theophylline, s Humans,” J. Pharm. Sci., 68(10): 1327–1329 (1979). Am. J. Health-Syst. Pharm., 54(17):2007–2008 (1997). Wein et al., “The Effects of Aminophylline on Ureteral and Bladder Contractility.” Invest. Urol, 9(4):290–293 (1972). * cited by examiner US 6,423,719 B1 1 2 METHOD FOR TREATING BENIGN Generally, the solubility of methylxanthines is low and is PROSTATE HYPERPLASA enhanced by the formation of complexes, Such as that between theophylline and ethylenediamine (to form CROSS-REFERENCE TO RELATED aminophylline). The formation of complex double salts APPLICATION (Such as caffeine and Sodium benzoate) or true Salts (such as This application claims the benefit of a provisional appli choline theophyllinate) also enhances aqueous Solubility. cation filed Feb. 16, 1999, entitled “Method for Treating These Salts or complexes dissociate to yield the parent Benign Prostate Hyperplasia,” and having Ser. No. 60/120, methylxanthine when dissolved in aqueous Solution. 099, which is incorporated herein by reference. Although Salts. Such as aminophylline have improved Solu bility over theophylline, they dissociate in solution to form FIELD OF INVENTION theophylline and hence have Similar toxicities. The present invention relates to a method of treating Dyphylline is a covalently modified derivative of Xanthine benign prostate hyperplasia in a Subject Suffering therefrom (1,3, -dimethyl-7-(2,3-dihydroxypropl)xanthine. Because it with an effective amount of dyphylline or an analog thereof. is covalently modified, dyphylline is not converted to free 15 theophylline in vivo. Instead, it is absorbed rapidly in BACKGROUND therapeutically active form. Dyphylline has a lower toxicity Xanthine is a dioxypurine that is structurally related to than theophylline. Dyphylline can be represented by the uric acid. Xanthine can be represented by the following following Structure: Structure: OH

H Ya N HC O action N 6 5 7 3 YN N 8 1. 3 9N / 25 or O1- NX H CH Caffeine, theophylline and theobromine are methylated Xanthines. Methylated Xanthines Such as caffeine and theo Dyphylline is an effective bronchodilator that is available phylline are typically used for their bronchodilating action in in oral and intramuscular preparations. Generally, dyphyl the management of obstructive airways diseases Such as line possesses less of the toxic Side effects associated with asthma. The bronchodilator effects of methylxanthines are theophylline. thought to be mediated by relaxation of airway Smooth 35 U.S. Pat. No. 4,031,218 (E1-Antably) discloses the use of muscle. Generally, methylxanthines function by inhibiting 7-(2,3-dihydroxypropyl)-1,3-di-n-propylxanthine, a deriva cyclic nucleotide phosphodiesterases and antagonizing tive of theophylline, as a bronchodilator. U.S. Pat. No. receptor-mediated actions of adenosine. 4,341,783 (Scheindlin) discloses the use of dyphylline in the Theophylline can be represented by the following struc treatment of psoriasis and other diseases of the skin by topical administration of dyphylline. U.S. Pat. No. 4,581, ture: 40 359 (Ayres) discloses methods for the management of bron chopulmonary insufficiency by administering an N-7- O H Substituted derivative of theophylline, including dyphylline, HC etophylline, and proxyphylline. 3 YN N 45 Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate that is due to excessive cellular O N growth of both glandular and Stromal elements of the prostate. The condition is very common in men over 40 CH years of age. BPH has two components: a Static component 50 that is related to the enlargement of the prostate and a However, when administered intravenously or orally, dynamic component that reflects the tone or degree of theophylline has numerous undesired or adverse effects that contraction of Smooth muscle within the prostate. The are generally Systemic in nature. It has a number of adverse Smooth muscle tone depends on extra-and intracellular Ca Side effects, particularly gastrointestinal disturbances and Stores and is regulated by various Second messenger CNS stimulation. Nausea and vomiting are the most com 55 pathways, including cyclic 3'-5'adenosine monophosphate mon Symptoms of theophylline toxicity. Moderate toxicity is (cAMP). due to relative epinephrine excess, and includes tachycardia, TranSurethral resection of the prostate is a common form arrhythmias, tremors, and agitation. Severe toxicity results of treatment. However, complications of transurethral resec in hallucinations, Seizures, dysrhythmias and hypotension. tion include retrograde ejaculation, impotence, postopera The Spectrum of theophylline toxicity can also include 60 tive urinary tract infection and Some urinary incontinence. death. Therefore, medical and/or minimally invasive treatments for Furthermore, theophylline has a narrow therapeutic range benign prostatic hyperplasia are more desirable. of Serum concentrations above which Serious Side effects can Minimally invasive treatments for BPH include transure occur. The pharmacokinetic profile of theophylline is depen thral incision of the prostate, balloon dilation of the prostate, dent on liver metabolism, which can be affected by various 65 prostatic Stents, microwave therapy, laser prostatectomy, factors including Smoking, age, disease, diet, and drug transrectal high-intensity focused ultrasound therapy and interactions. transurethral needle ablation of the prostate. US 6,423,719 B1 3 4 Known medical treatments for BPH include androgen A Second aspect of the present invention is a method of deprivation therapy, the use of 5C-reductase inhibitors and treating benign prostatic hyperplasia, or reducing the Symp C.-adrenergic-antagonist drugs. Androgen deprivation toms thereof, by administering a dyphylline-type compound, therapy includes administering agents which diminish described above, with a combination of an O-adrenergic androgen Secretion or action, Such as gonadotrophin antagonist, Such as phenoxybenzamine, thymoxamine, releasing hormone (GnRH) analogues, antiandrogens. alfuZosin, indoramin, praZosin, doxazosin, teraZOsin and 5C.-reductase inhibitors inhibit the action of type 2 tamsulosin and/or a 5C-reductase inhibitor Such as finas 5C-reductase, an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone in most androgen Sensi teride. tive tissues. Finasteride N-(2-methyl-2-propyl)3-oxo-4- A third aspect of the present invention includes pharma aza-5C.-androst-1-ene-173-carboxamide is a known 1O ceutical compositions containing a dyphylline-type com 5C-reductase inhibitor. C.-Adrenergic antagonist drugs block pound and an O-adrenergic antagonist and/or a 5C-reductase adrenergic receptors in hyperplastic prostatic tissue, the inhibitor. C.-Adrenergic antagonists include nonselective prostatic capsule, and the bladder neck, to decrease Smooth drugs. Such as phenoxybenzamine and thymoxamine; short muscle tone of these Structures. C.-Adrenergic receptors in acting Selective drugs Such as alfuzosin, indoramin and the trigone muscle of the bladder and urethra contribute to 15 prazosin; and long acting Selective drugs. Such as doxazosin, the resistance of outflow of urine. When Smooth muscle tone teraZOsin and tamsulosin. Finasteride is an example of a is decreased, resistance to urinary flow through the bladder 5C-reductase inhibitor. For a composition which includes a neck and the prostatic urethra decreases and urinary flow dyphylline-type compound and a nonselective C-adrenergic increases. A variety of C.-adrenergic antagonists are used in antagonist, a short acting Selective O-adrenergic antagonist, the treatment of BPH. Nonselective drugs include phenoxy or a 5C.-reductase inhibitor, it is preferred that the entire benzamine and thymoxamine. Short acting Selective drugs composition be prepared in a Sustained release formulation. include alfuZosin, indoramin and praZOsin. Long acting However, in a composition which includes a dyphylline-type Selective drugs including doxazosin, teraZoSin and tamsu compound and a long-acting C.-adrenergic antagonist, it is losin. preferred that the dyphylline-type compound be prepared in U.S. Pat. No. 5,753,641 (Gormley et al.) discloses a 25 a Sustained release formulation and the long-acting method for treating benign prostatic hyperplasia (BPH) C.-adrenergic antagonist be prepared in a quick release involving combination therapy of a 5C-reductase inhibitor in formulation. combination with an O-adrenergic receptor blocker. SUMMARY DETAILED DESCRIPTION The invention provides a method of treating benign The invention is directed towards a method of treatment prostatic hyperplasia or reducing the Symptoms of benign of benign prostatic hyperplasia by administering an effective prostatic hyperplasia by administering a therapeutic or pro amount of a dyphylline-type compound. phylactic effective amount of dyphylline or a dyphylline Dyphylline-type Compounds analog, or a pharmaceutically acceptable Salt thereof to the According to the invention, a dyphylline-type compound patient. According to the invention, the compound can be of 35 includes dyphylline and analogs thereof and can be repre the formula: sented by the following structure:

R1 i n N N 40 R1 1. X-R, N 6 R O N O--- N7 K. R2 45 R2 wherein R and R2, independently, are hydrogen or a R and R, independently, can be hydrogen or a C-C, C-C linear or branched alkyl optionally interrupted linear or branched alkyl optionally interrupted by a carbo by a carbonyl group. R is a C-C alkyl Substituted by nyl. C-C alkyl includes linear or branched species and one or more moieties Selected from the group consist 50 further includes Species that are interrupted in the chain by ing of a hydroxyl, amino, mercapto, dioxolan, a carbonyl group, e.g., 5-oxohexyl. C-C alkyl includes, carbonyl, and mixtures thereof. R is hydrogen; a but is not limited to, methyl, ethyl, n-propyl, isopropyl, Substituted or unsubstituted aromatic member Selected n-butyl, isobutyl, sec-butyl and t-butyl. Dyphylline-type from the group consisting of phenyl, biphenyl, benzyl, compounds with large nonpolar Substituents at R and R or furyl, in which the substituent is selected from the 55 usually display an enhancement in both the ability to inhibit group consisting of C C alkyl, C-C haloalkyl, cyclic nucleotide phosphodiesterases and to antagonize C-C alkoxy, C-C alkylthio, halo and nitro, or receptor-mediated actions of adenosine. Preferably, R and cyclohexyl and cyclopentyl. Preferably, R and R, are R are methyl. methyl, R is dihydroxypropyl, and R is hydrogen or R can be a C-C8 alkyl (preferably a C-C alkyl) a Substituted or unsubstituted aromatic member 60 Substituted by one or more moieties Selected from the group Selected from the group consisting of phenyl, biphenyl, consisting of a hydroxyl, amino, mercapto, dioxolan, benzyl, or furyl, in which the substituent is selected carbonyl, and mixtures thereof. C-C alkyl includes both from the group consisting of C-C alkyl, C-C, linear and branched species, including methyl, ethyl, haloalkyl, C-C alkoxy, C-C alkylthio, halo and n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl, t-butyl, nitro. Most preferred is dyphylline, wherein R and R. 65 n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. are methyl; R is 2,3-dihydroxypropyl, and R is Examples of Suitable Substituted alkyl groups include hydrogen. hydroxy methyl, hydroxyethyl, hydroxypropyl, US 6,423,719 B1 S 6 dihydroxypropyl, e.g., 2,3-dihydroxypropyl or 1,3- Sufficient amount of the desired acid to produce a Salt. The dihydroxypropyl, 1,3-dioxolan-2-ylmethyl, methanamino, dyphylline-type compound may be regenerated by treating ethanamino, pyrrollidinomethyl, morpholinomethyl, the Salt form with a base. The Salt forms differ from the piperidinomethyl, methanethio, ethanethio, and the like. In a dyphylline-type compounds in certain physical properties preferred embodiment, R is dihydroxypropyl. In a most Such as Solubility in polar Solvents, but the Salts are other preferred embodiment, R is 2,3-dihydroxypropyl. wise equivalent for purposes of this invention. R4 can be hydrogen; a Substituted or unsubstituted aro The compounds of the invention can exist in unsolvated matic member; or a cycloalkyl, Such as cyclohexyl or as well as Solvated forms, including hydrated forms. In cyclopentyl. Addition of an aromatic member or a general, the Solvated forms, including hydrated forms are cycloalkyl at R, usually markedly increases the affinity of equivalent to the unsolvated forms for the purposes of this the dyphylline-type compound for adenosine receptors, but invention. reduces inhibition of cyclic nucleotide phosphodiesterases. Method of Treatment Suitable aromatic members include phenyl, biphenyl, Dyphylline-type compounds are particularly well Suited benzyl, and furyl. Suitable Substituents on the aromatic ring for clinical use in the Symptomatic treatment of benign include C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C, 15 prostatic hyperplasia due to the functional uroSelectivity of alkylthio, halo and nitro. C-C alkyl includes both linear these compounds. AS used herein, uroSelective means that and branched species, including methyl, ethyl, n-propyl, the dyphylline-type compounds used in the method of the isopropyl, cyclopropyl, n-butyl, isobutyl, Sec-butyl, t-butyl, invention preferentially affect the smooth muscle tone of the and the like. C-C haloalkyl includes both linear and prostate as compared to other physiological functions. Func branched species of C-C alkyl, Substituted with chloro, tional uroSelectivity thus means that the dyphylline-type fluoro, bromo and iodo, preferably chloro. C-C alkoxy compounds preferentially act on the lower urinary tract includes linear or branched Species, including, but not rather than the vasculature or the central nervous System. limited to, methoxy, ethoxy, n-propoxy, isopropoxy, Whereas a dose of theophylline is generally metabolized n-butoxy, isobutoxy, Sec-butoxy, t-butoxy, preferably meth by the liver before being excreted in the urine (only about Oxy. C-C alkylthio includes linear or branched Species of 25 10% is unchanged), a dose of a dyphylline-type compound C-C alkyl, Substituted with at least one divalent thio is excreted mostly unchanged in the urine (about 83+/-5% (-S-) grouping including: methylthio, ethylthio, is unchanged). Thus, theophylline is present in urine in very isopropylthio, n-butylthio, and the like. Halo includes low concentrations. In contrast, dyphylline-type compounds chloro, fluoro, bromo, iodo, preferably chloro. undergo rapid and immediate renal excretion and are found Examples of dyphylline-type compounds include: at very high concentrations in the urine. Due to their high 7-(2,3-dihydroxypropyl)theophylline (also called concentration in urine, dyphylline-type compounds relax dyphylline); bladder Smooth muscle at a much lower blood and Systemic 7-(B-hydroxyethyl)theophylline; levels than theophylline. Furthermore, dyphylline-type com 7-(pyrrolidinomethyl)theophylline; pound pharmacokinetics and plasma levels are not influ 35 enced by various factors that affect liver function and hepatic 7-(2-hydroxypropyl)theophylline; enzyme activity, Such as Smoking, age, congestive heart 7-(morpholinomethyl)theophylline; failure, or concomitant use of drugs which affect liver 7-(B-hydroxypropyl)theophylline; function. 7-(piperidinomethyl)theophylline; According to the invention, dyphylline reduces Symptoms 40 asSociated with benign prostatic hyperplasia, including uri 7-2-(diethylamino)ethyl theophylline (also called nary retention, renal failure, bladder decompensation metescufylline); (incontinence), recurrent urinary tract infections and pro 7-(1,3-dioxolan-2-ylmethyl)theophylline (also called gressive voiding Symptoms. The Superior efficacy of the doxo?ylline); dyphylline-type compounds used in the method of the theophylline-7-acetate (also called acefylline); and 45 invention (as compared to other methylxanthines) is Surpris 1-(5-oxohexyl)-3,7-dimethylxanthine (also called ing. Generally, derivatives of methylxanthines which con pentoxyfylline). tain Substituents at position 7 Show a significant reduction in The preferred compounds are pentoxyfylline and dyphyl activity. For example, dyphylline doses of about 5 to 6 times line. Pentoxyfylline is water soluble and excretion is almost theophylline doses are required to produce equivalent bron totally urinary. The main biotransformation product is 50 chodilator response. Lawyer et al., J. Allergy& Clin. Immu metabolite V (1-(3-carboxypropyl)-3,7-dimethylxanthine). nol. 65:353–357 (1980). The most preferred compound is dyphylline. According to the invention, dyphylline-type compounds Dyphylline-type compounds are either commercially can be administered to effectively reduce Symptoms asso available or can be synthesized by methods known to those ciated with benign prostatic hyperplasia, including urinary skilled in the art. For example, a method of preparing 55 retention, renal failure, bladder decompensation dyphylline can be found in U.S. Pat. No. 2,575,344, the (incontinence), recurrent urinary tract infections and pro disclosure of which is incorporated herein by reference. gressive voiding Symptoms with less toxic effects than Also included within the Scope of this invention are theophylline. As used herein, “toxic effects” refer to adverse pharmaceutically acceptable Salts of the dyphylline-type effects commonly induced by high plasma concentrations of compounds shown above. The Salts are acid addition Salts 60 theophylline, including reduced blood preSSure, restleSSneSS, and can be formed where a basic group is present on the touch Sensitivity, nausea, headache, tremors, convulsions, dyphylline-type compound. Where a basic Substituent is Ventricular arrhythmias, Seizures and death. present, Suitable acids for Salt formation include, but are not The Symptoms of benign prostatic hyperplasia are par limited to, hydrochloric, Sulfuric, phosphoric, acetic, citric, tially caused by an increase prostatic Smooth muscle tone. Oxalic, malonic, Salicylic, malic, gluconic, fumaric, Succinic, 65 Dyphylline-type compounds relax bladder Smooth muscle ascorbic, maleic, and methaneSulfonic. The Salts are pre and thus relieve involuntary bladder spasms. Dyphylline pared by contacting the dyphylline-type compound with a also relaxes prostatic Smooth muscle and increases urine US 6,423,719 B1 7 8 flow through the hypertrophied prostate, thus relieving proS AlfuZOsin is a quinazoline derivative that is a competitive, tatism and the Symptoms thereof. Although not wishing to be Selective O-adrenergic antagonist. There is evidence that bound by theory, it is believed that the Superior efficacy of this compound might exhibit Some Selectivity for urethral dyphylline-type compounds is due to their high concentra rather than Vascular C.-adrenergic receptors. The elimina tion in urine. Dyphylline-type compounds thus have a much tion of the drug is largely by metabolism. The parent lower blood level and systemic level than theophylline, and compound has a half-life of about 5 hours. avoid the Serious and unacceptable Systemic toxicity of Formulations theophylline The dyphylline-type compounds can be administered in a Combination Therapy wide variety of oral, intravenous and intramuscular dosage The dyphylline-type compounds can be administered in forms, preferably the dyphylline-type compound is admin combination with known medical treatments for BPH, Such istered orally, most preferably the dyphylline-type com as androgen deprivation therapy, 5C-reductase inhibitors pound is administered orally in a Sustained release formu and C.-adrenergic antagonist drugs. 5C-reductase inhibitors lation. It will be obvious to those skilled in the art that the are compounds that inhibit the action of type 25C-reductase, dosage forms may comprise as the active component, either an enzyme that catalyzes the conversion of testosterone to 15 a dyphylline-type compound or a corresponding pharma dihydrotestosterone in most androgen Sensitive tissues. Fin ceutically acceptable salt thereof. The formulations of the asteride N-(2-methyl-2-propyl)3-oxo-4-aza-5C.-androst-1- invention further comprise a pharmacologically acceptable ene-17? 3-carboxamide is a known 5C.-reductase inhibitor. carrier. AS used herein, "pharmacologically acceptable' C-Adrenergic-antagonist drugs blockadrenergic receptors in means that the carrier is compatible with the other ingredi hyperplastic prostatic tissue, the prostatic capsule, and the ents of the formulations and not deleterious to the recipient. bladder neck, to decrease Smooth muscle tone of these Pharmaceutically acceptable carriers are known to those Structures. A variety of C.-adrenergic antagonists are used in of skill in the art and include both solid or liquid carriers. the treatment of BPH. Nonselective drugs include phenoxy Preferably, the dyphylline-type compound is prepared in a benzamine and thymoxamnine. Short acting Selective drugs Sustained release Solid preparation. Solid preparations include alfuZosin, indoramin and praZOsin. Long acting 25 include powders, tablets, dispersible granules, capsules, and Selective drugs including doxazosin, teraZoSin and tamsu cachets. A Solid carrier can be one or more Substances which losin. Combination therapy shows Synergy in producing may also act as diluents, flavoring agents, Solubilizers, both acute and chronic relief. lubricants, Suspending agents, binders, or tablet disintegrat Finasteride is available from Merck & Co. under the ing agents, it can also be an encapsulating material. In tradename PROSCAR(R). It slowly forms a stable enzyme powders, the carrier is a finely divided solid which is in complex with 5C-reductase, thus inhibiting the activity of admixture with the finely divided active compound. In the 5C.-reductase. Turnover from the enzyme complex is tablet, the active compound is mixed with carrier having the extremely slow (ti-30 days). Generally, Finasteride is necessary binding properties in Suitable proportions and administered in a single 5 mg once a day. Typically, Finas compacted in the shape and size desired. The powders and teride is administered orally. 35 tablets preferably contain from 5 to 10 to about 80% of the Phenoxybenzamine is a haloalkylamine that blockS C active ingredient. Suitable Solid carriers are magnesium and C2-adrenergic receptors irreversibly. Phenoxyben carbonate, magnesium Stearate, talc, Sugar, lactose, pectin, Zamine hydrochloride is available from SmithKline Bee dextrin, Starch, gelatin, tragacanth, methyl cellulose, Sodium cham Pharmaceuticals under the tradename DIBEN carboxymethyl cellulose, a low melting wax and cocoa ZYLINE(R). While the half life when orally administered is 40 butter. The term “preparation” is intended to include the unknown, the half life when administered intravenously is formulation of the active compound with encapsulating approximately 24 hours. Typically, 10 to 20 mg is admin material as carrier providing a capsule in which the active istered twice a day. component (with or without other carriers) is Surrounded by PraZosin contains a piperazinyl quinazoline nucleus and is carrier, which is thus in association with it. Similarly, a very potent and Selective C-antagonist. PraZOsin is well 45 cachets are included. Tablets, powders, cachets, and cap absorbed after oral administration, and bioavailability is Sules can be used as Solid dosage forms Suitable for oral about 50% to 70%. Peak concentrations of prazosin in administration. plasma are generally reached 1 to 3 hours after an oral dose. Alternately, the dyphylline-type compound can be The plasma half life is approximately 2 to 3 hours, and the included in a liquid preparation. Liquid preparations include duration of action is approximately 4 to 6 hours. Dosage 50 Solutions, Suspensions and emulsions. For example, water or ranges from 1 mg 2 to 3 times a day to 20 mg 2 to 3 times water-propylene glycol Solutions for parenteral injection. a day. Such Solutions are prepare So as to be acceptable to biologi TeraZosin is a close Structural analog of prazosin. cal Systems (isotonicity, pH, etc.). Liquid preparations can Although it is less potent than praZOsin, it is more water also be formulated in aqueous polyethylene glycol Solution. Soluble than praZoin and has a bioavailability greater than 55 Aqueous Solutions Suitable for oral use can be prepared by 90%. The half-time elimination of terazosin is approxi dissolving the active component in water and adding Suit mately 12 hours and its duration of action may extend able colorants, flavors, Stabilizing, and thickening agents as beyond 18 hours. Thus the drug is generally taken once desired. Aqueous Suspensions Suitable for oral use can be daily. Generally, 1 to 10 mg are administered once a day. made by dispersing finely divided active component in water Doxazosin is another Structural analog of prazosin. The 60 with Viscous material, i.e., natural or Synthetic gums, resins, half-life of doxazosin is 10 to 20 hours and its duration of methyl cellulose, Sodium carboxymethyl cellulose, and action may extend to 36 hours. The bioavailability is about other well-known Suspending agents. 50% to 70%. For medical use, the amount of dyphylline-type com Indoramin is a Selective, competitive C. antagonist. The pound or pharmacologically acceptable Salt thereof required elimination half life is about 5 hours. The bioavailability of 65 to achieve a therapeutic effect will vary with the particular indoramin is generally less than 30% with considerable compound and the route of administration. The half-life of variability. dyphylline-type compounds in normal adults is from about US 6,423,719 B1 9 10 2 to about 3 hours, and total body clearance is about 150 to poVidone/water Solution onto a mixture of dyphylline and 200 ml/kg-hr, although renal clearance can be reduced in hydroxypropylmethylcellulose (HPMC) in a fluid bed. The patients with impaired renal function. Due to the relatively material in the fluid bed is then dried and passed through a brief half-life in humans, dyphylline-type compounds must mill for Sizing. Silicon dioxide and magnesium Stearate are be given frequently or in high doses to achieve clinical combined with the dried material, which is then compressed utility. Alternately, the dyphylline-type compound can be into tablet form. The percentage of each constituent in the administered in a Sustained release formulation. A Suitable dose of a dyphylline-type compound or phar formulation and milligrams per tablet are shown in Table 1, macologically acceptable Salt thereof is about 200 mg to below. The polygel tablet provides 90-100% delivery of about 2500 mg, administered every 4 to 6 hours, more dyphylline at 12 hours. preferably, about 15 mg/kg, administered orally about every 6 hours. Preferably, the dyphylline-type compound is admin TABLE 1. istered in a Sustained release formulation as a tablet or capsule. Preferably, the dyphylline-type compound is Polygel Tablet, 12 hour Dyphylline administered in a Sustained release formulation that releases MATERIAL PERCENT MG/TABLET 15 about 90% to about 100% of the dyphylline-type compound Dyphylline 75.5 400 over a twelve hour period. Hydroxypropylmethylcellulose, USP 18.0 95 Sustained release formulations and methods of preparing Povidone, USP 6.O 32 them are known to those of skill in the art. Generally, a Silicon Dioxide, NF O.3 2 Sustained release formulation is a preparation that releases Magnesium Stearate, NF O.2 1. the active component over a desired period of time after administration. Typically, a Sustained release formulation is Total 1OO.O 530 prepared by applying a biodegradable, bioerodible or bio absorbable polymeric formulation that is biocompatible on the Surface of the active component. Examples of polymeric Example 2 formulations for Sustained release formulations include, but are not limited to, hydroxypropylmethylcellulose (HPMC), 25 A sustained release hydrogenated vegetable oil (HVO) hydrogenated vegetable oil (HVO), and ethylcellulose. tablet for use in the method of the invention is prepared by The term “biodegradable” means that the polymeric for Spraying melted vegetable oil onto dyphylline and allowing mulation degrades over time by the action of enzymes, by the oil to cool. Silicon dioxide and magnesium Stearate are hydrolytic action and/or by other Similar mechanisms in the then combined with the dyphilline/oil mixture, which is then human body. By “bioerodible,” it is meant that the poly compressed into tablet form. The percentage of each con meric formulation erodes or degrades over time due, at least Stituent in the formulation and milligrams per tablet are in part, to contact with Substances found in the Surrounding shown in Table 2, below. The HVO tablet provides 90–100% tissue fluids or cellular action. By “bioabsorbable,” it is delivery of dyphylline at 12 hours. meant that the polymeric formulation is broken down and absorbed within the human body, for example, by a cell or 35 tissue. “Biocompatible” means that the polymeric formula TABLE 2 tion does not cause Substantial tissue irritation or necrosis. HVO Tablet, 12 hour Dyphylline The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods MATERIAL PERCENT MG/TABLET well-known in the art of pharmacy. In unit dosage form, the 40 Dyphylline 73.O 400 preparation is Subdivided into unit doses containing appro Hydrogenated Vegetable Oil, NF 26.0 142 priate quantities of the active component. The unit dosage Silicon Dioxide, NF O.3 2 form can be a packaged preparation, the package containing Magnesium Stearate, NF O.7 4 discrete quantities of preparation, for example, packeted Total 1OO.O 548 tablets, capsules, or powders in Vials or ampoules. The unit 45 dosage form can also be a capsule, cachet, tablet itself or it can be the appropriate number of any of these packaged forms. Example 3 The invention also includes formulations of a dyphylline A Sustained release formulation of Solvent coated beads type compound and an O-adrenergic antagonist and/or a 50 5C-reductase inhibitor. For a composition which includes a for use in the method of the invention is prepared by dyphylline-type compound and a nonselective C.-adrenergic Spraying an ethylcellulose/Solvent Solution onto dyphilline antagonist, a short acting Selective O-adrenergic antagonist, in a fluid bed. The material in the fluid bed is dried and or a 5C.-reductase inhibitor, it is preferred that the entire passed through a Screen for Sizing. Microcrystalline composition be prepared in a Sustained release formulation. 55 cellulose, Silicon dioxide and magnesium Stearate are com However, in a composition which includes a dyphylline-type bined with the material, which is then compressed into tablet compound and a long-acting C-adrenergic antagonist, it is form. The percentage of each constituent in the formulation preferred that the dyphylline-type compound be prepared in and milligrams per tablet are shown in Table 3, below. The a Sustained release formulation and the long-acting tablet provides 90-100% delivery of dyphylline at 12 hours. C.-adrenergic antagonist be prepared in a quick release 60 formulation. The following examples illustrate formulations TABLE 3 Suitable for use in the method of the invention. Solvent Coated Beads-Tablet, 12 hour Dyphylline EXAMPLES MATERIAL PERCENT MG/TABLET Example 1 65 Dyphylline 71.1 400 A polygel tablet Sustained release formulation for use in Ethylcellulose, USP 19.0 107 the method of the invention is prepared by Spraying a US 6,423,719 B1 11 12 material, which material is then compressed into a tablet. TABLE 3-continued The percentage of each constituent in the formulation and milligrams per 530 milligram tablet are shown in Table 6, Solvent Coated Beads-Tablet, 12 hour Dyphylline below. The tablet provides 90–100% delivery of dyphylline MATERIAL PERCENT MG/TABLET and prazosin at 12 hours. Microcrystalline Cellulose, NF 9.O 51 TABLE 2 Croscarmellose Sodium, NF 0.5 3 Sorbitan Monooleate, NF 0.4 2 Hydrogenated Vegetable Oil (HVO) Tablet, 12 hour Dyphylline and Prazosin Total 1OO.O 563 1O MATERIAL PERCENT MG/TABLET Dyphylline 72.1 400 Example 4 PraZOsin HCI O.9 5 Hydrogenated Vegetable Oil, NF 26.0 144 A Sustained release formulation for the method of the 15 Silicon Dioxide, NF O.3 2 invention is prepared by Spraying an ethylcellulose/Solvent Magnesium Stearate, NF O.7 4 solution onto dyphilline in a fluid bed. The material in the fluid bed is dried and passed through a Screen for Sizing. Total 1OO.O 555 Sorbitan monooleate and magnesium Stearate are combined with the material, which is then filled into a capsule. The percentage of each constituent in the formulation and mil Example 7 ligrams per capsule are shown in Table 4, below. The capsule provides 90-100% delivery of dyphylline at 12 hours. A Sustained release formulation of Solvent coated beads is prepared by Spraying an ethylcellulose/Solvent Solution onto TABLE 4 dyphilline and prazosin in a fluid bed. The material in the 25 fluid bed is dried and passed through a Screen for sizing. Solvent Coated Beads Capsule, 12 hour DVphylline Microcrystalline cellulose, Silicon dioxide and magnesium Stearate are combined with the material, which material is MATERIAL PERCENT MG/CAPSULE then compressed into a tablet. The percentage of each Dyphylline 78.4 400 constituent in the formulation and milligrams per tablet are Ethylcellulose, USP 21.0 107 shown in Table 7, below. The tablet provides 90–100% Sorbitan Monooleate, NF 0.4 2 delivery of dyphylline and praZosin at 12 hours. Magnesium Stearate, NF O.2 1. Total 1OO.O 510 TABLE 7

35 Solvent Coated Beads-Tablet, 12 Hour Dyphylline and Prazosin Example 5 MATERIAL PERCENT MG/TABLET A polygel tablet containing dyphylline and prazosin is Dyphylline 70.2 400 prepared by Spraying a povidone/water Solution onto PraZOsin HCI O.9 5 Ethylcellulose, USP 19.O 109 dyphylline, praZosin and hydroxypropylmethylcellulose 40 Microcrystalline Cellulose, NF 9.O 51 (HPMC) in a fluid bed. The material in the fluid bed is dried Croscarmellose Sodium, NF 0.5 3 and passed through a mill for Sizing. Silicon dioxide and Sorbitan Monooleate, NF 0.4 2 magnesium Stearate are combined with the material, which is then compressed into a tablet form. The percentage of Total 1OO.O 570 each constituent in the formulation and milligrams per tablet are shown in Table 5, below. The tablet provides 90–100% 45 delivery of dyphylline and praZOsin at 12 hours. Example 8 TABLE 5 A Sustained release formulation of Solvent coated beads is prepared by Spraying an ethylcellulose/Solvent Solution onto Polygel Tablet, 12 Hour Dyphylline and PraZOsin 50 dyphylline and prazosin in a fluid bed. The material in the fluid bed is dried and passed through a Screen for sizing. MATERIAL PERCENT MG/TABLET Sorbitan monooleate and magnesium Stearate are combined Dyphylline 745 400 with the material, which is then filled into a capsule. The PraZOsin HCI O.9 5 Hydroxypropylmethylcellulose, USP 18.0 97 percentage of each constituent in the formulation and mil Povidone, USP 6.O 32 55 ligrams per tablet are shown in Table 8, below. The capsule Silicon Dioxide, NF O.3 2 provides 90–100% delivery of dyphylline and prazosin at 12 Magnesium Stearate, NF O.2 1. hours.

Total 1OO.O 537 TABLE 8 60 Solvent Coated Beads Capsule, 12 hour dyphylline and praZOsin Example 6 MATERIAL PERCENT MG/CAPSULE A sustained release hydrogenated vegetable oil (HVO) Dyphylline 77.4. 400 tablet containing dyphylline and praZosin is prepared by PraZOsin HCI 1.O 5 Spraying melted vegetable oil onto dyphylline and prazosin Ethylcellulose, USP 21.0 108 and allowing the oil to cool. Silicon dioxide and magnesium Sorbitan Monooleate, NF 0.4 2 Stearate are combined with the dyphylline/praZoSin/oil US 6,423,719 B1 13 14 formulation. The percentage of each constituent in the first TABLE 8-continued layer of the formulation in milligrams per tablet are shown in Table 11, below. Solvent Coated Beads Capsule, 12 hour dyphylline and prazosin MATERIAL PERCENT MG/CAPSULE TABLE 11 Magnesium Stearate, NF O.2 1. Solvent Coated Beads, 12 hour DVDhylline Total 1OO.O 517 MATERIAL, PERCENT MG/TABLET Dyphylline 71.1 400 Ethylcellulose, USP 19.O 107 Example 9 Microcrystalline Cellulose, NF 9.O 51 Croscarmellose Sodium, NF 0.5 3 A first layer of a formulation for Sustained release of Sorbitan Monooleate, NF 0.4 2 dyphylline and instant release of doxaZOsin is prepared by Total 1OO.O 563 Spraying a poVidone/water Solution onto dyphilline and 15 HPMC in a fluid bed. The material in the fluid bed is dried and passed through a mill for Sizing. Silicon dioxide and A Second layer of the formulation for Sustained release of magnesium Stearate are combined with the material to form dyphylline and instant release of doxazosin is prepared by the first layer of the formulation. The percentage of each mixing doxazosin, microcrystalline cellulose and calcium constituent in the formulation in the first layer and milli phosphate. Vegetable oil and magnesium Stearate are then grams per tablet are shown in Table 9, below. combined with the doxazosin/cellulose/calcium phosphate mixture. The percentage of each constituent in the formu TABLE 9 lation and milligrams per tablet are shown in Table 12, Polygel 12 Hr. Dyphylline below. The final mixture is then compressed with the first 25 layer. The solvent coated beads provide 90-100% delivery MATERIAL, 1st LAYER PERCENT MG/TABLET of dyphylline at 12 hours and instant release of doxazosin. Dyphylline 75.5 400 Hydroxypropylmethylcellulose, USP 18.0 95 TABLE 12 Povidone, USP 6.O 32 Silicon Dioxide, NF O.3 2 IR Doxazosin Magnesium Stearate, NF O.2 1. MGf Total 1OO.O 530 MATERIAL, 2nd LAYER PERCENT TABLET Doxazosin Mesylate 3.5 4 Microcrystalline Cellulose, NF 42.O 48 A Second layer of a formulation for Sustained release of 35 Calcium Phosphate, Bibasic, Dihydrate, NF SO.O 57 dyphylline and instant release of doxaZOsin is prepared by Hydrogenated Vegetable Oil, NF 4.0 5 mixing doxazosin, microcrystalline cellulose and calcium Magnesium Stearate, NF 0.5 1. phosphate. Vegetable oil and magnesium Stearate are then combined with the doxazosin/cellulose/calcium phosphate Total 1OO.O 114 mixture. The percentage of each constituent in the formu 40 lation and milligrams per tablet are shown in Table 10, Example 11 below. The final mixture is then compressed with the first layer. The bilayer tablet provides 90–100% delivery of A formulation of dyphylline and doxazosin is prepared by dyphylline at 12 hours and instant release of doxazosin. Spraying an ethylcellulose/Solvent Solution onto dyphylline 45 in a fluid bed. The material in the fluid bed is dried and TABLE 10 passed through a Screen for sizing. Doxazosin, Sorbitan monooleate, and magnesium Stearate are combined with the IR Doxazosin material. MGf MATERIAL, 2nd LAYER PERCENT TABLET 50 TABLE 13 Doxazosin Mesylate 3.5 4 Solvent Coated Beads Capsule, 12 hour DVphylline, IR Doxazosin Microcrystalline Cellulose, NF 42.O 48 Calcium Phosphate, Bibasic, Dihydrate, NF SO.O 57 MATERIAL, 1st LAYER PERCENT MG/CAPSULE Hydrogenated Vegetable Oil, NF 4.0 5 Magnesium Stearate, NF 0.5 1. 55 Dyphylline 79.6 400 Doxazosin Mesylate O.8 4 Total 1OO.O 114 Ethylcellulose, USP 19.O 96 Sorbitan Monooleate, NF 0.4 2 Magnesium Stearate, NF O.2 1.

Total 1OO.O 503 Example 10 60 A first layer of a formulation for Sustained release of dyphylline and instant release of doxaZOsin is prepared by All patents, patent applications, and publications cited Spraying an ethylcellulose/Solvent Solution onto dyphylline herein are hereby incorporated by reference as if individu in a fluid bed. The material in the fluid bed is dried and ally incorporated. It is to be understood that the above passed through a Screen for Sizing. Microcrystalline 65 description is intended to be illustrative, and not restrictive. cellulose, croScarmellose Sodium and Sorbitan monooleate Various modifications and alterations of this invention will are combined with the material to form the first layer of the become apparent to those skilled in the art from the fore US 6,423,719 B1 15 16 going description without departing from the Scope and the 7. The method of claim 1, wherein R and R are methyl; spirit of this invention, and it should be understood that this R is 2,3-dihydroxypropyl; and R is hydrogen. invention is not to be unduly limited to the illustrative 8. The method of claim 1, wherein the compound is embodiments set forth herein. administered orally. What is claimed is: 1. A method of Symptomatic treatment of benign prostatic 9. The method of claim 1, wherein the compound is hyperplasia in a Subject, comprising: administering to a administered in combination with a pharmaceutically Subject in need thereof, an effective amount of a compound acceptable carrier. of the formula: 10. The method of claim 1, wherein the compound is administered in a Sustained release carrier. 1O 11. The method of claim 1, wherein the compound is O i administered in combination with an C.-adrenergic R1 antagonist. NN N 12. The method of claim 11, wherein the O.-adrenergic antagonist is a nonselective C.-adrenergic-antagonist 1. X-R, 15 O N Selected from the group consisting of phenoxybenzamine and thymoxamine. R2 13. The method of claim 12, wherein the compound and the nonselective C.-adrenergic antagonist are administered in wherein R and R2, independently, are hydrogen or a a Sustained release formulation. C-C linear or branched alkyl optionally interrupted 14. The method of claim 11, wherein the O.-adrenergic by a carbonyl, antagonist is a short acting C-adrenergic-antagonist Selected R is a C-C alkyl Substituted by one or more moieties from the group consisting of alfuZoSin, indoramin, and Selected from the group consisting of hydroxyl, amino, prazosin. mercapto, dioxolan, carbonyl and mixtures thereof; and 15. The method of claim 14, wherein the compound and R is hydrogen; a Substituted or unsubstituted aromatic 25 the short acting C.-adrenergic antagonist are administered in member Selected from the group consisting of phenyl, a Sustained release formulation. biphenyl, benzyl, and furyl, wherein the substituent is 16. The method of claim 11, wherein the O.-adrenergic Selected from the group consisting of C-C alkyl, antagonist is a long acting C-adrenergic-antagonist Selected C-C haloalkyl, C-C alkoxy, C-C alkylthio, halo from the group consisting of doxazosin, teraZosin and tam and nitro, or a cycloalkyl Selected from the group Sulosin. consisting of cyclohexyl and cyclopentyl; or 17. The method of claim 16, wherein the compound is a pharmaceutically acceptable acid addition Salt thereof, included in a Sustained release formulation and the long in a unit dosage form. acting C-adrenergic antagonist is included in a quick release 2. The method of claim 1, wherein R and R are methyl. formulation. 3. The method of claim 1, wherein R is a C-C alkyl 35 18. The method of claim 1, wherein the compound is Substituted by one or more hydroxyl groups. administered in combination with a 5C.-reductase inhibitor. 4. The method of claim 1, wherein R is a substituted or 19. The method of claim 18, wherein the 5C-reductase unsubstituted aromatic member Selected from group con inhibitor is finasteride. Sisting of phenyl, and benzyl, and wherein the Substituent is 20. The method of claim 18, wherein the compound and Selected from the group consisting of C-C alkyl, C-C, 40 the 5C.-reductase inhibitor are included in a Sustained release haloalkyl, C-C alkoxy, C-C alkylthio, halo and nitro. formulation. 5. The method of claim 1, wherein R and R are methyl; 21. The method of claim 1, wherein the compound is R is a C-C alkyl Substituted by one or more hydroxyl administered in combination with a 5C.-reductase inhibitor groups; and R is hydrogen. and an O-adrenergic-antagonist. 6. The method of claim 1, wherein R and R are methyl; 45 R is dihydroxypropyl; and R is hydrogen. k k k k k