US010596127B2

(12 ) United States Patent ( 10 ) Patent No.: US 10,596,127 B2 Dill (45 ) Date of Patent : Mar. 24 , 2020

( 54 ) COMPOSITION FOR REDUCING THE 7,678,821 B2 3/2010 Paborji 2003/0191172 A1 10/2003 Versi FREQUENCY OF URINATION , METHOD OF 2003/0194428 A1 10/2003 Miller et al. MAKING AND USE THEREOF 2004/0054008 Al 3/2004 Araki 2004/0067908 A1 * 4/2004 Nakade A61K 31/00 ( 71) Applicant: WELLESLEY 514/54 PHARMACEUTICALS , LLC , 2004/0198822 A1 10/2004 Fraser et al . 2005/0008702 A1 1/2005 Faour et al. Newtown, PA (US ) 2006/0035923 Al 2/2006 Van Meeteren et al. 2006/0100195 Al 5/2006 Maruyama et al . (72 ) Inventor: David A. Dill , Newtown , PA (US ) 2007/0197666 A1 8/2007 Baiker et al. 2008/0009538 Al 1/2008 Skolnick ( 73 ) Assignee : WELLESLEY 2008/0085314 A1 4/2008 Shalaby PHARMACEUTICALS , LLC , 2008/0095843 Al 4/2008 Nutalapati et al. 2008/0166407 Al 7/2008 Shalaby et al. Newtown , PA (US ) 2009/0202634 A1 * 8/2009 Jans A61K 9/2018 424/468 ( * ) Notice : Subject to any disclaimer, the term of this 2012/0010294 Al 1/2012 Dill patent is extended or adjusted under 35 2012/0244221 Al 9/2012 Dill U.S.C. 154 ( b ) by 39 days . 2015/0044284 Al 2/2015 Santus et al. ( 21) Appl. No .: 14 /870,676 FOREIGN PATENT DOCUMENTS ( 22 ) Filed : Sep. 30 , 2015 CN 1658858 8/2005 CN 101889996 A 11/2010 Prior Publication Data EP 1053752 11/2000 (65 ) EP 1552825 7/2005 US 2016/0015660 A1 Jan. 21 , 2016 EP 1627876 2/2006 WO 0119350 3/2001 WO 03070233 8/2003 Related U.S. Application Data WO 2004093864 11/2004 WO 2006138609 A2 12/2006 (63 ) Continuation - in -part of application No. 14 /815,416 , WO 2007072503 6/2007 filed on Jul . 31, 2015 , which is a continuation of WO 2010138441 12/2010 application No. 13 /828,778 , filed on Mar. 14 , 2013 , WO WO 2010138441 A1 * 12/2010 A61K 9/2027 now Pat. No. 9,119,878 . WO 2011107755 9/2011 WO PCT /US2013 /031617 3/2013 ( 51) Int. Ci. (Continued ) A61K 31/167 ( 2006.01 ) A61K 31/192 ( 2006.01 ) OTHER PUBLICATIONS A61K 45/06 (2006.01 ) A61K 31/616 ( 2006.01) Therapy ' Sep. 2004 VHA Pharmacy Benefits Management Strategic A61K 31/18 (2006.01 ) Healthcare Group and the Medical Advisory Panel. * A61K 31/56 ( 2006.01 ) U.S. Appl. No. 13 / 828,778 , filed Mar. 14 , 2013 , Patented . A61K 9/28 ( 2006.01 ) U.S. Appl. No. 14 /815,416 , filed Jul. 31, 2015, Pending . A61K 31/58 ( 2006.01 ) U.S. Appl. No. 14 /870,676 , filed Sep. 30 , 2015, Pending . A61K 31/405 ( 2006.01 ) International Search Report and Written Opinion of the Interna A61K 31/12 ( 2006.01 ) tional Searching Authority on Patent Application No. PCT/ US2016 / (52 ) U.S. CI. 049246 , dated Nov. 4 , 2016 . CPC A61K 31/167 (2013.01 ) ; A61K 9/284 European Search Report issued in European Patent Application No. (2013.01 ) ; A61K 9/2846 (2013.01 ) ; A61K 13823428.1 dated Mar. 27 , 2015 . 9/2866 (2013.01 ) ; A61K 31/12 ( 2013.01 ) ; ( Continued ) A61K 31/18 (2013.01 ) ; A61K 31/192 ( 2013.01 ) ; A61K 31/405 (2013.01 ) ; AIK 31/56 (2013.01 ) ; A61K 31/58 ( 2013.01 ) ; A61K Primary Examiner Sarah Pihonak 31/616 (2013.01 ) ; A61K 45/06 (2013.01 ) Assistant Examiner Jason Deck (58 ) Field of Classification Search ??? A61K 31/167 ; A61K 31/12 ; A61K 31/58 ; (74 ) Attorney , Agent, or Firm — Ping Wang; Morris , A61K 9/2866 ; A61K 31/405 ; A61K Manning & Martin , LLP 9/284 ; A61K 9/2846 ; A61K 31/18 ; A61K 31/56 ; A61K 31/192 ; A61K 31/616 ; (57 ) ABSTRACT A61K 45/06 See application file for complete search history. A method for manufacturing a pharmaceutical composition for reducing the frequency of urination is disclosed . The (56 ) References Cited pharmaceutical composition comprises ( 1 ) an analgesic U.S. PATENT DOCUMENTS agent and ( 2 ) an a - blocker, a 5a -reductase inhibitor or both . 5,474,786 A 12/1995 Kotwal et al. 6,544,554 B1 4/2003 Maeda et al . 20 Claims, 1 Drawing Sheet US 10,596,127 B2 Page 2

( 56 ) References Cited Johnson , et al ., “ Changes in Nocturia from Medical Treatment of Benign Prostatic Hyperplasia : Secondary Analysis of the Depart ment of Veterans Affairs Cooperative Study Trial ” , Journal of FOREIGN PATENT DOCUMENTS Urology , vol. 170 , No. 1 , Jul. 2003 , pp . 145-148 ( Abstract Only ) . European Search Report issued in Application No. 13763665 dated WO 2013142274 A1 9/2013 Sep. 16 , 2015 . Miwa , et al. , “ Efficacy of Combination Therapy with Tamsulosin and Zolpidem on Nocturia in Patients with Benign Prostatic OTHER PUBLICATIONS Hyperplasia” , Central European Journal of Urology, vol . 64 , No. 4 , Al- Waili , “ Increased urinary nitrite excretion in primary enuresis : Apr. 2011, pp . 232-235 ( Abstract Only ). effects of indomethacin treatment on urinary and serum osmolality Yokoyama, et al. , “ Zolpidem Increases Bladder Capacity and Decreases Urine Excretion in Rats ”. , Neurourology and Urodynamics, vol. 29 , and electrolytes, urinary volumes and nitrite excretion ” , BJU Inter No. 4 , Apr. 2010 , pp . 587-591 ( Abstract Only ) . national, vol. 90 , No. 3 , pp . 294-301, XP55177413, ( Aug. 2002) . European Search Report of Application No. 13763764 dated Sep. Deshpande , et al ., “Medical management of nocturnal enuresis ” , 16 , 2015 . Pediatric Drugs, New Zealand , vol. 14 , No. 2 , pp . 71-77 , XP009183275, File history of U.S. Appl. No. 14 /815,416 , filed Jul. 31, 2015 . ( Apr. 2002 ) . Nusynowitz , M. L. et al. , " Effect on vasopressin action of analgesic International Preliminary Report on Patentability and Written Opin drugs in vitro " , The American Journal of the Medical Sciences , Oct. ion of the International Searching Authority of Application No. 1966 , vol. 252 ( 4 ) , pp . 424-428 . PCT/ US2013 /031617 , dated Oct. 2 , 2014 . Tie , Y., “ Encyclopedia of Family Medical Treatment” , Hualing Bisordi et al. , “ Interaction of Vasopressin and Prostaglandins in the Press , Jan. 1997 , p . 151. ( English Abstract ) . Toad Urinary Bladder, ” Journal of Clinical Investigation , Dec. Cai, M., “ TCM Perspective of Clinical Diseases: A handbook of 1980 , pp . 1200-1210 , vol . 66 . Common Internal Diseases” , Henan Science and Technology Press , Nusynowitz et al ., “ The Antidiuretic Action of Acetaminophen ,” Jan. 2012, pp . 126-127 . ( English Abstract ) . The American Journal of the Medical Sciences, Oct. 1966 , 77 / 429 Satoru Takahashi et.al. , “ Diagnosis and Treatment of Overactive 83/435 . Bladder Syndrome” ,Gerontology , New Horizon , 2005 , vol. 17 , No. Alon et al. , “ Hydrochlorothiazide - Amiloride in the Treatment of 2 , pp . 76-81. Congenital Nephrogenic Diabetes insipidus” American Journal of Osamu Yamaguchi, “ Latest Treatment for Lower Urinary Tract Nephrology , 1985 , pp . 9-13 , vol. 5 . Dysfunction : Therapeutic Agents and Mechanism of Action ” , Inter Asplund , " Nocturia in relation to steep , health , and medical treat national Journal of Urology, 2013 , vol . 20 , pp . 28-39 . ment in the elderly ," BJU International , 2005 , pp . 15-21 , vol. Kaplan et al ., “ Urinary Retention and Post - Void Residual Urine in 96Supplement 1 . Men : Separating Truth From Tradition ” , The Journal of Urology , International Search Report and Written Opinion of the Interna May 2008, vol . 180 , issue . 1 , pp . 47-54 . tional Searching Authority issued in International Patent Applica Song et al. , “ Zolpidem Pharmacotherapy Combined with Alpha tion No. PCT /US2012 /051888 dated Jan. 17 , 2013 . Blocker Therapy for Nocturia Unresponsive to Alpha- Blocker International Search Report and Written Opinion of the Interna Monotherapy in Men with Lower Urinary Tract Symptoms: a tional Searching Authority, issued in International Patent Applica Preliminary Study ” , International Urology Nephrology, 2007, vol . tion No. PCT/ US2010 / 061606 dated Sep. 21, 2011 . 39 , pp . 1147-1152 . File history of U.S. Appl. No. 13 / 343,332 , filed Jan. 4 , 2012 . Robinson et al. , " A Randomized Double - Blind Placebo - controlled File history of U.S. Appl. No. 13 / 424,000 , filed Mar. 19 , 2012 . Multicentre Study to Explore the Efficacy and Safety of Tamsulosin File history of U.S. Appl. No. 13 /487,348 , filed Jun . 4 , 2012 . and Tolterodine in Women with Overactive Bladder Syndrome” , File history of U.S. Appl. No. 12 / 956,634 , filed Nov. 30, 2010 . BJU International, Oct. 2007 , vol. 100 , issue . 4 , pp . 840-845 . File history of U.S. Appl. No. 13 /828,778 , filed Mar. 14 , 2013 . Ozdemir et al. , “ Combination Therapy With Doxazosin and Tenoxicam Painful Urination Practice , “ Benign Prostatic Hyperplasia (BPH ) for the Management of Lower Urinary Tract Symptoms” , Urology, and Nocturia (Night Urination )" , 2010 , vol. 18 , No. In , pp . 32-37 . Aug. 2009 , vol. 74 , issue . 2 , pp . 431-435 . Journal published by Japan Academy of Urology, “ PP -402 (0906 ) Johnson et al ., “ The Effect of Doxazosin , Finasteride and Combi Effects of al Receptor- Blocker and 5a -Reductase Inhibitor on nation Therapy on Nocturia in Men With Benign Prostatic Hyperplasia ” , Canine Urination -Disorder Model ” , 2002 , vol. 93 , No. 2 , p . 348 . The Journal of Urology, Nov. 2007 , vol. 178 , issue . 5 , pp . 2045 Pinna , et al ., “ Altered Neurogenic and Mechanical Responses to 2051. Acetylcholine, ATP and Substance P in Detrusor From Rat with Smith et al. , “ Outcomes of PharmacologicalManagement of Nocturia Outlet Obstruction " , Life Sciences, vol. 79 , No. 13 , Aug. 2006 , pp . with Non - autidiuretic Agents : Does Statistically Significant Equal 1301-1306 ( Abstract Only ). Clinically Significant” , BJU International, May 2011, vol. 107 , Addla , et al. , “ Diclofenac for Treatment of Nocturia Caused by issue. 10 , pp . 1550-1554 . Nocturnal Polyuria : a Prospective, Randomised , Double -Blind , Johnson et al. , “ Changes in Nocturia from Medical Treatment of Placebo -Controlled Crossover Study” , European Urology, vol. 49 , Benign Prostatic Hyperplasia : Secondary Analysis of the Depart No. 4 , Apr. 2006 , pp . 720-725 (Abstract Only ) . ment of Veterans Affairs Cooperative Study Trial ” , Journal of Wein , et al. , " Overactive Bladder: a Better Understanding of Urology , Jul. 2013 , vol. 170 , issue 1 , pp . 145-148. Pathophysiology , Diagnosis and Management” , Journal of Urology, Search Report and Written Opinion of the Intellectual Property vol. 175 , No. 3 , Mar. 2006 , pp . S5 - S10 (Abstract Only ). Office of Singapore, Application No. 11201500409S , dated Feb. 10 , Weiss , et al. , “ Nocturia ” , Journal of Urology , vol. 163 , No. 1, Jan. 2016 . 2000 , pp . 5-12 (Abstract Only ). Lopatkin N.A., “Urology ” , “Geotar -Media ” , 2002 , pp . 216 . Matthiesen , et al ., “ Nocturnal Polyuria and Natriuresis in Male Pushkar. D.Yu et al. , “ Therapy with Alpha - Blockers : Procedure of Patients with Nocturia and Lower Urinary Tract Symptoms” , Jour Choice in the Treatment of Obstructive Urination in Men and nal of Urology, vol. 156 , No. 4 , Oct. 1996 , pp . 1292-1299 ( Abstract Women ” , Pharmatheka , 2002 , No. 10 , pp . 12-22 . Only ) . Mazo E.B. et al. , “ Tonocardin (Doxazosin ) in Treating Lower Smith , et al ., “ Outcomes of Pharmacological Management of Nocturia Urinary Tract Symptoms” , “ Urologiia ” , 2003 , vol. 3. May - June, pp . with Non - Antidiuretic Agents : Does Statistically significant Equal 15-16 , abstract. Clinically significant? ” , BJU International, vol. 107 , No. 10 , Aug. 2011, pp . 1550-1554 (Abstract Only ). * cited by examiner U.S. Patent Mar. 24 , 2020 US 10,596,127 B2

NSAID alone NSAID + LPS 350 300 Acetaminophen 120 warmee we Åspirin 250 fbuprofen 200 30 cellsCD40+CD80 150 Acetaminophen withoutNSAIDPercentofcontrol( 100 20 Ibuprofen Naproxen 5000 500 5 0.5 0.050.005 0.0005 0.00005 500 50 0.5 0.050.005 0.0005 0.00005 Dose of NSAID Dose of NSAID (5000-0.00005 uM ) (5000-0.00005 UM )

FIG . 1A FIG . 1B US 10,596,127 B2 1 2 COMPOSITION FOR REDUCING THE desire to urinate to start when the volume of urine in the FREQUENCY OF URINATION , METHOD OF bladder exceeds around 100 % of its working volume. MAKING AND USE THEREOF SUMMARY This application is a continuation - in -part of U.S. patent 5 application Ser. No. 14 / 815,416 , filed on Jul. 31, 2015 , One aspect of the present application relates to methods of which is a continuation application of U.S. patent applica manufacturing extended - release pharmaceutical composi tion Ser. No. 13 / 828,778 , filed on Mar. 14 , 2013 , now U.S. tions for reducing the frequency of urination . In some Pat. No. 9,119,878 . The entirety of the aforementioned embodiments , the method comprises the steps of forming a applications is incorporated herein by reference . 10 first mixture having a first active ingredient formulated for immediate release and a second active ingredient formulated FIELD for extended release ; coating the firstmixture with a delayed release coating to form a core structure ; and then coating the The present application generally relates to methods and core structure with a second mixture comprising a third compositions for inhibiting the contraction of muscles and , 15 active ingredient formulated for immediate release and a in particular, to methods and compositions for inhibiting the fourth active ingredient formulated for extended release , contraction of smooth muscles of the urinary bladder. wherein at least one of the first , second , third and fourth active ingredients comprises an analgesic agent and at least BACKGROUND 20 one of the first, second , third and fourth active ingredients comprises an a -blocker , a 5a -reductase inhibitor or both . The detrusor muscle is a layer of the urinary bladder wall Another aspect of the present application relates to a made of smooth muscle fibers arranged in spiral, longitudi method for manufacturing a pharmaceutical composition for nal, and circular bundles . When the bladder is stretched , this reducing the frequency of urination . The method comprises signals the parasympathetic nervous system to contract the 25 the steps of forming a core structure comprising a first active detrusor muscle . This encourages the bladder to expel urine ingredient formulated for immediate release and a second through the urethra . active ingredient formulated for extended release ; coating For the urine to exit the bladder , both the autonomically the core structure with a delayed release coating to form a controlled internal sphincter and the voluntarily controlled coated core structure; coating the coated core structure with external sphincter must be opened . Problems with these 30 a third active ingredient formulated for extended release to muscles can lead to incontinence . If the amount of urine form an extended -release layer coated core structure, and reaches 100 % of the urinary bladder's absolute capacity , the coating the extended - release layer coated core structure with voluntary sphincter becomes involuntary and the urine will a fourth active ingredient, wherein at least one of the first be ejected instantly . second , third and fourth active ingredients comprises an The human adult urinary bladder usually holds about 35 analgesic agent and at least one of the first, second ,third and 300-350 ml of urine ( the working volume) , but a full adult fourth active ingredients comprises an a -blocker , a 5a -re bladder may hold up to about 1000 ml ( the absolute vol ductase inhibitor or both . ume) , varying among individuals . As urine accumulates , the Another aspect of the present application relates to a ridges produced by folding of the wall ofthe bladder ( rugae ) 40 methodreducing for the manufacturing frequency of aurination pharmaceutical . The method composition comprises for flatten and the wall of the bladder thins as it stretches , the steps of forming a core structure comprising a first active allowing the bladder to store larger amounts of urine without ingredient formulated for immediate release and a second a significant rise in internal pressure . active ingredient formulated for extended release ; coating In most individuals , the desire to urinate usually starts the core structure with a delayed release coating to form a when the volume of urine in the bladder reaches around 200 45 coated core structure ; coating the coated core structure with ml. At this stage it is easy for the subject, if desired , to resist a third active ingredient formulated for immediate release to the urge to urinate . As the bladder continues to fill , the desire form a double - coated core structure, wherein at least one of to urinate becomes stronger and harder to ignore . Eventu the first , second and third active ingredients comprises an ally , the bladder will fill to the point where the urge to urinate analgesic agent and at least one of the first, second and third becomes overwhelming , and the subject will no longer be 50 active ingredients comprises an a - blocker , a 5a - reductase able to ignore it. In some individuals , this desire to urinate inhibitor or both . starts when the bladder is less than 100 % full in relation to Another aspect of the present application relates to a its working volume. Such increased desire to urinate may pharmaceutical composition , comprising : a first component interfere with normal activities , including the ability to sleep comprising an immediate -release subcomponent and an for sufficient uninterrupted periods of rest . In some cases , 55 extended -release subcomponent, wherein the first compo this increased desire to urinate may be associated with nent is formulated to release the subcomponents immedi medical conditions such as benign prostate hyperplasia or ately after administration , and a second component com prostate cancer in men , or pregnancy in women . However, prising an immediate -release subcomponent and an increased desire to urinate also occurs in individuals , both extended -release subcomponent, wherein the second com male and female , who are not affected by another medical 60 ponent is formulated for a delayed - release of the subcom condition . ponents , wherein the immediate - release subcomponent and Accordingly , there exists a need for compositions and the extended -release subcomponent in the first component methods for the treatment ofmale and female subjects who each comprises an active ingredient comprising one or more suffer from a desire to urinate when the bladder is less than agents selected from the group consisting of analgesic 100 % full of urine in relation to its working volume. Said 65 agents , a -blockers and 5a - reductase inhibitors' wherein the compositions and methods are needed for the inhibition of immediate - release subcomponent and the extended -release muscle contraction in order to allow in said subjects the subcomponent in the second component each comprises an US 10,596,127 B2 3 4 active ingredient comprising one or more agents selected invention . However, it will be apparent to one skilled in the from the group consisting of analgesic agents , a -blockers art that these specific details are not required to practice the and 5a - reductase inhibitors . invention . Descriptions of specific applications are provided Another aspect of the present application relates to a only as representative examples. The present invention is not pharmaceutical composition , comprising: a first component 5 intended to be limited to the embodiments shown , but is to comprising an immediate -release subcomponent , wherein be accorded the broadest possible scope consistent with the the immediate - release subcomponent comprises an active principles and features disclosed herein . ingredient comprising one or more agents selected from the As used herein , the term “ an effective amount” means an group consisting of analgesic agents , a -blockers and 5a -re amount necessary to achieve a selected result . ductase inhibitors , wherein the first component is formulated 10 As used herein , the term “ analgesic ” refers to agents , to release its subcomponent immediately after oral admin compounds or drugs used to relieve pain and inclusive of istration , and a second component comprising an immedi anti -inflammatory compounds. Exemplary analgesic and /or ate -release subcomponent and an extended - release subcom anti- inflammatory agents , compounds or drugs include , but ponent, wherein the second component is formulated to are not limited to , the following substances : non -steroidal release its subcomponent after gastric emptying of the 15 anti -inflammatory drugs (NSAIDs ), salicylates , aspirin , sali second component, wherein the immediate - release subcom cylic acid ,methyl salicylate , diflunisal, salsalate , olsalazine, ponent and the extended - release subcomponent in the sec sulfasalazine , para - aminophenol derivatives , acetanilide, ond component each comprises an active ingredient com acetaminophen , phenacetin , fenamates , mefenamic acid , prising one or more agents selected from the group meclofenamate , sodium meclofenamate , heteroaryl acetic consisting of analgesic agents , a -blockers and 5a -reductase 20 acid derivatives , tolmetin , ketorolac , diclofenac , propionic inhibitors . acid derivatives, ibuprofen , naproxen sodium , naproxen , Another aspect of the present application relates to a fenoprofen , ketoprofen , flurbiprofen , oxaprozin ; enolic pharmaceutical composition for reducing the frequency of acids, oxicam derivatives , piroxicam , meloxicam , tenoxi urination , comprising : a first component comprising an cam , ampiroxicam , droxicam , pivoxicam , pyrazolon deriva immediate - release subcomponent and an extended -release 25 tives, phenylbutazone, oxyphenbutazone, antipyrine , amin subcomponent, wherein the first component is formulated to opyrine , dipyrone , coxibs, celecoxib , rofecoxib , release the subcomponents immediately after administra nabumetone , apazone, indomethacin , sulindac , etodolac , tion , and a second component comprising an immediate isobutylphenyl propionic acid , lumiracoxib , etoricoxib , release subcomponent and an extended -release subcompo parecoxib , valdecoxib , tiracoxib , etodolac , darbufelone, nent, wherein the second component is formulated for a 30 dexketoprofen , aceclofenac , licofelone , bromfenac , loxo delayed - release of the subcomponents , wherein the imme profen , pranoprofen , piroxicam , nimesulide, cizolirine , diate -release subcomponent and the extended -release sub 3 - formylamino - 7 -methylsulfonylamino - 6 -phenoxy -4H - 1 component in the first component each comprises an active benzopyran - 4 -one , meloxicam , lornoxicam , d - indobufen , ingredient comprising ( 1 ) acetaminophen , and (2 ) tamsu mofezolac , amtolmetin , pranoprofen , tolfenamic acid , flur losin or finasteride or both , wherein the immediate - release 35 biprofen , suprofen , oxaprozin , zaltoprofen , alminoprofen , subcomponent and the extended -release subcomponent in tiaprofenic acid , pharmacological salts thereof, hydrates the second component each comprises an active ingredient thereof, and solvates thereof. comprising (1 ) acetaminophen , and ( 2 ) tamsulosin or finas As used herein , the terms “ coxib ” and “ COX inhibitor" teride or both , wherein the pharmaceutical composition refer to a composition of compounds that is capable of reduces the frequency of urination in patients in need 40 inhibiting the activity or expression of COX1 and /or COX2 thereof. enzymes or is capable of inhibiting or reducing the severity , Another aspect of the present application relates to a including pain and swelling , of a severe inflammatory pharmaceutical composition , comprising : an immediate - re response . lease component comprising acetaminophen and an NSAID , As used herein , the term “ derivative” refers to a chemi each in an amount of 5-2000 mg; and an extended -release 45 cally modified compound wherein the modification is con component comprising acetaminophen and an NSAID , each sidered routine by the ordinary skilled chemist , such as an in an amount of 5-2000 mg, wherein the immediate -release ester or an amide of an acid , protecting groups , such as a component, or the extended -release component, or both , benzyl group for an alcohol or thiol, and tert -butoxycarbonyl further comprise one or more agent selected from the group group for an amine . consisting of a -blockers and 5a - reductase inhibitors . 50 As used herein , the term “ analogue” refers to a compound which comprises a chemically modified form of a specific BRIEF DESCRIPTION OF DRAWINGS compound or class thereof, and which maintains the phar maceutical and /or pharmacological activities characteristic FIGS. 1A and 1B are diagrams showing that analgesics of said compound or class. regulate expression of co - stimulatory molecules by Raw 264 55 As used herein “ subject” or “ patient” encompasses mam macrophage cells in the absence (FIG . 1A ) or presence (FIG . mals . In one aspect , the mammal is a human . In another 1B ) of LPS . Cells were cultures for 24 hrs in the presence aspect, the mammal is a non -human primate such as chim of analgesic alone or together with Salmonella typhimurium panzee , and other apes and monkey species. In one aspect, LPS (0.05 ug /ml ) . Results are mean relative % of CD40 + the mammal is a domestic animal such as rabbit , dog , or cat. CD80 + cells. 60 In another aspect , the mammal is a farm animal such as cattle , horse , sheep , goat, or swine. In another aspect , the DETAILED DESCRIPTION mammal is a laboratory animal, including rodents , such as rats , mice and guinea pigs, and the like . The following detailed description is presented to enable As used herein , “ pharmaceutically acceptable salts ” refer any person skilled in the art to make and use the invention . 65 to derivatives of the disclosed compounds wherein the For purposes of explanation , specific nomenclature is set parent compound is modified by making acid or base salts forth to provide a thorough understanding of the present thereof . Examples of pharmaceutically acceptable salts US 10,596,127 B2 5 6 include, but are not limited to , mineral or organic acid salts composition comprising an active ingredient comprising one of basic residues such as amines; alkali or organic salts of or more analgesic agents , an a - blocker , and a pharmaceu acidic residues such as carboxylic acids; and the like . The tically acceptable carrier . pharmaceutically acceptable salts include the conventional Alpha -blockers , also called c -adrenergic -antagonists or non - toxic salts or the quaternary ammonium salts of the 5 a -blockers , are pharmacological agents that act as receptor parent compound formed , for example, from non - toxic antagonists of a -adrenergic receptors , which are further inorganic or organic acids . For example , such conventional divided into al -adrenergic receptors and a2 -adrenergic non - toxic salts include those derived from inorganic acids receptors . Alpha blockers can be classified as selective such as hydrochloric , hydrobromic , sulfuric , sulfamic , phos blockers that selectively act at al- adrenoceptors or a2 - ad phoric, nitric and the like; and the salts prepared from 10 renoceptorstypes of a - adrenergic, and non - selectivereceptors alpha . blockers that act at both organic acids such as acetic , propionic , succinic , glycolic , Examples of selective al- adrenergic blockers include ,but stearic , lactic , malic , tartaric , citric , ascorbic , pamoic , are not limited to , alfuzosin , prazosin , doxazosin , tamsu maleic , hydroxymaleic , phenylacetic , glutamic , benzoic , losin , terazosin , carvedilol, labetalol and silodosin . salicylic , sulfanilic , 2 -acetoxybenzoic , fumaric , toluensulfo 15 Examples of selective a2 - adrenergic blockers include , but nic , methanesulfonic , ethane dislfonic , oxalic , isethionic , are not limited to , atipamezole , idazoxane and yohimbine. and the like . Examples of non - selective a -adrenergic blockers include : As used herein , the phrase “ pharmaceutically acceptable ” phenoxybenzamine , phentolamine , tolazoline , trazodone , is used with reference to compounds, materials , composi typical and atypical antipsychotics . tions, and / or dosage forms which are , within the scope of 20 In some embodiments , the one or more analgesic agents sound medical judgment, suitable for use in contact with the are administered orally in an individual or combined daily tissues of human beings and animals without excessive dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, toxicity , irritation , allergic response , or other problems or 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, complications commensurate with a reasonable benefit/ risk 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 ratio . 25 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, The urinary bladder has two important functions: storage 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200 of urine and emptying . Storage of urine occurs at low 2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200 pressure , which implies that the detrusor muscle relaxes 800 mg, 200-600 mg, 200-400 mg, 400-2000 mg , 400-1500 during the filling phase. Emptying of the bladder requires a mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, coordinated contraction of the detrusor muscle and relax- 30 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, ation of the sphincter muscles of the urethra . Disturbances of 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, the storage function may result in lower urinary tract symp 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 toms, such as urgency, frequency, and urge incontinence, the mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and components of the overactive bladder syndrome. The over the one or more a - blockers are administered orally in an active bladder syndrome, which may be due to involuntary 35 individual or combined daily dose of between 0.01-100 mg, contractions of the smooth muscle of the bladder (detrusor ) 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0.01-0.3 during the storage phase , is a common and underreported mg, 0.01-0.1 mg, 0.01-0.03 mg, 0.03-100 mg, 0.03-30 mg, problem , the prevalence of which has only recently been 0.03-10 mg, 0.03-3 mg, 0.03-1 mg, 0.03-0.3 mg, 0.03-0.1 assessed . mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, One aspect of the present application relates to a method 40 0.1-0.3 mg , 0.3-100 mg, 0.3-30 mg , 0.3-10 mg, 0.3-3 mg , for reducing the frequency of urination . The method com 0.3-1 mg and 0.2-1 mg. prises administering to a subject in need thereof an effective In some embodiments , the a -blocker is a non -selective amount of one or more analgesic agents , and an effective a -blocker . In other embodiments , the a -blocker is a selec amount of an a - blocker. In some embodiments , the one or tive al -adrenergic blocker. In other embodiments , the more analgesic agents and the a -blocker are administered 45 a -blocker is a selective a2 -adrenergic blocker. In other separately in different dosage forms. In other embodiments , embodiments , the a -blocker is tamsulosin . the one or more analgesic agents and the a -blocker are Another aspect of the present application relates to a administered simultaneously in a single dosage form ( e.g., in pharmaceutical composition comprising : one or more anal a single pill or tablet ). In some embodiments , both the one gesic agents ; one or more a -blockers ; and a pharmaceuti or more analgesic agents and the a - blocker are formulated 50 cally acceptable carrier . In some embodiments , the one or for immediate release after administration . In other embodi more analgesic agents are selected from the group consisting ments , both the one or more analgesic agents and the of aspirin , ibuprofen , naproxen , naproxen sodium , indo a -blocker are formulated for delayed -release after adminis methacin , nabumetone , and acetaminophen . tration . In other embodiments , both the one or more anal In some embodiments , the pharmaceutical composition gesic agents and the a -blocker are formulated for extended 55 comprises one or more analgesic agent( s) , individually or in release after administration . In other embodiments , both the combination , in an amount between 50-2000 mg, 50-1500 one or more analgesic agents and the a -blocker are formu mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, lated for delayed -extended release after administration . In 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, other embodiments , the one or more analgesic agents are 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, formulated for delayed -release , extended release or delayed 60 100-1000 mg , 100-800 mg, 100-600 mg, 100-500 mg, extended release , and the a -blocker is formulated for imme 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, diate release . In yet other embodiments , the one or more 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, analgesic agents are formulated for immediate release , and 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, the a -blocker is formulated for delayed -release , extended 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, release or delayed extended release . The method can be used 65 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, for the treatment of nocturia or overactive bladder. Another 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, aspect of the present application relates to a pharmaceutical 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 US 10,596,127 B2 7 8 mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, or one or more a -blockers in an amount between 0.01-100 mg, 1000-1200 mg and tamsulosin in an amountbetween 0.1-1.2 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0.01-0.3 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or 0.9-1.2 mg, mg, 0.01-0.1 mg, 0.01-0.03 mg, 0.03-100 mg, 0.03-30 mg, wherein the composition is formulated for extended release 0.03-10 mg, 0.03-3 mg, 0.03-1 mg, 0.03-0.3 mg, 0.03-0.1 5 with a two -phase release profile in which 20-60 % of the mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, acetaminophen and tamsulosin are released within 2 hours 0.1-0.3 mg, 0.3-100 mg, 0.3-30 mg , 0.3-10 mg, 0.3-3 mg, of administration , and the remainder are released , continu 0.3-1 mg and 0.2-1 mg. ously , or at a steady rate , in a period of 5-24 hours, 5-8 hours , In some embodiments , the a -blocker is a non -selective 8-16 hours or 16-24 hours . a -blocker . In other embodiments , the a -blocker is a selec- 10 " Extended - release, ” also known as sustained -release tive al -adrenergic blocker. In other embodiments , the (SR ), sustained -action (SA ) , time- release ( TR ) , controlled a -blocker is a selective a2 - adrenergic blocker . In other release (CR ), modified release (MR ) , or continuous- release embodiments , the a - blocker is tamsulosin . (CR ) , is a mechanism used in medicine tablets or capsules In some embodiments , the pharmaceutical composition to dissolve slowly and release the active ingredient over comprises acetaminophen in an amount between 100-200 15 time. The advantages of extended- release tablets or capsules mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, are that they can often be taken less frequently than imme or 1000-1200 mg and tamsulosin in an amount between diate - release formulations of the same drug , and that they 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg , 0.9-1.2 mg or 1.2-1.5 keep steadier levels of the drug in the bloodstream , thus mg . extending the duration of the drug action and lowering the In other embodiments , both the one or more analgesic 20 peak amount of drug in the bloodstream . For example , an agents and the one or more a -blockers are formulated for extended - release analgesic may allow a person to sleep immediate release. In other embodiments , the one or more through the night without getting up for the bathroom . analgesic agents are formulated for immediate release and In one embodiment, the pharmaceutical composition is the one or more a - blockers are formulated for extended formulated for extended -release by embedding the active release . 25 ingredient in a matrix of insoluble substance( s ) such as In other embodiments , the one or more analgesic agents acrylics or chitin . An extended -release form is designed to are formulated for extended release and the one or more release the analgesic compound at a predetermined rate by a -blockers are formulated for immediate release . In some maintaining a constant drug level for a specific period of embodiments , the one or more analgesic agents are released time. This can be achieved through a variety of formulations , continuously , or at a steady rate , over a period or 5-24 hours , 30 including , but not limited to , liposomes and drug -polymer 5-8 hours, 8-16 hours or 16-24 hours . In some embodiments , conjugates, such as hydrogels . at least 90 % of the one or more analgesic agents are released An extended - release formulation can be designed to continuously , or at a steady rate , over a period or 5-24 hours, release the active agents at a predetermined rate so as to 5-8 hours , 8-16 hours or 16-24 hours . maintain a constant drug level for a specified , extended In some other embodiments , the one or more analgesic 35 period of time, such as up to about 24 hours , about 20 hours , agents are released within 2 hours of administration and the about 16 hours , about 12 hours , about 10 hours , about 9 remainder are released continuously , or at a steady rate , over hours , about 8 hours , about 7 hours, about 6 hours, about 5 a period of 5-24 hours , 5-8 hours , 8-16 hours or 16-24 hours . hours , about 4 hours , about 3 hours , about 2 hours , or about In other embodiments , both the one or more analgesic 1 hour following administration or following a lag period agents and the one or more a - blockers are formulated for 40 associated with delayed - release of the drug . extended release . In some embodiments , both the one or In certain preferred embodiments , the active agents are more analgesic agents and the one or more a -blockers are released over a time interval of between about 2 to about 10 formulated for extended release such that the one or more hours . Alternatively , the active agents may be released over analgesic agents and the one or more a - blockers are released about 3 hours , about 4 hours, about 5 hours, about 6 hours , continuously , or at a steady rate , over a period or 5-24 hours , 45 about 7 hours , about 8 hours , about 9 , about 10 hours , about 5-8 hours , 8-16 hours or 16-24 hours . In some other embodi 12 hours, about 16 hours , about 20 hours or about 24 hours . ments , both the one or more analgesic agents and the one or In yet other embodiments , the active agents are released over more a -blockers are formulated for extended release with a a time period between about three to about eight hours two- phase release profile in which 20-60 % of the that the following administration . one or more analgesic agents and the one or more a -blockers 50 In some embodiments , the extended -release formulation are released within 2 hours of administration and the remain comprises an active core comprised of one or more inert der are released continuously , or at a steady rate , over a particles , each in the form of a bead , pellet , pill , granular period of 5-24 hours , 5-8 hours , 8-16 hours or 16-24 hours. particle , microcapsule , microsphere , microgranule , nano In some embodiments , the pharmaceutical composition capsule , or nanosphere coated on its surfaces with drugs in comprises acetaminophen in amount between 50-1000 mg, 55 the form of e.g., a drug- containing coating or film - forming 50-250 mg, 250-400 mg, 400-600 mg, 600-800 mg or composition using , for example, fluid bed techniques or 800-1000 mg in combination with tamsulosin in an amount other methodologies known to those of skill in the art . The between 0.1-1.2 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or inert particle can be of various sizes , so long as it is large 0.9-1.2 mg, wherein the composition is formulated for enough to remain poorly dissolved . Alternatively , the active extended release of both acetaminophen and tamsulosin with 60 core may be prepared by granulating and milling and /or by a drug release profile in which at least 90 % of the acet extrusion and spheronization of a polymer composition aminophen and tamsulosin is released , continuously , or at a containing the drug substance . steady rate , over a period of 5-24 hours , 5-8 hours , 8-16 The active agents may be introduced to the inert carrier by hours or 16-24 hours . techniques known to one skilled in the art, such as drug In other embodiments , the pharmaceutical composition 65 layering , powder coating, extrusion / spheronization , roller comprises acetaminophen in an amount between 500-1000 compaction or granulation . The amount of drug in the core mg, 50-200 mg, 50-400 mg, 100-400 mg, 100-300 mg, will depend on the dose that is required , and typically varies US 10,596,127 B2 9 10 from about 5 to 90 weight % . Generally , the polymeric 0.1-1 mg , 0.3-250 mg , 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, coating on the active core will be from about 1 to 50 % based 0.3-3 mg, 0.3-1 mg, 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, on the weight of the coated particle , depending on the lag 3-7 mg and 4-6 mg. time required and / or the polymers and coating solvents In some embodiments , the 5a - reductase inhibitor is tam chosen . Those skilled in the art will be able to select an 5 sulosin . Another aspect of the present application relates to a appropriate amount of drug for coating onto or incorporating pharmaceutical composition comprising : one or more anal into the core to achieve the desired dosage. In one embodi gesic agents ; one or more 5a -reductase inhibitors; and a ment, the inactive core may be a sugar sphere or a buffer pharmaceutically acceptable carrier. In some embodiments , crystal or an encapsulated buffer crystal such as calcium 10 the one or more analgesic agents are selected from the group carbonate , sodium bicarbonate , fumaric acid , tartaric acid , consisting of aspirin , ibuprofen , naproxen , naproxen etc. which alters the microenvironment of the drug to sodium , indomethacin , nabumetone, and acetaminophen . facilitate its release . In some embodiments, the pharmaceutical composition Another aspect of the present application relates to a comprises one or more analgesic agent ( s ) , individually or in method for reducing the frequency of urination . The method 15 combination , in an amount between 50-2000 mg, 50-1500 comprises administering to a subject in need thereof an mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, effective amount of one or more analgesic agents , and an 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, effective amount of a 5a - reductase inhibitor. Examples of 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 5a - reductase inhibitors include, but are not limited to , 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, finasteride , bexlosteride , epristeride, izonsteride, lapisteride, 20 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, and turosteride. In some embodiments , the 5a -reductase 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, inhibitor is finasteride . 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, In some embodiments , the one or more analgesic agents 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, and the 5a - reductase inhibitor are administered separately in 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, different dosage forms. In other embodiments , the one or 25 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, more analgesic agents and the a - blocker are administered 800-1000 mg, 1000-2000 mg , 1000-1500 mg, 1000-1200 simultaneously in a single dosage form (e.g. , in a single pill mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and or tablet) . In some embodiments , both the one or more one or more 5a -reductase inhibitor in an amount between analgesic agents and the 5a -reductase inhibitor are formu 0.1-250 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, lated for immediate release after administration . In other 30 0.1-1 mg, 0.3-250 mg, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, embodiments , both the one or more analgesic agents and the 0.3-3 mg, 0.3-1 mg, 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, 5a - reductase inhibitor are formulated for delayed - release 3-7 mg and 4-6 mg. after administration . In other embodiments , both the one or In some embodiments , the a -blocker is a non - selective more analgesic agents and the 5a - reductase inhibitor are a -blocker . In other embodiments , the a -blocker is a selec formulated for extended release after administration . In 35 tive al -adrenergic blocker . In other embodiments , the other embodiments , both the one or more analgesic agents a - blocker is a selective a2 -adrenergic blocker. In other and the 5a -reductase inhibitor are formulated for delayed embodiments , the a -blocker is tamsulosin . extended release after administration . In other embodiments , In some embodiments , the pharmaceutical composition the one or more analgesic agents are formulated for delayed comprises acetaminophen in an amount between 100-200 release , extended release or delayed extended release , and 40 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, the 5a -reductase inhibitor is formulated for immediate or 1000-1200 mg and finasteride in an amount between release . In yet other embodiments , the one or more analgesic 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg, 0.9-1.2 mg or 1.2-1.5 agents are formulated for immediate release , and the 5a -re mg . ductase inhibitor is formulated for delayed - release , extended In other embodiments , both the one or more analgesic release or delayed extended release . The method can be used 45 agents and the one or more 5a -reductase inhibitors are for the treatment of nocturia or overactive bladder . Another formulated for immediate release . In other embodiments, the aspect of the present application relates to a pharmaceutical one or more analgesic agents are formulated for immediate composition comprising an active ingredient comprising one release and the one or more a - blockers are formulated for or more analgesic agents , a 5a -reductase inhibitor, and a extended release . pharmaceutically acceptable carrier. 50 In other embodiments , the one or more analgesic agents In some embodiments , the one or more analgesic agents are formulated for extended release and the one or more are administered orally in an individual or combined daily 5a - reductase inhibitors are formulated for immediate dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, release . In some embodiments , the one or more analgesic 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, agents are released continuously , or at a steady rate , over a 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 55 period or 5-24 hours , 5-8 hours , 8-16 hours or 16-24 hours . mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg , In some embodiments , at least 90 % of the one or more 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200 analgesic agents are released continuously , or at a steady 2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200 rate , over a period or 5-24 hours , 5-8 hours , 8-16 hours or 800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 16-24 hours . mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 60 In some other embodiments , the one or more analgesic 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, agents are released within 2 hours of administration and the 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, remainder are released continuously, or at a steady rate , over 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 a period of 5-24 hours , 5-8 hours , 8-16 hours or 16-24 hours . mg, 1200-2000 mg, 1200-1500 mg or 1500-2000 mg; and In other embodiments , both the one or more analgesic the one or more 5a -reductase inhibitors are administered 65 agents and the one or more 5a - reductase inhibitors are orally in an individual or combined daily dose of between formulated for extended release . In some embodiments , both 0.1-250 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, the one or more analgesic agents and the one or more US 10,596,127 B2 11 12 5a - reductase inhibitors are formulated for extended release about 16 hours , about 12 hours , about 10 hours, about 9 such that the one or more analgesic agents and the one or hours, about 8 hours , about 7 hours , about 6 hours , about 5 more 5a -reductase inhibitors are released continuously , or at hours, about 4 hours , about 3 hours , about 2 hours , or about a steady rate , over a period or 5-24 hours , 5-8 hours , 8-16 1 hour following administration or following a lag period hours or 16-24 hours . In some other embodiments , both the 5 associated with delayed -release of the drug . one or more analgesic agents and the one or more 5a -re In certain preferred embodiments , the active agents are ductase inhibitors are formulated for extended release with released over a time interval of between about 2 to about 10 a two- phase release profile in which 20-60 % of the that the hours. Alternatively , the active agents may be released over one or more analgesic agents and the one or more 5a -re about 3 hours, about 4 hours , about 5 hours, about 6 hours, ductase inhibitors are released within 2 hours of adminis- 10 about 7 hours , about 8 hours , about 9 , about 10 hours , about tration and the remainder are released continuously , or at a 12 hours, about 16 hours, about 20 hours or about 24 hours . steady rate , over a period of 5-24 hours , 5-8 hours , 8-16 In yet other embodiments , the active agents are released over hours or 16-24 hours . a time period between about three to about eight hours In some embodiments , the pharmaceutical composition following administration . comprises acetaminophen in amount between 50-1000 mg, 15 In some embodiments , the extended - release formulation 50-250 mg, 250-400 mg, 400-600 mg, 600-800 mg or comprises an active core comprised of one or more inert 800-1000 mg in combination with finasteride in an amount particles , each in the form of a bead , pellet, pill, granular between 1-20 mg, 1-3 mg, 3-7 mg, 7-10 mg, 10-15 mg or particle , microcapsule , microsphere , microgranule , nano 15-20 mg, wherein the composition is formulated for capsule , or nanosphere coated on its surfaces with drugs in extended release of both acetaminophen and finasteride with 20 the form of e.g., a drug - containing coating or film - forming a drug release profile in which at least 90 % of the acet composition using , for example, fluid bed techniques or aminophen and finasteride is released , continuously , or at a other methodologies known to those of skill in the art . The steady rate , over a period of 5-24 hours , 5-8 hours, 8-16 inert particle can be of various sizes , so long as it is large hours or 16-24 hours . enough to remain poorly dissolved . Alternatively , the active In other embodiments , the pharmaceutical composition 25 core may be prepared by granulating and milling and /or by comprises acetaminophen in an amount between 50-1000 extrusion and spheronization of a polymer composition mg, 50-100 mg, 50-200 mg, 50-300 mg , 50-400 mg, 50-600 containing the drug substance . mg, 50-800 mg, 100-200 mg, 100-300 mg, 100-400 mg, The active agents may be introduced to the inert carrier by 100-600 mg, 100-800 mg, 100-1000 mg, 200-400 mg, techniques known to one skilled in the art, such as drug 200-600 mg, 200-800 mg, 200-1000 mg, 400-600 mg, 30 layering , powder coating, extrusion / spheronization , roller 400-800 mg, 400-1000 mg, 600-800 mg, 600-1000 mg, compaction or granulation . The amount of drug in the core 800-1000 mg, or 1000-1200 mg and finasteride in an amount will depend on the dose that is required , and typically varies between 1-20 mg, 1-3 mg, 1-7 mg, 1-10 mg, 1-15 mg, 3-7 from about 5 to 90 weight % . Generally , the polymeric mg, 3-10 mg , 3-15 mg , 3-20 mg, 7-10 mg, 7-15 mg, 7-20 coating on the active core will be from about 1 to 50 % based mg, 10-15 mg, 10-20 mg or 15-20 mg, wherein the com- 35 on the weight of the coated particle , depending on the lag position is formulated for extended release with a two -phase time required and / or the polymers and coating solvents release profile in which 20-60 % of the acetaminophen and chosen . Those skilled in the art will be able to select an finasteride are released within 2 hours of administration , and appropriate amount of drug for coating onto or incorporating the remainder are released , continuously , or at a steady rate , into the core to achieve the desired dosage . In one embodi in a period of 5-24 hours , 5-8 hours, 8-16 hours or 16-24 40 ment, the inactive core may be a sugar sphere or a buffer hours . crystal or an encapsulated buffer crystal such as calcium “ Extended -release , ” also known as sustained - release carbonate, sodium bicarbonate , fumaric acid , tartaric acid , (SR ), sustained -action (SA ) , time- release ( TR ) , controlled etc. which alters the microenvironment of the drug to release (CR ), modified release (MR ), or continuous- release facilitate its release . (CR ), is a mechanism used in medicine tablets or capsules 45 Extended -release formulations may utilize a variety of to dissolve slowly and release the active ingredient over extended -release coatings or mechanisms facilitating the time. The advantages of extended -release tablets or capsules gradual release of active agents over time. In some embodi are that they can often be taken less frequently than imme ments , the extended - release agent comprises a polymer diate -release formulations of the same drug , and that they controlling release by dissolution controlled release. In a keep steadier levels of the drug in the bloodstream , thus 50 particular embodiment , the active agent( s ) are incorporated extending the duration of the drug action and lowering the in a matrix comprising an insoluble polymer and drug peak amount of drug in the bloodstream . For example, an particles or granules coated with polymeric materials of extended - release analgesic may allow a person to sleep varying thickness . The polymeric material may comprise a through the night without getting up for the bathroom . lipid barrier comprising a waxy material, such as carnauba In one embodiment, the pharmaceutical composition is 55 wax, beeswax , spermaceti wax , candellila wax , shallac wax , formulated for extended -release by embedding the active cocoa butter , cetostearyl alcohol, partially hydrogenated ingredient in a matrix of insoluble substance ( s ) such as vegetable oils , ceresin , paraffin wax , ceresine, myristyl acrylics or chitin . An extended -release form is designed to alcohol, stearyl alcohol, cetyl alcohol and stearic acid , along release the analgesic compound at a predetermined rate by with surfactants , such as polyoxyethylene sorbitan maintaining a constant drug level for a specific period of 60 monooleate . When contacted with an aqueous medium , such time. This can be achieved through a variety of formulations, as biological fluids, the polymer coating emulsifies or erodes including, but not limited to , liposomes and drug -polymer after a predetermined lag - time depending on the thickness of conjugates, such as hydrogels . the polymer coating . The lag time is independent of gastro An extended - release formulation can be designed to intestinal motility , pH , or gastric residence. release the active agents at a predetermined rate so as to 65 In other embodiments , the extended - release agent com maintain a constant drug level for a specified , extended prises a polymeric matrix effecting diffusion controlled period of time, such as up to about 24 hours , about 20 hours , release . The matrix may comprise one or more hydrophilic US 10,596,127 B2 13 14 and /or water -swellable , matrix forming polymers, pH -de hydrophilic compound to form a hydrophilic polymer matrix pendent polymers , and /or pH -independent polymers . ( i.e., a gel matrix ) in an aqueous medium , including bio In one embodiment, the extended - release formulation logical fluids. comprises a water soluble or water- swellable matrix - form Exemplary binders include homopolysaccharides , such as ing polymer, optionally containing one or more solubility- 5 galactomannan gums, guar gum , hydroxypropyl guar gum , enhancing excipients and /or release -promoting agents . hydroxypropylcellulose (HPC ; e.g., Klucel EXF ) and locust Upon solubilization of the water soluble polymer, the active bean gum . In other embodiments , the binder is an alginic agent( s ) dissolve (if soluble ) and gradually diffuse through acid derivative, HPC or microcrystallized cellulose (MCC ) . the hydrated portion of the matrix . The gel layer grows with Other binders include , but are not limited to , starches , time as more water permeates into the core of the matrix , 10 microcrystalline cellulose , hydroxypropyl cellulose , increasing the thickness of the gel layer and providing a hydroxyethyl cellulose , hydroxypropylmethyl cellulose and diffusion barrier to drug release . As the outer layer becomes polyvinylpyrrolidone . fully hydrated , the polymer chains become completely In one embodiment, the introduction method is drug relaxed and can no longer maintain the integrity of the gel layering by spraying a suspension of active agent( s ) and a layer, leading to disentanglement and erosion of the outer 15 binder onto the inert carrier. hydrated polymer on the surface of the matrix . Water con The binder may be present in the bead formulation in an tinues to penetrate towards the core through the gel layer, amount of from about 0.1 % to about 15 % by weight, and until it has been completely eroded . Whereas soluble drugs preferably of from about 0.2 % to about 10 % by weight. are released by this combination of diffusion and erosion In some embodiments , the hydrophilic polymer matrix mechanisms, erosion is the predominant mechanism for 20 may further include an ionic polymer, a non - ionic polymer , insoluble drugs, regardless of dose . or water - insoluble hydrophobic polymer to provide a stron Similarly , water- swellable polymers typically hydrate and ger gel layer and /or reduce pore quantity and dimensions in swell in biological fluids forming a homogenous matrix the matrix so as to slow diffusion and erosion rates and structure that maintains its shape during drug release and concomitant release of the active agent( s ). This may addi serves as a carrier for the drug, solubility enhancers and /or 25 tionally suppress the initial burst effect and produce a more release promoters . The initial matrix polymer hydration steady, “ zero order release ” of active agent( s ). phase results in slow -release of the drug ( lag phase ). Once Exemplary ionic polymers for slowing dissolution rate the water swellable polymer is fully hydrated and swollen , include both anionic and cationic polymers . Exemplary water within the matrix can similarly dissolve the drug anionic polymers include, for example , sodium carboxym substance and allow for its diffusion out through the matrix 30 ethylcellulose (Na CMC ), sodium alginate , polymers of coating acrylic acid or carbomers ( e.g., CARBOPOL® 934 , 940 , Additionally , the porosity of the matrix can be increased 974P NF) ; enteric polymers , such as polyvinyl acetate due to the leaching out of pH -dependent release promoters phthalate ( PVAP ) , methacrylic acid copolymers ( e.g., so as to release the drug at a faster rate . The rate of the drug EUDRAGIT® L100 , L 30D 55 , A , and FS 30D ) , hypromel release then becomes constant and is a function of drug 35 lose acetate succinate (AQUAT HPMCAS ) ; and xanthan diffusion through the hydrated polymer gel . The release rate gum . Exemplary cationic polymers include, for example , from the matrix is dependent upon various factors, including dimethylaminoethyl methacrylate copolymer ( e.g. , polymer type and level ; drug solubility and dose ; polymer : EUDRAGIT® E 100 ) . Incorporation of anionic polymers , drug ratio ; filler type and level ; polymer to filler ratio ; particularly enteric polymers, is useful for developing a particle size of drug and polymer ; and porosity and shape of 40 pH - independent release profile for weakly basic drugs as the matrix . compared to hydrophilic polymer alone . Exemplary hydrophilic and /or water- swellable , matrix Exemplary non - ionic polymers for slowing dissolution forming polymers include, but are not limited to , cellulosic rate , include, for example, hydroxypropylcellulose (HPC ) polymers, including hydroxyalkyl celluloses and carboxy and polyethylene oxide (PEO ) ( e.g., POLYOXTM ) alkyl celluloses, such as hydroxypropylmethylcellulose 45 Exemplary hydrophobic polymers include ethylcellulose (HPMC ), hydroxypropylcellulose (HPC ), hydroxyethylcel ( e.g., ETHOCELTM , SURELEASE® ) , cellulose acetate , lulose (HEC ), methylcellulose (MC ) , carboxymethylcellu methacrylic acid copolymers ( e.g., EUDRAGIT® NE 30D ) , lose (CMC ) , powdered cellulose such as microcrystalline ammonio -methacrylate copolymers ( e.g. , EUDRAGIT® RL cellulose , cellulose acetate , ethylcellulose , salts thereof , and 100 or PO RS100 ), polyvinyl acetate , glyceryl monostear combinations thereof; alginates, gums, including heteropo- 50 ate , fatty acids, such as acetyl tributyl citrate , and combi lysaccharide gums and homopolysaccharide gums, such as nations and derivatives thereof . xanthan , tragacanth , pectin , acacia , karaya , alginates, agar , The swellable polymer can be incorporated in the formu guar, hydroxypropyl guar , veegum , carrageenan , locust bean lation in proportion from 1 % to 50 % by weight, preferably gum , gellan gum , and derivatives thereofrom ; acrylic resins, from 5 % to 40 % by weight, most preferably from 5 % to 20 % including polymers and copolymers of acrylic acid , meth- 55 by weight. The swellable polymers and binders may be acrylic acid , methyl acrylate and methyl methacrylate and incorporated in the formulation either prior to or after cross- linked polyacrylic acid derivatives such as Carbomers granulation . The polymers can also be dispersed in organic (e.g. , CARBOPOL® , such as including CARBOPOL® 716 solvents or hydro -alcohols and sprayed during granulation . NF , available in various molecular weight grades from Exemplary release- promoting agents include pH -depen Noveon , Inc., Cincinnati, Ohio ) ; carageenan ; polyvinyl 60 dent enteric polymers that remain intact at pH value lower acetate ( e.g. , KOLLIDON® SR ) ; polyvinyl pyrrolidone and than about 4.0 and dissolve at pH values higher than 4.0 , its derivatives such as crospovidone; polyethylene oxides ; preferably higher than 5.0 , most preferably about 6.0 , are and polyvinyl alcohol. Preferred hydrophilic and water considered useful as release -promoting agents for this inven swellable polymers include the cellulosic polymers , espe tion . Exemplary pH -dependent polymers include, but are not cially HPMC . 65 limited to , methacarylic acid copolymers , methacrylic acid The extended - release formulation may further comprise methyl methacrylate copolymers (e.g. , EUDRAGIT® L100 at least one binder that is capable of cross- linking the ( Type A ) , EUDRAGIT® S100 ( Type B ) , Rohm GmbH , US 10,596,127 B2 15 16 Germany; methacrylic acid - ethyl acrylate copolymers ( e.g. , as low molecular weight polyvinyl pyrrolidone and low EUDRAGIT® L100-55 ( Type C ) and EUDRAGIT® L30D molecular weight hydroxypropyl methyl cellulose; mol 55 copolymer dispersion , Rohm GmbH , Germany ) ; copo ecules that aid solubility by molecular entrapment such as lymers of methacrylic acid -methyl methacrylate and methyl cyclodextrins , and pH modifying agents , including acidify methacrylate (EUDRAGIT® FS ) ; terpolymers of meth- 5 ing agents such as citric acid , fumaric acid , tartaric acid , and acrylic acid , methacrylate , and ethyl acrylate ; cellulose hydrochloric acid ; and alkalizing agents such as meglumine acetate phthalates (CAP ); hydroxypropyl methylcellulose and sodium hydroxide . phthalate (HPMCP ) (e.g. , HP -55 , HP- 50 , HP -55S , Shinetsu Solubility enhancing agents typically constitute from 1 % Chemical, Japan ) ; polyvinyl acetate phthalates (PVAP ) ( e.g. , to 80 % by weight, preferably from 1 % to 60 % ,9 more COATERIC® , OPADRY® enteric white OY- P -7171 ) ; poly- 10 preferably from 1 % to 50 % , of the dosage form and can be vinylbutyrate acetate ; cellulose acetate succinates (CAS ) ; incorporated in a variety of ways . They can be incorporated hydroxypropyl methylcellulose acetate succinate (HPM in the formulation prior to granulation in dry or wet form . CAS ), e.g., HPMCAS LF Grade , MF Grade , HF Grade, They can also be added to the formulation after the rest of including AQOAT® LF and AQOAT® MF (Shin - Etsu the materials are granulated or otherwise processed . During Chemical, Japan ) ; Shinetsu Chemical, Japan ) ; shellac ( e.g., 15 granulation , solubilizers can be sprayed as solutions with or MARCOATTM 125 & MARCOATTM 125N ) ; vinyl acetate without a binder . maleic anhydride copolymer ; styrene -maleic monoester In some embodiments , the extended -release formulation copolymer ; carboxymethyl ethylcellulose ( CMEC , Freund comprises a polymeric matrix that can provide for release of Corporation , Japan ) ; cellulose acetate phthalates (CAP ) the drug after a certain time, independent of the pH . For ( e.g., AQUATERIC® ) ; cellulose acetate trimellitates (CAT ); 20 purposes of the present invention , “ pH independent” is and mixtures of two or more thereof at weight ratios between defined as having characteristics (e.g. , dissolution ) which about 2 : 1 to about 5 : 1, such as, for instance, a mixture of are substantially unaffected by pH . pH independent poly EUDRAGIT® L 100-55 and EUDRAGIT® S 100 at a mers are often referred to in the context of “ time- controlled ” weight ratio of about 3 :1 to about 2 : 1, or a mixture of or " time- dependent " release profiles. EUDRAGIT® L 30 D - 55 and EUDRAGIT® FS at a weight 25 A pH independent polymer may be used to coat the active ratio of about 3 : 1 to about 5 : 1 . agent and /or provide a polymer for a hydrophilic matrix in These polymers may be used either alone or in combina the extended -release coating thereover. The pH independent tion , or together with polymers other than those mentioned polymer may be water- insoluble or water soluble. Exem above . Preferred enteric pH - dependent polymers are the plary water insoluble pH independent polymers include, but pharmaceutically acceptable methacrylic acid copolymers . 30 are not limited to , neutral methacrylic acid esters with a These copolymers are anionic polymers based on meth small portion of trimethylammonioethyl methacrylate chlo acrylic acid and methyl methacrylate and , preferably, have a ride ( e.g., EUDRAGIT® RS and EUDRAGIT® RL ; neutral mean molecular weight of about 135,000 . A ratio of free ester dispersions without any functional groups ( e.g. , carboxyl groups to methyl- esterified carboxyl groups in EUDRAGIT® NE30D and EUDRAGIT® NE30 ) ; cellu these copolymers may range , for example , from 1 : 1 to 1 : 3 , 35 losic polymers , such as ethylcellulose , hydroxyl ethyl cel e.g. around 1 :1 or 1 :2 . Such polymers are sold under the lulose, cellulose acetate or mixtures and other pH indepen trade name Eudragit® such as the Eudragit L series e.g., dent coating products . Exemplary water soluble pH Eudragit L 12.5® , Eudragit L 12.5P® , Eudragit L100® , independent polymers include hydroxyalkyl cellulose Eudragit L 100-55® , Eudragit L - 30D® , Eudragit L - 30 ethers , such as hydroxypropylmethylcellulose (HPMC ) , and D -55® , the Eudragit S® series e.g., Eudragit S 12.5® , 40 hydroxypropyl cellulose (HPC ); polyvinylpyrrolidone Eudragit S 12.5P® , Eudragit S100® . The release promoters (PVP ), methylcellulose , OPADRY® amb, guar gum , xan are not limited to pH dependentpolymers . Other hydrophilic than gum , gum arabic , hydroxyethyl cellulose and ethyl molecules that dissolve rapidly and leach out of the dosage acrylate and methyl methacrylate copolymer dispersion or form quickly leaving a porous structure can be also be used combinations thereof. for the same purpose . 45 In one embodiment, the extended -release formulation The release -promoting agent can be incorporated in an comprises a water- insoluble water - permeable polymeric amount from 10 % to 90 % , preferably from 20 % to 80 % and coating or matrix comprising one or more water - insoluble most preferably from 30 % to 70 % by weight of the dosage water - permeable film - forming over the active core . The unit. The agent can be incorporated into the formulation coating may additionally include one or more water soluble either prior to or after granulation . The release - promoting 50 polymers and / or one or more plasticizers . The water- in agent can be added into the formulation either as a dry soluble polymer coating comprises a barrier coating for material, or it can be dispersed or dissolved in an appropriate release of active agents in the core , wherein lower molecular solvent, and dispersed during granulation . weight (viscosity ) grades exhibit faster release rates as In some embodiments , the matrix may include a combi compared to higher viscosity grades . nation of release promoters and solubility enhancers . The 55 In preferred embodiments , the water- insoluble film - form solubility enhancers can be ionic and non - ionic surfactants , ing polymers include one or more alkyl cellulose ethers , complexing agents , hydrophilic polymers , pH modifiers , such as ethyl celluloses and mixtures thereof, ( e.g. , ethyl such as acidifying agents and alkalinizing agents , as well as cellulose grades PR100 , PR45, PR20 , PR10 and PR7 ; molecules that increase the solubility of poorly soluble drug ETHOCEL® , Dow ). through molecular entrapment. Several solubility enhancers 60 An exemplary water - soluble polymer such as polyvi can be utilized simultaneously. nylpyrrolidone (POVIDONE® ), hydroxypropyl methylcel Solubility enhancers may include surface active agents , lulose, hydroxypropyl cellulose and mixtures thereof. such as sodium docusate , sodium lauryl sulfate , sodium In some embodiments , the water- insoluble polymer pro stearyl fumarate , Tweens® and Spans (PEO modified sor vides suitable properties ( e.g. , extended - release characteris bitan monoesters and fatty acid sorbitan esters ) , poly ( ethyl- 65 tics , mechanical properties , and coating properties ) without ene oxide ) -polypropylene oxide- poly ( ethylene oxide ) block the need for a plasticizer. For example , coatings comprising copolymers (aka PLURONICSTM ) ; complexing agents such polyvinyl acetate ( PVA ) , neutral copolymers of acrylate / US 10,596,127 B2 17 18 methacrylate esters such as commercially available Eudragit In a particular embodiment, the formulation comprises at NE30D from Evonik Industries , ethyl cellulose in combi least one non - ionic gel - forming polymer and at least one nation with hydroxypropylcellulose, waxes, etc. can be anionic gel - forming polymer. In another embodiment, the applied without plasticizers . formulation comprises two different non - ionic gel- forming In yet another embodiment, the water -insoluble polymer 5 polymers . In yet another embodiment, the formulation com matrix may further include a plasticizer. The amount of prises a combination of non - ionic gel - forming polymers of plasticizer required depends upon the plasticizer , the prop the same chemistry , but having different solubilities , vis erties of the water - insoluble polymer, and the ultimate cosities , and / or molecular weights ( for example a combina desired properties of the coating . Suitable levels of plasti tion of hydroxyproplylmethylcellulose of different viscosity cizer range from about 1 % to about 20 % , from about 3 % to 10 grades, such as HPMC K100 and HPMC K15M or HPMC about 20 % , about 3 % to about 5 % , about 7 % to about 10 % , K100M ) . about 12 % to about 15 % , about 17 % to about 20 % , or about Exemplary anionic gel forming polymers include , but are 1 % , about 2 % , about 3 % , about 4 % , about 5 % , about 6 % , not limited to , sodium carboxymethylcellulose ( Na CMC ) , about 7 % , about 8 % , about 9 % , about 10 % , about 15 % , or carboxymethyl cellulose (CMC ) , anionic polysaccharides about 20 % by weight relative to the total weight of the 15 such as sodium alginate , alginic acid , pectin , polyglucuronic coating, inclusive of all ranges and sub - ranges therebetween . acid (poly - a- and -B - 1,4 - glucuronic acid ), polygalacturonic Exemplary plasticizers include, but are not limited to , acid (pectic acid ) , chondroitin sulfate , carrageenan , furcel triacetin , acetylated monoglyceride, oils (castor oil, hydro laran , anionic gums such as xanthan gum , polymers of genated castor oil , rape seed oil, sesame oil, olive oil, etc. ); acrylic acid or carbomers (Carbopol® 934 , 940 , 974P NF) , citrate esters , triethyl citrate , acetyltriethyl citrate acetyl- 20 Carbopol® copolymers, a Pemulen® polymer, polycarbo tributyl citrate, tributyl citrate , acetyl tri- n - butyl citrate, phil , and others . diethyl phthalate , dibutyl phthalate , dioctyl phthalate , Exemplary non -ionic gel - forming polymers include, but methyl paraben , propylparaben , propyl paraben , butyl para are not limited to , Povidone (PVP : polyvinyl pyrrolidone ) , ben , diethyl sebacate , dibutyl sebacate , glyceroltributyrate , polyvinyl alcohol, copolymer of PVP and polyvinyl acetate , substituted triglycerides and glycerides, monoacetylated and 25 HPC (hydroxypropyl cellulose ), HPMC (hydroxypropyl diacetylated glycerides (e.g. , MYVACET® 9-45 ) , glyceryl methylcellulose ) , hydroxyethyl cellulose , hydroxymethyl monostearate , glycerol tributyrate , polysorbate 80 , polyeth cellulose, gelatin , polyethylene oxide, acacia , dextrin , yleneglycol (such as PEG -4000 , PEG - 400 ), propylenegly starch , polyhydroxyethylmethacrylate (PHEMA ) , water col, 1,2 - propyleneglycol, glycerin , sorbitol, diethyl oxalate , soluble nonionic polymethacrylates and their copolymers , diethyl malate , diethyl fumarate , diethylmalonate , dibutyl 30 modified cellulose, modified polysaccharides , nonionic succinate , fatty acids , glycerin , sorbitol, diethyl oxalate , gums, nonionic polysaccharides and / or mixtures thereof. diethyl malate , diethyl maleate , diethyl fumarate , diethyl The formulation may optionally comprise an enteric poly succinate , diethyl malonate , dioctyl phthalate , dibutyl seba mer as described above , and/ or at least one excipient , such cate , and mixtures thereof. The plasticizer can have surfac as a filler , a binder (as described above ), a disintegrant, tant properties , such that it can act as a release modifier . For 35 and /or a flow aid or glidant. example , non -ionic detergents such at Brij 58 (polyoxyeth Exemplary fillers include but are not limited to , lactose , ylene (20 ) cetyl ether ), and the like , can be used . glucose, fructose , sucrose, dicalcium phosphate , sugar alco Plasticizers can be high boiling point organic solvents hols also known as “ sugar polyol” such as sorbitol, manitol, used to impart flexibility to otherwise hard or brittle poly lactitol, Xylitol, isomalt, erythritol, and hydrogenated starch meric materials and can affect the release profile for the 40 hydrolysates ( a blend of several sugar alcohols ) , corn starch , active agent( s ) . Plasticizers generally cause a reduction in potato starch , sodium carboxymethycellulose , ethylcellulose the cohesive intermolecular forces along the polymer chains and cellulose acetate , enteric polymers, or a mixture thereof. resulting in various changes in polymer properties including Exemplary binders , include but are not limited to , water a reduction in tensile strength , and increase in elongation soluble hydrophilic polymers , such as Povidone (PVP : poly and a reduction in the glass transition or softening tempera- 45 vinyl pyrrolidone ), copovidone (a copolymer of polyvinyl ture of the polymer . The amount and choice of the plasticizer pyrrolidone and polyvinyl acetate ) , low molecular weight can affect the hardness of a tablet , for example , and can even HPC (hydroxypropyl cellulose ) low molecular weight affect its dissolution or disintegration characteristics , as well HPMC (hydroxypropyl methylcellulose ), low molecular as its physical and chemical stability . Certain plasticizers can weight carboxy methyl cellulose , ethylcellulose, gelatin , increase the elasticity and / or pliability of a coat , thereby 50 polyethylene oxide, acacia , dextrin , magnesium aluminum decreasing the coat's brittleness. silicate , starch , and polymethacrylates such as Eudragit NE In another embodiment, the extended - release formulation 30D , Eudragit RL , Eudragit RS , Eudragit E , polyvinyl comprises a combination of at least two gel- forming poly acetate , and enteric polymers , or mixtures thereof. mers, including at least one non - ionic gel- forming polymer Exemplary disintegrants include but are not limited to and /or at least one anionic gel - forming polymer. The gel 55 low -substituted carboxymethyl cellulose sodium , crospovi formed by the combination of gel - forming polymers pro done (cross - linked polyvinyl pyrrolidone ), sodium car vides controlled release , such that when the formulation is boxymethyl starch (sodium starch glycolate ), cross -linked ingested and comes into contact with the gastrointestinal sodium carboxymethyl cellulose (Croscarmellose ), pregela fluids, the polymers nearest the surface hydrate to form a tinized starch ( starch 1500 ) , microcrystalline cellulose , viscous gel layer. Because of the high viscosity , the viscous 60 water insoluble starch , calcium carboxymethyl cellulose , layer dissolves away only gradually , exposing the material low substituted hydroxypropyl cellulose , and magnesium or below to the same process. The mass thus dissolves away aluminum silicate . slowly , thereby slowly releasing the active ingredient into Exemplary glidants include but are not limited to , mag the gastrointestinal fluids. The combination of at least two nesium , silicon dioxide, talc , starch , titanium dioxide, and gel - forming polymers enables properties ofthe resultant gel, 65 the like . such as viscosity , to be manipulated in order to provide the In yet another embodiment, the extended -release formu desired release profile . lation is formed by coating a water soluble /dispersible US 10,596,127 B2 19 20 drug - containing particle , such as a bead or bead population In other embodiments , the extended -release formulation therein ( as described above ) , with a coating material , and , is formulated to release the active agent( s ) by an osmotic optionally , a pore former and other excipients . The coating mechanism . By way of example , a capsule may be formu material is preferably selected from a group comprising lated with a single osmotic unit or it may incorporate 2 , 3 , cellulosic polymers , such as ethylcellulose ( e.g. , SURE- 5 4 , 5 , or 6 push -pull units encapsulated within a hard gelatin LEASER ), methylcellulose , hydroxypropyl cellulose , capsule , whereby each bilayer push pull unit contains an hydroxypropylmethyl cellulose , cellulose acetate , and cel osmotic push layer and a drug layer , both surrounded by a lulose acetate phthalate ; polyvinyl alcohol; acrylic polymers semi- permeable membrane . One or more orifices are drilled such as polyacrylates, polymethacrylates and copolymers through the membrane next to the drug layer . This mem thereof, and other water- based or solvent- based coating 10 brane may be additionally covered with a pH -dependent materials . The release - controlling coating for a given bead enteric coating to prevent release until after gastric empty population may be controlled by at least one parameter of ing . The gelatin capsule dissolves immediately after inges the release controlling coating, such as the nature of the tion . As the push pull unit( s ) enter the small intestine , the coating, coating level, type and concentration of a pore 15 throughenteric coating the semibreaks- permeable down , which membrane then allows, swelling fluid to flowthe former , process parameters and combinations thereof. Thus, osmotic push compartment to force to force drugs out changing a parameter , such as a pore former concentration , through the orifice (s ) at a rate precisely controlled by the rate or the conditions of the curing , allows for changes in the of water transport through the semi- permeable membrane . release of active agent( s ) from any given bead population , Release of drugs can occur over a constant rate for up to 24 thereby allowing for selective adjustment of the formulation 20 hours or more . to a pre -determined release profile . The osmotic push layer comprises one or more osmotic Pore formers suitable for use in the release controlling agents creating the driving force for transport of water coating herein can be organic or inorganic agents , and through the semi-permeable membrane into the core of the include materials that can be dissolved , extracted or leached delivery vehicle . One class of osmotic agents includes from the coating in the environment of use . Exemplary pore 25 water- swellable hydrophilic polymers , also referred to as forming agents include, but are not limited to , organic " osmopolymers” and “ hydrogels , " including , but not limited compounds such as mono-, oligo-, and polysaccharides to , hydrophilic vinyl and acrylic polymers , polysaccharides including sucrose , glucose , fructose , mannitol, mannose , such as calcium alginate , polyethylene oxide (PEO ), poly galactose, sorbitol, pullulan , dextran ; polymers soluble in ethylene glycol (PEG ) , polypropylene glycol (PPG ), poly the environment of use such as water -soluble hydrophilic 30 ( 2 -hydroxyethyl methacrylate ), poly ( acrylic ) acid , poly polymers , hydroxyalkylcelluloses, carboxyalkylcelluloses , (methacrylic acid , polyvinylpyrrolidone (PVP ) , crosslinked hydroxypropylmethylcellulose , cellulose ethers, acrylic res PVP, polyvinyl alcohol (PVA ) , PVA /PVP copolymers , PVA / ins, polyvinylpyrrolidone , cross - linked polyvinylpyrroli PVP copolymers with hydrophobic monomers such as done , polyethylene oxide , Carbowaxes, Carbopol, and the methyl methacrylate and vinyl acetate , hydrophilic polyure like, diols , polyols , polyhydric alcohols , polyalkylene gly- 35 thanes containing large PEO blocks, sodium croscarmellose , cols, polyethylene glycols, polypropylene glycols , or block carrageenan , hydroxyethyl cellulose (HEC ) , hydroxypropyl polymers thereof, polyglycols , poly ( a - 2 ) alkylenediols ; cellulose (HPC ) , hydroxypropyl methyl cellulose (HPMC ) , inorganic compounds such as alkali metal salts , lithium carboxymethyl cellulose (CMC ) and carboxyethyl, cellulose carbonate , sodium chloride, sodium bromide, potassium ( CEC ) , sodium alginate , polycarbophil , gelatin , xanthan chloride , potassium sulfate , potassium phosphate , sodium 40 gum , and sodium starch glycolate . acetate , sodium citrate , suitable calcium salts , combination Another class of osmotic agents includes osmogens, thereof, and the like . which are capable of imbibing water to effect an osmotic The release controlling coating can further comprise other pressure gradient across the semi- permeable membrane . additives known in the art , such as plasticizers , anti- adher Exemplary osmogens include, but are not limited to , inor ents , glidants (or flow aids) , and antifoams. 45 ganic salts , such as magnesium sulfate , magnesium chloride , In some embodiments , the coated particles or beads may calcium chloride, sodium chloride, lithium chloride, potas additionally include an " overcoat, ” to provide , e.g., moisture sium sulfate, potassium phosphates, sodium carbonate , protection , static charge reduction , taste -masking , flavoring, sodium sulfite , lithium sulfate , potassium chloride , and coloring, and /or polish or other cosmetic appeal to the beads. sodium sulfate ; sugars , such as dextrose, fructose, glucose , Suitable coating materials for such an overcoat are known in 50 inositol, lactose, maltose , mannitol, raffinose , sorbitol, the art , and include, but are not limited to , cellulosic sucrose , trehalose , and xylitol; organic acids, such as ascor polymers such as hydroxypropylmethylcellulose , hydroxy bic acid , benzoic acid , fumaric acid , citric acid , maleic acid , propylcellulose and microcrystalline cellulose , or combina sebacic acid , sorbic acid , adipic acid , edetic acid , glutamic tions thereof ( for example , various OPADRY® coating acid , p - toluenesulfonic acid , succinic acid , and tartaric acid ; materials) . 55 urea ; and mixtures thereof. The coated particles or beads may additionally contain Materials useful in forming the semipermeable membrane enhancers that may be exemplified by, but not limited to , include various grades of acrylics , vinyls , ethers, poly solubility enhancers , dissolution enhancers , absorption amides, polyesters, and cellulosic derivatives that are water enhancers , permeability enhancers , stabilizers , complexing permeable and water - insoluble at physiologically relevant agents , enzyme inhibitors, p - glycoprotein inhibitors , and 60 pHs, or are susceptible to being rendered water -insoluble by multidrug resistance protein inhibitors . Alternatively, the chemical alteration , such as crosslinking . formulation can also contain enhancers that are separated In some embodiments , the extended -release formulation from the coated particles, for example in a separate popu may comprise a polysaccharide coating that is resistant to lation of beads or as a powder . In yet another embodiment, erosion in both the stomach and intestine. Such polymers the enhancer( s ) may be contained in a separate layer on 65 can be only degraded in the colon , which contains a large coated particles either under or above the release controlling microflora containing biodegradable enzymes breaking coating down , for example , the polysaccharide coatings to release US 10,596,127 B2 21 22 the drug contents in a controlled , time- dependent manner. extended /delayed - release component is coated with an Exemplary polysaccharide coatings may include , for enteric coating . In other embodiments , the immediate -re example , amylose , arabinogalactan , chitosan , chondroitin lease component and / or the extended /delayed - release com sulfate , cyclodextrin , dextran , guar gum , pectin , xylan , and ponent further comprises an antimuscarinic agent selected combinations or derivatives therefrom . 5 from the group consisting of oxybutynin , solifenacin , In some embodiments , the pharmaceutical composition of darifenacin and atropine . In other embodiments , the imme the present application is formulated for delayed extended diate - release component and / or the extended / delayed - re release. As used herein , the term “ delayed - release” refers to lease component further comprises an antidiuretic agent, an a medication that does not immediately disintegrate and antimuscarinic agent or both . In other embodiments , the release the active ingredient( s ) into the body. In some 10 treatment method includes administering to a subject a embodiments , the term " delayed extended -release ” is used diuretic at least 8 or 7 hours prior to a target time, such as with reference to a drug formulation having a release profile bedtime, and administering to the subject the pharmaceutical in which there is a predetermined delay in the release of the composition comprising the immediate - release component drug following administration . In some embodiments , the and /or the extended /delayed -release component within 2 delayed extended - release formulation includes an extended- 15 hours prior to the target time. release formulation coated with an enteric coating , which is In other embodiments , the “ immediate- release " compo a barrier applied to oral medication that prevents release of nent provide about 5-50 % of the total dosage of the active medication before it reaches the small intestine. Delayed agent( s ) and the “ extended -release ” component provides release formulations , such as enteric coatings , prevent drugs 50-95 % of the total dosage of the active agent( s ) to be having an irritant effect on the stomach , such as aspirin , from 20 delivered by the pharmaceutical formulation . For example , dissolving in the stomach . Such coatings are also used to the immediate -release component may provide about protect acid -unstable drugs from the stomach's acidic expo 20-60 % , or about 20 % , 25 % , 30 % , 35 % , 40 % , 45 % , 50 % , sure , delivering them instead to a basic pH environment 55 % , 60 % of the total dosage of the active agent( s ) to be ( intestine’s pH 5.5 and above ) where they do not degrade , delivered by the pharmaceutical formulation . The extended and give their desired action . Accordingly , a formulation that 25 release component provides about 40 % , 45 % , 50 % , 55 % , releases it component “ after gastric emptying ” refers to a 60 % , 65 % , 70 % , 75 % or 80 % of the total dosage of the delayed formulation that releases the active ingredient( s ) active agent( s ) to be delivered by the formulation . In some after the formulation is emptied from the stomach . embodiments , the extended -release component further com The term “ pulsatile release ” is a type of delayed - release , prises a barrier coating to delay the release of the active which is used herein with reference to a drug formulation 30 agent. that provides rapid and transient release of the drug within A barrier coating for delayed -release may consist of a a short time period immediately after a predetermined lag variety of different materials , depending on the objective. In period , thereby producing a " pulsed " plasma profile of the addition , a formulation may comprise a plurality of barrier drug after drug administration . Formulations may be coatings to facilitate release in a temporal manner . The designed to provide a single pulsatile release or multiple 35 coating may be a sugar coating, a film coating ( e.g., based pulsatile releases at predetermined time intervals following on hydroxypropyl methylcellulose , methylcellulose , methyl administration , or a pulsatile release ( e.g. , 20-60 % of the hydroxyethylcellulose , hydroxypropylcellulose , carboxym active ingredient ) followed with extended release over a ethylcellulose , acrylate copolymers, polyethylene glycols period of time (e.g. , a continuous release of the remainder of and /or polyvinylpyrrolidone) , or a coating based on meth the active ingredient) . 40 acrylic acid copolymer, cellulose acetate phthalate , hydroxy A delayed - release or pulsatile release formulation gener propyl methylcellulose phthalate , hydroxypropyl methylcel ally comprises one or more elements covered with a barrier lulose acetate succinate , polyvinyl acetate phthalate , shellac , coating, which dissolves , erodes or ruptures following a and /or ethylcellulose. Furthermore , the formulation may specified lag phase. In some embodiments , the pharmaceu additionally include a time delay material such as, for tical composition of the present application is formulated for 45 example , glyceryl monostearate or glyceryl distearate . extended - release or delayed extended - release and comprises In some embodiments , the delayed , extended - release for 100 % of the total dosage of a given active agent adminis mulation includes an enteric coating comprised one or more tered in a single unit dose . In other embodiments , the polymers facilitating release of active agents in proximal or pharmaceutical composition comprises an extended /de distal regions of the gastrointestinal tract . As used herein , the layed -release component and an immediate - release compo- 50 term “ enteric polymer coating ” is a coating comprising of nent. In some embodiments , the immediate -release compo one or more polymers having a pH dependent or pH nent and the extended /delayed -release component contain independent release profile . Typically the coating resists the same active ingredient. In other embodiments , the imme dissolution in the acidic medium of the stomach , but dis diate -release component and the extended /delayed - release solves or erodes in more distal regions of the gastrointestinal component contain different active ingredients ( e.g., an 55 tract ,such as the small intestine or colon . An enteric polymer analgesic in one component and an a -blocker in another coating typically resists releases of the active agents until component) . In some embodiments, the first and second sometime after a gastric emptying lag period of about 3-4 components each comprises an a - blocker and an analgesic hours after administration . selected from the group consisting of aspirin , ibuprofen , pH dependent enteric coatings comprises one or more naproxen sodium , indomethacin , nabumetone, and acet- 60 pH -dependent or pH - sensitive polymers that maintain their aminophen . In other embodiments , the first and second structural integrity at low pH , as in the stomach , but dissolve components each comprises a 5a - reductase inhibitor in higher pH environments in more distal regions of the selected from the group consisting of finasteride, bexlos gastrointestinal tract , such as the small intestine , where the teride , epristeride, izonsteride , lapisteride and turosteride, drug contents are released . For purposes of the present and an analgesic selected from the group consisting of 65 invention , “ pH dependent ” is defined as having character aspirin , ibuprofen , naproxen sodium , indomethacin , nabu istics ( e.g. , dissolution ) which vary according to environ metone , and acetaminophen . In other embodiments , the mental pH . Exemplary pH - dependent polymers include, but US 10,596,127 B2 23 24 are not limited to , methacarylic acid copolymers , meth one or more swelling agents , such as swellable hydrophilic acrylic acid -methyl methacrylate copolymers (e.g. , polymers that swell and retain water in their structures. EUDRAGIT® L100 ( Type A ) , EUDRAGIT® S100 ( Type Exemplary water swellable materials to be used in the B ) , Rohm GmbH , Germany ;methacrylic acid - ethyl acrylate delayed -release coating include, but are not limited to , copolymers ( e.g. , EUDRAGIT® L100-55 ( Type C ) and 5 polyethylene oxide (having e.g. , an average molecular weight between 1,000,000 to 7,000,000 , such as EUDRAGIT® L30D - 55 copolymer dispersion , Rohm POLYOX® ), methylcellulose , hydroxypropyl cellulose , GmbH , Germany ) ; copolymers of methacrylic acid -methyl hydroxypropyl methylcellulose ; polyalkylene oxides having methacrylate and methyl methacrylate (EUDRAGIT® FS ) ; a weight average molecular weight of 100,000 to 6,000,000 , terpolymers of methacrylic acid , methacrylate , and ethyl 10 including but not limited to poly (methylene oxide ), poly acrylate ; cellulose acetate phthalates ( CAP) ; hydroxypropyl (butylene oxide ); poly (hydroxy alkylmethacrylate ) having a methylcellulose phthalate ( HPMCP ) ( e.g. , HP - 55 , HP - 50 , molecular weight of from 25,000 to 5,000,000 ; poly (vinyl ) HP -55S , Shinetsu Chemical , Japan ); polyvinyl acetate alcohol, having a low acetal residue, which is cross - linked phthalates (PVAP ) (e.g. , COATERIC® , OPADRY® enteric with glyoxal, formaldehyde or glutaraldehyde and having a white OY- P -7171 ) ; cellulose acetate succinates (CAS ) ; 15 degree of polymerization of from 200 to 30,000 ; mixtures of hydroxypropyl methylcellulose acetate succinate (HPM methyl cellulose , cross - linked agar and carboxymethyl cel CAS ) , e.g., HPMCAS LF Grade , MF Grade , HF Grade , lulose ; hydrogel forming copolymers produced by forming including AQOAT® LF and AQOAT® MF (Shin -Etsu a dispersion of a finely divided copolymer ofmaleic anhy Chemical, Japan ); Shinetsu Chemical, Japan ) ; shellac ( e.g. , dride with styrene , ethylene, propylene, butylene or isobu MarcoatTM 125 & MarcoatTM 125N ) ; carboxymethyl ethyl- 20 tylene cross - linked with from 0.001 to 0.5 moles of saturated cellulose (CMEC , Freund Corporation , Japan ) , cellulose cross -linking agent per mole of maleic anyhydride in the acetate phthalates (CAP ) ( e.g., AQUATERIC® ) ; cellulose copolymer ; CARBOPOL® acidic carboxy polymers having acetate trimellitates (CAT ) ; and mixtures of two or more a molecular weight of 450,000 to 4,000,000 ; CYANA thereof at weight ratios between about 2 : 1 to about 5 : 1 , such MER® polyacrylamides ; cross -linked water swellable as, for instance , a mixture of EUDRAGIT® L 100-55 and 25 indenemaleicanhydride polymers ; GOODRITE® poly EUDRAGIT® S 100 at a weight ratio of about 3 : 1 to about acrylic acid having a molecular weightof 80,000 to 200,000 ; 2 : 1 , or a mixture of EUDRAGIT® L 30 D - 55 and starch graft copolymers ; AQUA -KEEPS® acrylate polymer EUDRAGIT® FS at a weight ratio of about 3 : 1 to about 5 : 1 . polysaccharides composed of condensed glucose units such pH -dependent polymers typically exhibit a characteristic as diester cross - linked polyglucan ; carbomers having a pH optimum for dissolution . In some embodiments , the 30 viscosity of 3,000 to 60,000 mPa as a 0.5 % -1 % w /v aqueous pH - dependent polymer exhibits a pH optimum between solution ; cellulose ethers such as hydroxypropylcellulose about 5.0 and 5.5 , between about 5.5 and 6.0 , between about having a viscosity of about 1000-7000 mPa s as a 1 % w / w 6.0 and 6.5 , or between about 6.5 and 7.0 . In other embodi aqueous solution (25 ° C.) ; hydroxypropyl methylcellulose ments , the pH -dependent polymer exhibits a pH optimum of having a viscosity of about 1000 or higher, preferably 2,500 25.0 , of 25.5 , of 26.0 , of 26.5 , or of 27.0 . 35 or higher to a maximum of 25,000 mPa as a 2 % w / v aqueous In certain embodiment, the coating methodology employs solution ; polyvinylpyrrolidone having a viscosity of about the blending of one or more pH -dependent and one or more 300-700 mPa s as a 10 % w /v aqueous solution at 20 ° C .; and pH - independent polymers . The blending of pH -dependent combinations thereof. and pH - independent polymers can reduce the release rate of Alternatively , the release time of the drugs can be con active ingredients once the soluble polymer has reached its 40 trolled by a disintegration lag time depending on the balance optimum pH of solubilization . between the tolerability and thickness of a water insoluble In some embodiments , a " time- controlled ” or “ time polymer membrane (such as ethyl cellulose, EC ) containing dependent” release profile can be obtained using a water predefined micropores at the bottom of the body and the insoluble capsule body containing one or more active amount of a swellable excipient, such as low substituted agents , wherein the capsule body closed at one end with an 45 hydroxypropyl cellulose ( L -HPC ) and sodium glycolate . insoluble , but permeable and swellable hydrogel plug . Upon After oral administration , GI fluids permeate through the contact with gastrointestinal fluid or dissolution medium , the micropores, causing swelling of the swellable excipients, plug swells , pushing itself out of the capsule and releasing which produces an inner pressure disengaging the capsular the drugs after a pre -determined lag time, which can be components , including a first capsule body containing the controlled by e.g., the position and dimensions of the plug . 50 swellable materials , a second capsule body containing the The capsule body may be further coated with an outer drugs, and an outer cap attached to the first capsule body. pH -dependent enteric coating keeping the capsule intact The enteric layer may further comprise anti - tackiness until it reaches the small intestine . Suitable plug materials agents , such as talc or glyceryl monostearate and / or plasti include , for example , polymethacrylates , erodible com cizers . The enteric layer may further comprise one or more pressed polymers ( e.g., HPMC , polyvinyl alcohol) , con- 55 plasticizers including , but not limited to , triethyl citrate, gealed melted polymer ( e.g. , glyceryl mono oleate ) and acetyl triethyl citrate , acetyltributyl citrate , polyethylene enzymatically controlled erodible polymers ( e.g., polysac glycol acetylated monoglycerides , glycerin , triacetin , pro charides , such as amylose , arabinogalactan , chitosan , chon pylene glycol, phthalate esters ( e.g. , diethyl phthalate , dibu droitin sulfate , cyclodextrin , dextran , guar gum , pectin and tyl phthalate ), titanium dioxide , ferric oxides, castor oil , xylan ). 60 sorbitol and dibutyl sebacate. In other embodiments , capsules or bilayered tablets may In another embodiment, the delayed release formulation be formulated to contain a drug - containing core , covered by employs a water -permeable but insoluble film coating to a swelling layer, and an outer insoluble , but semi- permeable enclose the active ingredient and an osmotic agent . As water polymer coating or membrane . The lag time prior to rupture from the gut slowly diffuses through the film into the core , can be controlled by the permeation and mechanical prop- 65 the core swells until the film bursts , thereby releasing the erties of the polymer coating and the swelling behavior of active ingredients . The film coating may be adjusted to the swelling layer. Typically , the swelling layer comprises permit various rates of water permeation or release time. US 10,596,127 B2 25 26 In another embodiment, the delayed release formulation inner layer membrane can largely control the rate of drug employs a water - impermeable tablet coating whereby water release following imbibition of water or body fluids into the enters through a controlled aperture in the coating until the core , while the outer layer membrane can provide for a core bursts . When the tablet bursts , the drug contents are desired lag time (the period of no or little drug release released immediately or over a longer period of time. These 5 following imbibition of water or body fluids into the core ) . and other techniques may be modified to allow for a pre The inner layer membrane may comprise a water insoluble determined lag period before release of drugs is initiated . polymer, or a mixture of water insoluble and water soluble In another embodiment, the active agents are delivered in polymers . a formulation to provide both delayed -release and extended The polymers suitable for the outer membrane , which release (delayed -sustained ). The term “ delayed -extended- 10 largely controls the lag timeof up to 6 hours , may comprise release” is used herein with reference to a drug formulation an enteric polymer , as described above, and a water providing pulsatile release of active agents at a pre -deter insoluble polymer at 10 to 50 weight % . The ratio of water mined time or lag period following administration , which is insoluble polymer to enteric polymer may vary from 4 : 1 to then followed by extended -release of the active agents 1 :2 , preferably the polymers are present at a ratio of about thereafter. 15 1: 1. The water insoluble polymer typically used is ethylcel In some embodiments , immediate - release , extended -re lulose . lease , delayed - release , or delayed - extended - release formu Exemplary water insoluble polymers include ethylcellu lations comprises an active core comprised of one or more lose, polyvinyl acetate (Kollicoat SR #OD from BASF ) , inert particles, each in the form of a bead , pellet , pill , neutral copolymers based on ethyl acrylate and methylmeth granular particle , microcapsule , microsphere ,microgranule , 20 acrylate , copolymers of acrylic and methacrylic acid esters nanocapsule , or nanosphere coated on its surfaces with with quaternary ammonium groups such as EUDRAGIT® drugs in the form of e.g., a drug - containing film - forming NE , RS and RS30D , RL or RL30D and the like. Exemplary composition using , for example, fluid bed techniques or water soluble polymers include low molecular weight other methodologies known to those of skill in the art . The HPMC , HPC ,methylcellulose , polyethylene glycol ( PEG of inert particle can be of various sizes, so long as it is large 25 molecular weight > 3000 ) at a thickness ranging from 1 enough to remain poorly dissolved . Alternatively , the active weight % up to 10 weight % depending on the solubility of core may be prepared by granulating and milling and / or by the active in water and the solvent or latex suspension based extrusion and spheronization of a polymer composition coating formulation used . The water insoluble polymer to containing the drug substance. water soluble polymer may typically vary from 95 : 5 to The amount of drug in the core will depend on the dose 30 60:40 , preferably from 80:20 to 65:35 . that is required , and typically varies from about 5 to 90 In some embodiments , AMBERLITETM IRP69 resin is weight % . Generally , the polymeric coating on the active used as an extended -release carrier . AMBERLITETM IRP69 core will be from about 1 to 50 % based on the weight of the is an insoluble , strongly acidic , sodium form cation coated particle , depending on the lag time and type of exchange resin that is suitable as carrier for cationic (basic ) release profile required and /or the polymers and coating 35 substances . In other embodiments, DUOLITETM AP143 / solvents chosen . Those skilled in the art will be able to select 1093 resin is used as an extended - release carrier. DUO an appropriate amount of drug for coating onto or incorpo LITETM AP143 /1093 is an insoluble , strongly basic , anion rating into the core to achieve the desired dosage. In one exchange resin that is suitable as a carrier for anionic embodiment, the inactive core may be a sugar sphere , or a ( acidic ) substances . buffer crystal or an encapsulated buffer crystal such as 40 When used as a drug carrier , AMBERLITE IRP69 or /and calcium carbonate , sodium bicarbonate , fumaric acid , tar DUOLITETM AP143/ 1093 resin provides a means for bind taric acid , etc. which alters the microenvironment of the ing medicinal agents onto an insoluble polymeric matrix . drug to facilitate its release . Extended -release is achieved through the formation of resin In some embodiments , for example , delayed - release or drug complexes (drug resinates ). The drug is released from delayed - extended -release compositions may formed by 45 the resin in vivo as the drug reaches equilibrium with the coating a water soluble /dispersible drug - containing particle , high electrolyte concentrations, which are typical of the such as a bead , with a mixture of a water insoluble polymer gastrointestinal tract. More hydrophobic drugs will usually and an enteric polymer , wherein the water insoluble polymer elute from the resin at a lower rate , owing to hydrophobic and the enteric polymer may be present at a weight ratio of interactions with the aromatic structure of the cation from 4 :1 to 1: 1, and the total weight of the coatings is 10 to 50 exchange system . 60 weight % based on the total weight of the coated beads. Most enteric coatings work by presenting a surface that is The drug layered beads may optionally include an inner stable at the highly acidic pH found in the stomach , but dissolution rate controlling membrane of ethylcellulose . The breaks down rapidly at a less acidic ( relatively more basic ) composition of the outer layer, as well as the individual pH . Therefore , an enteric coated pill will not dissolve in the weights of the inner and outer layers of the polymeric 55 acidic juices of the stomach (pH ~ 3 ), but they will in the membrane are optimized for achieving desired circadian alkaline (pH 7-9 ) environment present in the small intestine . rhythm release profiles for a given active , which are pre Examples of enteric coating materials include, but are not dicted based on in vitro / in vivo correlations. limited to , methyl acrylate -methacrylic acid copolymers , In other embodiments the formulations may comprise a cellulose acetate succinate , hydroxy propyl methyl cellulose mixture of immediate - release drug - containing particles 60 phthalate , hydroxy propyl methyl cellulose acetate succinate without a dissolution rate controlling polymer membrane (hypromellose acetate succinate ), polyvinyl acetate phtha and delayed - extended -release beads exhibiting , for example , late (PVAP ) , methyl methacrylate -methacrylic acid copoly a lag time of 2-4 hours following oral administration , thus mers, sodium alginate and stearic acid . In some embodi providing a two- pulse release profile . ments , the pharmaceutical composition is formulated for In some embodiments , the active core is coated with one 65 oral administration . Oral dosage forms include , for example , or more layers of dissolution rate -controlling polymers to tablets , capsules, caplets , and may also comprise a plurality obtain desired release profiles with or without a lag time. An of granules , beads, powders or pellets that may or may not US 10,596,127 B2 27 28 be encapsulated . Tablets and capsules represent the most In some embodiments , the pharmaceutical composition convenient oral dosage forms, in which case solid pharma comprises one or more analgesics and one or more 5a -re ceutical carriers are employed . ductase inhibitors. In another embodiment, the pharmaceu In a delayed - release formulation , one or more barrier tical composition comprises ( 1) one or more analgesics , ( 2) coatings may be applied to pellets , tablets , or capsules to 5 one or more 5a -reductase inhibitors, and ( 3 ) one or more facilitate slow dissolution and concomitant release of drugs antimuscarinic agents . In another embodiment , the pharma into the intestine. Typically , the barrier coating contains one ceutical composition comprises ( 1 ) one or more analgesics, or more polymers encasing, surrounding , or forming a layer, ( 2 ) one or more 5a - reductase inhibitors and ( 3 ) one or more or membrane around the therapeutic composition or active antidiuretics. In another embodiment , the pharmaceutical core . 10 composition comprises ( 1 ) one or more analgesics, (2 ) one In some embodiments , the active agents are delivered in or more 5a - reductase inhibitors, and ( 3 ) one or more spas a formulation to provide delayed -release at a pre -determined molytics. In another embodiment , the pharmaceutical com time following administration. The delay may be up to about position comprises ( 1 ) one or two analgesics , ( 2 ) one or 10 minutes, about 20 minutes, about 30 minutes , about 1 more 5a -reductase inhibitors , ( 3 ) one or two antimuscarinic hour, about 2 hours, about 3 hours , about 4 hours, about 5 15 agents , and (4 ) one or two antidiuretics . In another embodi hours, about 6 hours , or longer. ment , the pharmaceutical composition comprises ( 1 ) one or Various coating techniques may be applied to granules, more analgesics , ( 2) one or more 5a - reductase inhibitors , (3 ) beads, powders or pellets , tablets , capsules or combinations one or more spasmolytics agents , and ( 4 ) one or more thereof containing active agents to produce different and antidiuretics . distinct release profiles . In some embodiments , the pharma- 20 In another embodiment, the pharmaceutical composition ceutical composition is in a tablet or capsule form containing comprises ( 1 ) one or more analgesics , ( 2 ) one or more a single coating layer. In other embodiments , the pharma 5a - reductase inhibitors , and ( 3 ) one or more a -blockers . In ceutical composition is in a tablet or capsule form containing another embodiment, the pharmaceutical composition com multiple coating layers . prises ( 1 ) one or more analgesics , ( 2 ) one or more 5a -re In some embodiments , the pharmaceutical composition 25 ductase inhibitors , (3 ) one or more a -blockers and (4 ) one or comprises one or more analgesics, one or more a -blockers , more antidiuretics . In another embodiment, the pharmaceu and one or more other active ingredients selected from the tical composition comprises (1 ) one or more analgesics, (2 ) group consisting of antimuscarinic agents , antidiuretics and one or more 5a -reductase inhibitors , ( 3 ) one or more spasmolytics. In some embodiments , the pharmaceutical a -blockers and ( 4 ) one or more spasmolytics. In another composition comprises one or more analgesics, one or more 30 embodiment , the pharmaceutical composition comprises ( 1 ) 5a - reductase inhibitors , and one or more other active ingre one or two analgesics, ( 2 ) one or more 5a -reductase inhibi dients selected from the group consisting of antimuscarinic tors , ( 3 ) one or two antimuscarinic agents , ( 4 ) one or two agents , antidiuretics, a -blockers and spasmolytics. antidiuretics and (5 ) one or more a -blockers . In another Examples of antimuscarinic agents include, but are not embodiment, the pharmaceutical composition comprises ( 1 ) limited to , oxybutynin , solifenacin , darifenacin and atropine. 35 one or more analgesics, ( 2 ) one or more 5a - reductase Examples of antidiuretics include, but are not limited to , inhibitors , ( 3 ) one or more spasmolytics agents , ( 4 ) one or antidiuretic hormone (ADH ), angiotensin II , aldosterone, more antidiuretics, and (5 ) one or more a -blockers . vasopressin , vasopressin analogs ( e.g., desmopressin argi In one embodiment, the plurality of active ingredients are pressin , lypressin , felypressin , ornipressin , terlipressin ; formulated for immediate -release . In other embodiment, the vasopressin receptor agonists , atrial natriuretic peptide 40 plurality of active ingredients are formulated for extended ( ANP ) and C - type natriuretic peptide (CNP ) receptor (i.e. , release . In other embodiment , the plurality of active ingre NPR1, NPR2 , NPR3 ) antagonists ( e.g., HS - 142-1 , isatin , dients are formulated for both immediate - release and [Asu7,23 ' ]b -ANP- ( 7-28 )] , anantin , a cyclic peptide from extended -release ( e.g., a first portion of each active ingre Streptomyces coerulescens, and 3G12 monoclonal anti dient is formulated for immediate -release and a second body ); somatostatin type 2 receptor antagonists (e.g. , soma- 45 portion of each active ingredient is formulated for extended tostatin ) , and pharmaceutically - acceptable derivatives, ana release ). In yet other embodiment, some of the plurality of logs, salts , hydrates , and solvates thereof . Examples of active ingredients are formulated for immediate -release and spasmolytics include, but are not limited to , carisoprodol, someof the plurality of active ingredients are formulated for benzodiazepines , baclofen , cyclobenzaprine , metaxalone, extended -release ( e.g. , active ingredients A , B , C are for methocarbamol, clonidine , clonidine analog , and dantrolene . 50 mulated for immediate - release and active ingredients C and In some embodiments , the pharmaceutical composition D are formulated for extended - release ). In some other comprises one or more analgesics and one or more a -block embodiments , the immediate -release component and/ or the ers . In another embodiment, the pharmaceutical composition extended -release component is further coated with a comprises ( 1 ) one or more analgesics , ( 2 ) one or more delayed - release coating, such as an enteric coating. a -blockers , and ( 3 ) one or more antimuscarinic agents . In 55 In certain embodiments , the pharmaceutical composition another embodiment, the pharmaceutical composition com comprises an immediate -release component and an prises (1 ) one or more analgesics , (2 ) one or more a -block extended -release component. The immediate -release com ers and (3 ) one or more antidiuretics. In another embodi ponent may comprise one or more active ingredients ment, the pharmaceutical composition comprises ( 1 ) one or selected from the group consisting of analgesics, a -blockers , more analgesics, ( 2 ) one or more a -blockers , and ( 3 ) one or 60 5a - reductase inhibitors , antimuscarinic agents , antidiuretics more spasmolytics . In another embodiment , the pharmaceu and spasmolytics . The extended - release component may tical composition comprises ( 1 ) one or two analgesics, ( 2 ) comprise one or more active ingredients selected from the one or more a - blockers , ( 3 ) one or two antimuscarinic group consisting of analgesics , a -blockers , antimuscarinic agents , and ( 4 ) one or two antidiuretics . In another embodi agents , antidiuretics and spasmolytics . In some embodi ment, the pharmaceutical composition comprises ( 1) one or 65 ments, the immediate -release component and the extended more analgesics, ( 2 ) one or more a -blockers , ( 3 ) one or release component have exactly the same active ingredients . more spasmolytics agents , and (4 ) one ormore antidiuretics . In other embodiments , the immediate -release component US 10,596,127 B2 29 30 and the extended - release component have different active An immediate - release composition may comprise 100 % ingredients . In yet other embodiments , the immediate - re of the total dosage of a given active agent administered in a lease component and the extended - release component have single unit dose . Alternatively , an immediate - release com one or more common active ingredients . In some other ponent may be included as a component in a combined embodiments , the immediate -release component and /or the 5 release profile formulation that may provide about 1 % to extended - release component is further coated with a about 60 % of the total dosage of the active agent ( s ) to be delayed -release coating, such as an enteric coating . delivered by the pharmaceutical formulation . For example , In one embodiment, the pharmaceutical composition the immediate -release component may provide about comprises two or more active ingredients ( e.g., a mixture of 5 % -60 % , about 10 % to about 60 % , about 10 % to about one or more analgesic agents , and one or more a -blockers , 10 50 % , about 10 % to about 40 % , about 10 % to about 30 % , one or more 5a - reductase inhibitors , one or more antimus about 10 % to about 20 % , about 20 % to about 60 % , about carinic agents or antidiuretics or spasmolytics ), formulated 20 % to about 50 % , about 20 % to about 30 % , about 30 % to for immediate - release at about the same time . In another about 60 % , about 30 % to about 50 % , about 40 % to about embodiment, the pharmaceutical composition comprises 60 % , about 40 % to about 50 % , about 45 % to about 60 % or two or more active ingredients , formulated for extended- 15 about 45 % to about 50 % of the total dosage of the active release at about the same time . In another embodiment, the agent( s ) to be delivered by the formulation . In alternate pharmaceutical composition comprises two or more active embodiments , the immediate - release component provides ingredients formulated as two extended - release components , about 2 , 4 , 5 , 10 , 15 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 55 or 60 % each providing a different extended -release profile . For of the total dosage of the active agent( s ) to be delivered by example , a first extended - release component releases a first 20 the formulation . active ingredient at a first release rate and a second In some embodiments , the immediate - release or delayed extended -release component releases a second active ingre release formulation comprises an active core comprised of dient at a second release rate . In another embodiment, the one or more inert particles, each in the form of a bead , pellet , pharmaceutical composition comprises two or more active pill, granular particle , microcapsule, microsphere, micro ingredients , both formulated for delayed release . In another 25 granule , nanocapsule , or nanosphere coated on its surfaces embodiment, the pharmaceutical composition comprises with drugs in the form of e.g. , a drug - containing film two or more active ingredients formulated for delayed forming composition using, for example , fluid bed tech release. In another embodiment, the pharmaceutical compo niques or other methodologies known to those of skill in the sition comprises two or more active ingredients formulated art . The inert particle can be of various sizes , so long as it as two delayed - release components, each providing a dif- 30 is large enough to remain poorly dissolved . Alternatively , ferent delayed - release profile . For example , a first delayed the active core may be prepared by granulating and milling release component releases a first active ingredient at a first and /or by extrusion and spheronization of a polymer com time point and a second delayed - release component releases position containing the drug substance . a second active ingredient at a second time point. In another The amount of drug in the core will depend on the dose embodiment, the pharmaceutical composition comprises 35 that is required , and typically varies from about 5 to 90 two or more active ingredients , one or more of which are weight % . Generally , the polymeric coating on the active formulated for immediate - release and the others are formu core will be from about 1 to 50 % based on the weight of the lated for extended -release . In another embodiment, the phar coated particle , depending on the lag time and type of maceutical composition comprises two or more active ingre release profile required and /or the polymers and coating dients , a fraction of which is formulated for immediate- 40 solvents chosen . Those skilled in the art will be able to select release and the remainder is formulated for extended an appropriate amount of drug for coating onto or incorpo release . rating into the core to achieve the desired dosage . In one In some embodiments , the pharmaceutical composition embodiment, the inactive core may be a sugar sphere or a comprises one or more analgesic agents , and one or more buffer crystal or an encapsulated buffer crystal such as a -blockers , 5c -reductase inhibitors, an antidiuretic , wherein 45 calcium carbonate, sodium bicarbonate , fumaric acid , tar the one or more analgesic agents and one ormore a - blockers taric acid , etc. which alters the microenvironment of the are formulated for delayed release and wherein the antidi drug to facilitate its release . uretic is formulated for immediate release . In other embodi In some embodiments , the delayed - release formulation is ments , the pharmaceutical composition further comprises an formed by coating a water soluble /dispersible drug -contain additional agent selected from the group consisting of an 50 ing particle , such as a bead , with a mixture of a water analgesic agent, a -blocker , a 5a -reductase inhibitor, an insoluble polymer and an enteric polymer, wherein the water antimuscarinic agent, an antidiuretic agent and a spasmo insoluble polymer and the enteric polymer may be present at lytic , wherein the additional agent is formulated for delayed a weight ratio of from 4 : 1 to 1 : 1 , and the total weight of the release . In some embodiments , the delayed release formu coatings is 10 to 60 weight % based on the total weight of lation delays the release of the active ingredient for a period 55 the coated beads. The drug layered beads may optionally of 1 , 2 , 3 , 4 or 5 hours . include an inner dissolution rate controlling membrane of The term " immediate -release ” is used herein with refer ethylcellulose. The composition of the outer layer, as well as ence to a drug formulation that does not contain a dissolution the individual weights of the inner and outer layers of the rate controlling material. There is substantially no delay in polymeric membrane are optimized for achieving desired the release of the active agents following administration of 60 circadian rhythm release profiles for a given active, which an immediate -release formulation . An immediate -release are predicted based on in vitro / in vivo correlations. coating may include suitable materials immediately dissolv In other embodiments the formulations comprise a mix ing following administration so as to release the drug ture of immediate - release drug - containing particles without contents therein . Exemplary immediate -release coating a dissolution rate controlling polymer membrane and materials include gelatin , polyvinyl alcohol polyethylene 65 delayed - release beads exhibiting, for example , a lag time of glycol (PVA -PEG ) copolymers ( e.g. , KOLLICOAT® ) and 2-4 hours following oral administration , thus providing a various others materials known to those skilled in the art. two - pulse release profile . In yet other embodiments the US 10,596,127 B2 31 32 formulations comprise a mixture of two types of delayed day to about 50 mg/ kg body weight/ day, 1 mg/ kg body release beads : a first type that exhibits a lag time of 1-3 hours weight/ day to about 10 mg/ kg body weight /day , 5 mg/kg and a second type that exhibits a lag time of 4-6 hours . body weight/ dose to about 100 mg/ kg body weight/ day , 5 Preferably, the formulations are designed with release mg/ kg body weight/ dose to about 50 mg/ kg body weight/ profiles to limit interference with restful sleep , wherein the 5 day , 10 mg/ kg body weight/ day to about 100 mg/ kg body formulation releases the medicine when the individual weight/ day , and 10 mg/ kg body weight/ day to about 50 would normally be awakened by an urge to urinate . For mg/ kg body weight/ day . example , consider an individual who begins sleeping at 11 The active agent( s ) described herein may be included in PM and is normally awakened at 12:30 AM , 3:00 AM , and an immediate- release component or an extended -release 6:00 AM to urinate . A delayed , extended -release vehicle 10 component, a delayed -extended -release component or com could be taken at 10 PM and start delivering the medicine at binations thereof for daily oral administration at a single 12 AM and gradually release the medicine over a period of dose or combined dose range of 1 mg to 2000 mg, 5 mg to 5-8 hours , thereby delaying or eliminating the need to 2000 mg, 10 mg to 2000 mg, 50 mg to 2000 mg, 100 mg to urinate . In other embodiments , the formulations are 2000 mg, 200 mg to 2000 mg, 500 mg to 2000 mg, 5 mg to designed with a release profile that a fraction of themedicine 15 1800 mg, 10 mg to 1600 mg, 50 mg to 1600 mg, 100 mg to ( e.g. , 20-60 % ) is released immediately or within 2 hours of 1500 mg , 150 mg to 1200 mg, 200 mg to 1000 mg, 300 mg administration and the rest is released over an extended to 800 mg, 325 mg to 500 mg, 1 mg to 1000 mg , 1 mg to period of time. The pharmaceutical composition may be 500 mg, 1 mg to 200 mg, 5 mg to 1000 mg, 5 mg to 500 mg, administered daily or administered on an as needed basis . In 5 mg to 200 mg, 10 mg to 1000 mg, 10 mg to 500 mg, 10 certain embodiments , the pharmaceutical composition is 20 mg to 200 mg, 50 mg to 1000 mg, 50 mg to 500 mg, 50 mg administered to the subject prior to bedtime. In some to 200 mg, 250 mg to 1000 mg , 250 mg to 500 mg, 500 mg embodiments , the pharmaceutical composition is adminis to 1000 mg, 500 mg to 2000 mg. As expected , the dosage tered immediately before bedtime. In some embodiments , will be dependent on the weight, size , age and condition of the pharmaceutical composition is administered within the patient. about two hours before bedtime, preferably within about one 25 In some embodiments , the pharmaceutical composition hour before bedtime. In another embodiment, the pharma comprises a single analgesic agent, and one or more ceutical composition is administered about two hours before a -blockers or one or more 5a -reductase inhibitors . In one bedtime . In a further embodiment, the pharmaceutical com embodiment, the single analgesic agent is aspirin . In another position is administered at least two hours before bedtime. embodiment, the single analgesic agent is ibuprofen . In In another embodiment, the pharmaceutical composition is 30 another embodiment, the single analgesic agent is naproxen administered about one hour before bedtime. In a further or naproxen sodium . In another embodiment, the single embodiment, the pharmaceutical composition is adminis analgesic agent is indomethacin . In another embodiment, the tered at least one hour before bedtime . In a still further single analgesic agent is nabumetone . In another embodi embodiment, the pharmaceutical composition is adminis ment , the single analgesic agent is acetaminophen . In tered less than one hour before bedtime. In still another 35 another embodiment , the single analgesic agent is acet embodiment, the pharmaceutical composition is adminis aminophen and the one or more a - blockers comprise tam tered immediately before bedtime. Preferably , the pharma sulosin . In another embodiment, the single analgesic agent is ceutical composition is administered orally . Suitable com acetaminophen and the one or more 5a -reductase inhibitors positions for oral administration include, but are not limited comprise finasteride. to : tablets , coated tablets , dragees, capsules , powders , granu- 40 In some embodiments , the single analgesic agent is given lates and soluble tablets , and liquid forms, for example , at a daily dose of 1 mg to 2000 mg, 5 mg to 2000 mg, 20 mg suspensions, dispersions or solutions . to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 mg to The appropriate dosage (" therapeutically effective 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to amount” ) of the active agent ( s ) in the immediate - release 1000 mg or 500 mg to 1000 mg. In certain embodiments , the component or the extended - release component will depend , 45 pharmaceutical composition comprises acetylsalicylic acid , for example , on the severity and course of the condition , the ibuprofen , naproxen , naproxen sodium , indomethancin , mode of administration , the bioavailability of the particular nabumetone or acetaminophen as a single analgesic agent agent( s ) , the age and weight of the patient, the patient's and the analgesic agent is administered orally at a daily dose clinical history and response to the active agent( s ) , discre in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg tion of the physician , etc. 50 to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg As a general proposition , the therapeutically effective to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg or 500 amount of the active agent( s) in the immediate - release mg to 1000 mg. In some embodiments , a second analgesic component, the extended -release component or the delayed agent is given at a daily dose of 1 mg to 2000 mg, 5 mg to extended - release component is administered in the range of 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to about 100 ug /kg body weight/ day to about 100 mg/ kg body 55 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to weight/ day whether by one ormore administrations. In some 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg. embodiments , the range of each active agent administered In other embodiments , the pharmaceutical composition daily in a single dose or in multiple does is from about 100 comprises a pair of analgesic agents and one or more ug/ kg body weight/ day to about 50 mg/kg body weight/ day, a -blockers . Examples of such paired analgesic agents 100 ug /kg body weight/ day to about 10 mg/ kg body weight/ 60 include , but are not limited to , acetylsalicylic acid and day , 100 ug /kg body weight/ day to about 1 mg/ kg body ibuprofen , acetylsalicylic acid and naproxen sodium , ace weight/ day, 100 ug /kg body weight/ day to about 10 mg/kg tylsalicylic acid and nabumetone , acetylsalicylic acid and body weight/ day , 500 ug/ kg body weight/ day to about 100 acetaminophen , acetylsalicylic acid and indomethancin , ibu mg/ kg body weight/ day , 500 ug/ kg body weight/ day to about profen and naproxen sodium , ibuprofen and nabumetone , 50 mg /kg body weight/ day , 500 ug/ kg body weight/ day to 65 ibuprofen and acetaminophen , ibuprofen and indomethan about 5 mg/ kg body weight/ day , 1 mg/ kg body weight/ day cin , naproxen , naproxen sodium and nabumetone , naproxen to about 100 mg/ kg body weight/ day , 1 mg/ kg body weight/ sodium and acetaminophen , naproxen sodium and indo US 10,596,127 B2 33 34 methancin , nabumetone and acetaminophen , nabumetone is aspirin . In another embodiment , the single analgesic agent and indomethancin , and acetaminophen and indomethancin . is ibuprofen . In another embodiment, the single analgesic The paired analgesic agents are mixed at a weight ratio in the agent is naproxen or naproxen sodium . In another embodi range of 0.1 : 1 to 10 : 1 , 0.2 : 1 to 5 : 1 or 0.3 : 1 to 3 : 1 , with a ment, the single analgesic agent is indomethacin . In another combined dose in the range of 5 mg to 2000 mg, 20 mg to 5 embodiment , the single analgesic agent is nabumetone . In 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg another embodiment, the single analgesic agent is acet to 2000 mg, 5 mg to 1500 mg, 20 mg to 1500 mg, 100 mg aminophen . In another embodiment, the single a - blocker is to 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg tamsulosin . The analgesic agent, a -blocker , 5a - reductase to 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg inhibitor and antimuscarinic agent may be given at doses in to 500 mg, 250 mg to 1000 mg, 250 mg to 1500 mg, 500 mg 10 the ranges described above . In some embodiments , the to 1000 mg, 500 mg to 1500 mg, 1000 mg to 1500 mg, and pharmaceutical composition further comprises an antidi 1000 mg to 2000 mg. In one embodiment, the paired uretic agent or a spasmolytic . analgesic agents are mixed at a weight ratio of 1 : 1 . In some embodiments , the pharmaceutical composition sitionIn some of the other present embodiments application , the further pharmaceutical comprises compoone or 15 comprises one or more analgesic agents , individually or in more antimuscarinic agents . Examples of the antimuscarinic combination , in an amount between 50-2000 mg, 50-1500 agents include, but are not limited to , oxybutynin , solifena mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, cin , darifenacin , fesoterodine , tolterodine, trospium and 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, atropine. The daily dose of antimuscarinic agent is in the 50-150 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100 range of 0.01 mg to 100 mg, 0.1 mg to 100 mg, 1 mg to 100 20 1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 10 mg to 100 mg, 0.01 mg to 25 mg, 0.1 mg to 25 mg, mg, 100-250 mg, 250-2000 mg, 250-1500 mg, 250-1200 1 mg to 25 mg, 10 mg to 25 mg , 0.01 mg to 10 mg, 0.1 mg mg, 250-1000 mg, 250-800 mg, 250-600 mg, 250-400 mg, to 10 mg, 1 mg to 10 mg, 10 mg to 100 mg and 10 mg to 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 25 mg 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, In certain embodiments , the pharmaceutical composition 25 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, comprises one or more a -blockers , an analgesic agent 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, selected from the group consisting of cetylsalicylic acid , 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 ibuprofen , naproxen , naproxen sodium , nabumetone, acet mg or 1500-2000 mg, wherein the composition is formu aminophen and indomethancin , and an antimuscarinic agent lated for extended release with a release profile in which the selected from the group consisting of oxybutynin , solifena- 30 one or more analgesic agents are released continuously over cin , darifenacin and atropine . a period of 5-24 hours , 5-8 , 8-16 hours or 16-24 hours. Another aspect of the present application relates to a In some embodiments , the composition is formulated for method for reducing the frequency of urination by admin extended release with a release profile in which at least 90 % istering to a person in need thereof a pharmaceutical com of the active ingredients are released continuously over a position formulated in an immediate- release formulation . 35 period of 5-24 hours , 5-8 , 8-16 hours or 16-24 hours. The pharmaceutical composition comprises one or more In some embodiments , the composition is formulated for analgesic agents and one or more additional active ingredi extended release with a release profile in which the active ents selected from the group consisting of 5a - reductase ingredients are released continuously over a period of 5 , 6 , inhibitors , a -blockers , antimuscarinic agents , antidiuretic 7 , 8 , 10 , 12 , 14 , 16 , 18 , 20 , 22 or 24 hours . agents and spasmolytics . The pharmaceutical composition 40 In other embodiments , the composition is formulated for may be formulated into a tablet , capsule , dragee, powder, extended release with a release profile in which the active granulate , liquid , gel or emulsion form . Said liquid , gel or ingredients and are released at a steady rate over a period of emulsion may be ingested by the subject in naked form or 5-24 hours , 5-8 , 8-16 hours or 16-24 hours . In other embodi contained within a capsule. ments , the composition is formulated for extended release In certain embodiments , the analgesic agent is selected 45 with a release profile in which the active ingredients are from the group consisting of salicylates , aspirin , salicylic released at a steady rate over a period of 5 , 6 , 7 , 8 , 10 , 12 , acid , methyl salicylate , diflunisal , salsalate , olsalazine , sul 14 , 16 , 18 , 20 , 22 or 24 hours. As used herein , “ a steady rate fasalazine , para - aminophenol derivatives , acetanilide , acet over a period of time ” is defined as a release profile in which aminophen, phenacetin , fenamates , mefenamic acid , the release rate at any point during a given period of time is meclofenamate , sodium meclofenamate , heteroaryl acetic 50 within 30 % -300 % of the average release rate over that given acid derivatives , tolmetin , ketorolac, diclofenac, propionic period of time . For example , if 80 mg of aspirin is released acid derivatives, ibuprofen , naproxen sodium , naproxen , at a steady rate over a period of 8 hours , the average release fenoprofen , ketoprofen , flurbiprofen , oxaprozin ; enolic rate is 10 mg/ hr during this period of time and the actual acids, oxicam derivatives, piroxicam , meloxicam , tenoxi release rate at any time during this period is within the range cam , ampiroxicam , droxicam , pivoxicam , pyrazolon deriva- 55 of 3 mg/ hr to 30 mg/ hr (i.e. , within 30 % -300 % of the tives, phenylbutazone , oxyphenbutazone , antipyrine, amin average release rate of 10 mg/ hr during the 8 hour period ). opyrine , dipyrone , coxibs , celecoxib , rofecoxib , In some embodiments , the analgesic agent is selected nabumetone, apazone, nimesulide, indomethacin , sulindac , from the group consisting of aspirin , ibuprofen , naproxen etodolac , diflunisal and isobutylphenyl propionic acid . The sodium , naproxen , indomethacin , nabumetone and acet antimuscarinic agent is selected from the group consisting of 60 aminophen . The pharmaceutical composition is formulated oxybutynin , solifenacin , dari fenacin and atropine . to provide a steady release of small amount of the analgesic In some embodiments , the pharmaceutical composition agent to maintain an effective drug concentration in the comprises a single analgesic agent, a single a -blocker and a blood such that the overall amount of the drug in a single single antimuscarinic agent. In some embodiments , the dosage is reduced compared to the immediate release for pharmaceutical composition comprises a single analgesic 65 mulation . The other active ingredients may be released agent, a single 5a - reductase inhibitor and a single antimus immediately after administration or released with the anal carinic agent. In one embodiment, the single analgesic agent gesic agent. US 10,596,127 B2 35 36 In some embodiments , the pharmaceutical composition profile in which 20 , 30 , 40 or 50 % of the analgesic agent( s ) comprises 50-400 mg, 50-250 mg, 250-400 mg or 400-600 are released within 2 hours of administration and the remain mg of an analgesic agent formulated for extended release der are released continuously , or at a steady rate , over a with a release profile in which at least 90 % of the analgesic period of 5-8 , 8-16 or 16-24 hours. In one embodiment, the agent is released continuously , or at a steady rate , over a 5 analgesic agent( s ) are selected from the group consisting of period of 5-8 , 8-16 or 16-24 hours . The other active ingre aspirin , ibuprofen , naproxen sodium , naproxen , indometha dients may be released immediately after administration or cin , nabumetone and acetaminophen . In another embodi released with the analgesic agent. ment, the analgesic agent is acetaminophen . In some In one particular embodiment, the pharmaceutical com embodiments , the pharmaceutical composition further com position comprises 50-250 mg of acetaminophen formulated 10 prises an antimuscarinic agent, an antidiuretic agent or a for extended release with a release profile in which at least spasmolytic . The other active ingredients may be released 90 % of acetaminophen is released continuously , or at a immediately after administration or released with the anal steady rate , over a period of 5-8 , 8-16 or 16-24 hours. The gesic agent. other active ingredients may be released immediately after In another embodiment, the pharmaceutical composition administration or released with the analgesic agent. 15 comprises 50-400 mg of acetaminophen formulated for In another particular embodiment, the pharmaceutical extended release with a two -phase release profile in which composition comprises 250-400 mg of acetaminophen for 20 % , 30 % , 40 % or 50 % of the acetaminophen is released mulated for extended release with a release profile in which within 2 hours of administration and the remainder is 90 % of acetaminophen is released continuously , or at a released continuously , or at a steady rate , over a period of steady rate over a period of 5-8 , 8-16 or 16-24 hours . The 20 5-8 , 8-16 or 16-24 hours . The other active ingredients may other active ingredients may be released immediately after be released immediately after administration or released administration or released with the analgesic agent . with the analgesic agent. In another particular embodiment, the pharmaceutical In another embodiment, the pharmaceutical composition composition comprises 400-600 mg of acetaminophen for comprises 100-300 mg of acetaminophen formulated for mulated for extended release with a release profile in which 25 extended release with a two -phase release profile in which 90 % of acetaminophen is released continuously , or at a 20 % , 30 % , 40 % or 50 % of the acetaminophen is released steady rate over a period of 5-8 , 8-16 or 16-24 hours . The within 2 hours of administration and the remainder is other active ingredients may be released immediately after released at a steady rate over a period of 5-8 , 8-16 or 16-24 administration or released with the analgesic agent. hours . The other active ingredients may be released imme In another particular embodiment, the pharmaceutical 30 diately after administration or released with the analgesic composition comprises 600-800 mg of acetaminophen for agent. mulated for extended release with a release profile in which In another embodiment, the pharmaceutical composition 90 % of acetaminophen is released continuously , or at a comprises 400-600 mg of acetaminophen formulated for steady rate over a period of 5-8 , 8-16 or 16-24 hours. The extended release with a two -phase release profile in which other active ingredients may be released immediately after 35 20 % , 30 % , 40 % or 50 % of the acetaminophen is released administration or released with the analgesic agent. within 2 hours of administration and the remainder is In yet another embodiment, the pharmaceutical compo released continuously , or at a steady rate , in a period of 5-8 , sition comprises 800-1000 mg of acetaminophen formulated 8-16 or 16-24 hours . The other active ingredients may be for extended release with a release profile in which at least released immediately after administration or released with 90 % of acetaminophen is released continuously , or at a 40 the analgesic agent. steady rate over a period of 5-8 , 8-16 or 16-24 hours . The In another embodiment, the pharmaceutical composition other active ingredients may be released immediately after comprises 600-800 mg of acetaminophen formulated for administration or released with the analgesic agent. extended release with a two- phase release profile in which In some other embodiments , the pharmaceutical compo 20 % , 30 % , 40 % or 50 % of the acetaminophen is released sition comprises one or more analgesic agent( s) , individu- 45 within 2 hours of administration and the remainder is ally or in combination , in an amount between 50-2000 mg, released continuously , or at a steady rate , in a period of 5-8 , 50-1500 mg, 50-1200 mg , 50-1000 mg, 50-800 mg 50-600 8-16 or 16-24 hours. The other active ingredients may be mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 released immediately after administration or released with mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 the analgesic agent. mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 50 In another embodiment, the pharmaceutical composition 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, comprises 800-1000 mg of acetaminophen formulated for 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, extended release with a two -phase release profile in which 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 20 % , 30 % , 40 % or 50 % of the acetaminophen is released 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, within 2 hours of administration and the remainder is 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 55 released continuously , or at a steady rate , in a period of 5-8 , 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 8-16 or 16-24 hours . The other active ingredients may be 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 released immediately after administration or released with mg, 1200-1500 mg or 1500-2000 mg, wherein the analgesic the analgesic agent. agent( s ) are formulated for extended release , characterized In another embodiment, the pharmaceutical composition by a two -phase release profile in which 20-50 % of the 60 comprises 1000-1200 mg of acetaminophen formulated for analgesic agent( s) are released within 2 hours of adminis extended release with a two -phase release profile in which tration and the remainder are released continuously , or at a 20 % , 30 % , 40 % or 50 % of the acetaminophen is released steady rate , over a period of 5-24 hours . The other active within 2 hours of administration and the remainder is ingredients may be released immediately after administra released continuously , or at a steady rate , in a period of 5-8 , tion or released with the analgesic agent. 65 8-16 or 16-24 hours . The other active ingredients may be In yet another embodiment, the analgesic agent( s ) is released immediately after administration or released with formulated for extended release with a two- phase release the analgesic agent. US 10,596,127 B2 37 38 Another aspect of the present application relates to a pharmaceutical composition may be formulated in immedi method for treating nocturia by administering to a subject in ate -release formulation or delayed -release formulation or need thereof (1 ) one or more analgesic agents , (2 ) an extended -release formulation . In some other embodiments , a - blocker or a 5a -reductase inhibitor or both , and ( 3 ) one or the second pharmaceutical composition further comprises more antidiuretic agents . In certain embodiments , the antidi- 5 one ormore antidiuretic agents . In some other embodiments , uretic agent ( s ) act to : ( 1 ) increase vasopressin secretion ; ( 2 ) the second pharmaceutical composition further comprises increase vasopressin receptor activation ; ( 3 ) reduce secre one or more spasmolytics. Another aspect of the present tion of atrial natriuretic peptide (ANP ) or C -type natriuretic application relates to a method for reducing the frequency of peptide ( CNP ) ; or ( 4 ) reduce ANP and /or CNP receptor urination by administering to a subject in need thereof, two activation . 10 Exemplary antidiuretic agents include, but are not limited or more analgesic agents alternatively to prevent the devel to , antidiuretic hormone (ADH ) , angiotensin II , aldosterone, opment of drug resistance. In one embodiment, the method vasopressin , vasopressin analogs ( e.g., desmopressin argi comprises administering a first analgesic agent for a first pressin , lypressin , felypressin , ornipressin , terlipressin ); period of time and then administering a second analgesic vasopressin receptor agonists, atrial natriuretic peptide 15 agent for a second period of time. In another embodiment , ( ANP) and C - type natriuretic peptide (CNP ) receptor (i.e. , themethod further comprises administering a third analgesic NPR1 , NPR2, NPR3 ) antagonists (e.g. , HS - 142-1, isatin , agent for a third period of time. The first, second and third [ Asu7,23 ' ] b -ANP- ( 7-28 ) ] , anantin , a cyclic peptide from analgesic agents are different from each other and at least Streptomyces coerulescens, and 3G12 monoclonal anti one of which is formulated for extended -release or delayed , body ) ; somatostatin type 2 receptor antagonists ( e.g. , soma- 20 extended - release. In one embodiment, the first analgesic tostatin ), and pharmaceutically -acceptable derivatives, ana agent is acetaminophen , the second analgesic agent is ibu logs, salts , hydrates , and solvates thereof. profen and the third analgesic agent is naproxen sodium . The In certain embodiments , the one or more analgesic agents , length of each period may vary depending on the subject's the a - blocker and / or the 5a -reductase inhibitor are formu response to each analgesic agent. In some embodiments , lated for extended release , and the one or more antidiuretic 25 each period lasts from 3 days to three weeks . In another agents are formulated for immediate release . In other embodiment, the first , second and third analgesic are all embodiments , the one or more analgesic agents , the formulated for extended - release or delayed , extended - re a -blocker and/ or the 5a - reductase inhibitor are formulated lease . for delayed release and the antidiuretic is formulated for Another aspect of the present application relates to a immediate release . In some embodiments , the delayed 30 pharmaceutical composition comprising a plurality of active release formulation delays the release of the active ingredi ingredients and a pharmaceutically acceptable carrier, ent ( e.g., the analgesic agent, antimuscarinic agent , antidi wherein at least one of the plurality of active ingredients is uretic agent and spasmolytic ) for a period of 1 , 2 , 3 , 4 or 5 formulated for extended -release or delayed , extended -re hours . lease . In some embodiments , the plurality of active ingre Another aspect of the present application relates to a 35 dients comprises one or more analgesics and one or more method for reducing the frequency of urination by admin antidiuretic agents. In other embodiments , the plurality of istering to a person in need thereof a first pharmaceutical active ingredients comprises one or more analgesics , one or composition comprising a diuretic , followed with a second more a -blockers , one or more 5a -reductase inhibitors and pharmaceutical composition comprising (1 ) one or more one or more antimuscarinic agents . In other embodiments , analgesic agents and ( 1 ) one or more a - blockers , one or 40 the plurality of active ingredients comprises one or more more 5a - reductase inhibitors , or both . The first pharmaceu analgesics , one or more a -blockers , one or more antidiuretic tical composition is dosed and formulated to have a diuretic agents and one or more antimuscarinic agent. In other effect within 6 hours of administration and is administered embodiments , the pharmaceutical composition comprises at least 8 or 7 hours prior to bedtime. The second pharma two different analgesics selected from the group consisting ceutical composition is administered within 2 hours prior to 45 of cetylsalicylic acid , ibuprofen , naproxen sodium , bedtime . The first pharmaceutical composition is formulated naproxen , nabumetone , acetaminophen and indomethancin . for immediate - release and the second pharmaceutical com In yet other embodiments , the pharmaceutical composition position is formulated for extended - release or delayed , comprises one analgesic selected from the group consisting extended -release . of cetylsalicylic acid , ibuprofen , naproxen sodium , nabume Examples of diuretics include, but are not limited to , 50 tone , acetaminophen and indomethancin ; one or more acidifying salts , such as CaCl , and NH4Cl; arginine vaso a -blockers and an antimuscarinic agent selected from the pressin receptor 2 antagonists , such as amphotericin B and group consisting of oxybutynin , solifenacin , darifenacin and lithium citrate ; aquaretics, such as Goldenrod and Junipe ; atropine . Na - H exchanger antagonists , such as dopamine; carbonic In other embodiments , the pharmaceutical composition of anhydrase inhibitors , such as acetazolamide and dorzol- 55 the present application further comprises one or more spas amide; loop diuretics, such as bumetanide, ethacrynic acid , molytics and / or one or more antidiuretics. Examples of furosemide and torsemide; osmotic diuretics, such as glu spasmolytics include , but are not limited to , carisoprodol, cose and mannitol; potassium - sparing diuretics , such as benzodiazepines, baclofen , cyclobenzaprine, metaxalone, amiloride, spironolactone , triamterene , potassium canreno methocarbamol, clonidine , clonidine analog, and dantrolene . ate ; thiazides , such as bendroflumethiazide and hydrochlo- 60 In some embodiments , the spasmolytics is used at a daily rothiazide ; and xanthines, such as caffeine , theophylline and dose of 1 mg to 1000 mg, 1 mg to 100 mg, 10 mg to 1000 theobromine . mg, 10 mg to 100 mg, 20 mg to 1000 mg, 20 mg to 800 mg, In some embodiments , the second pharmaceutical com 20 mg to 500 mg, 20 mg to 200 mg, 50 mg to 1000 mg, 50 position further comprises one or more antimuscarinic mg to 800 mg, 50 mg to 200 mg, 100 mg to 800 mg, 100 mg agents . Examples of the antimuscarinic agents include, but 65 to 500 mg, 200 mg to 800 mg, and 200 mg to 500 mg. The are not limited to , oxybutynin , solifenacin , darifenacin , spasmolytics may be formulated , alone or together with fesoterodine , tolterodine , trospium and atropine. The second other active ingredient( s ) in the pharmaceutical composi US 10,596,127 B2 39 40 tion , for immediate - release , extended - release , delayed - ex conventional media or agent is incompatible with the active tended - release or combinations thereof. ingredient , its use in the therapeutic compositions is con In some embodiments , the pharmaceutical composition templated . comprises one or more analgesic agents selected from the Another aspect of the present application relates to a group consisting of aspirin , ibuprofen , naproxen, naproxen 5 pharmaceutical composition that comprises a first compo sodium , indomethacin , nabumetone and acetaminophen in a nent having an immediate - release subcomponent and an total amount of 50-400 mg per agent, one or more a -block extended - release subcomponent, wherein the first compo ers and one or more antimuscarinic agents selected from the nent is formulated to release the subcomponents immedi group consisting of oxybutynin , solifenacin , darifenacin and ately after administration , and a second component com 10 prising an immediate -release subcomponent and an atropine in a total amount of 1-25 mg, wherein the pharma extended - release subcomponent, wherein the second com ceutical composition is formulated for extended release with ponent is formulated for a delayed -release of the subcom a two -phase release profile in which 20-60 % of the active ponents . In some embodiments , at least one of the subcom ingredients are released within 2 hours of administration , ponents in the first component or the second component and the remainder of the active ingredients are released 15 comprises an active ingredient comprising one or more continuously , or at a steady rate , in a period of 5-24 hours , analgesic agents , and at least one of the subcomponents in 5-8 hours, 8-16 hours or 16-24 hours . the first component or the second component comprises an In some embodiments , the pharmaceutical composition active ingredient comprising an a -blocker , a 5a - reductase comprises one or more analgesic agents selected from the inhibitor or both . group consisting of aspirin , ibuprofen , naproxen , naproxen 20 In some embodiments , each of the subcomponents in the sodium , indomethacin , nabumetone and acetaminophen in first component or the second component comprises an an amount of 50-400 mg per agent, one or more a - blockers active ingredient comprising one or more analgesic agents and one or more antidiuretic agents selected from the group and /or an a - blocker, and /or a 5a -reductase inhibitor . consisting of antidiuretic hormone (ADH ), angiotensin II , In some embodiments , the one or more analgesic agents aldosterone, vasopressin , vasopressin analogs ( e.g. , desmo- 25 are selected from the group consisting of aspirin , ibuprofen , pressin argipressin , lypressin , felypressin , ornipressin , terli naproxen , naproxen sodium , indomethacin , nabumetone , pressin ) ; vasopressin receptor agonists , atrial natriuretic and acetaminophen . peptide ( ANP ) and C -type natriuretic peptide ( CNP) recep In some related embodiments , the immediate -release sub tor (i.e. , NPR1, NPR2 , NPR3) antagonists (e.g. , HS -142-1 , component and the extended - release subcomponent in the isatin , [ Asu7,23' ] b - ANP- ( 7-28 ) ] , anantin , a cyclic peptide 30 first component each comprises an active ingredient com from Streptomyces coerulescens, and 3G12 monoclonal prising one or more analgesic agents , and /or an a -blocker , antibody ) ; somatostatin type 2 receptor antagonists ( e.g. , and / or a 5a - reductase inhibitor. In other embodiments , the somatostatin ) , and pharmaceutically -acceptable derivatives , immediate - release subcomponent and the extended - release analogs , salts , hydrates , and solvates thereof, wherein the subcomponent in the second component each comprises an pharmaceutical composition is formulated for extended 35 active ingredient comprising one or more analgesic agents , release with a two -phase release profile in which 20-60 % of and / or an a - blocker , and / or a 5a -reductase inhibitor . the active ingredients are released within 2 hours of admin In some embodiments , the one or more analgesic agents istration , and the remainder are released continuously , or at comprise acetaminophen . In yet other embodiments , at least a steady rate, in a period of 5-24 hours , 5-8 hours, 8-16 hours one of the subcomponents in the first component or the or 16-24 hours . 40 second component comprises an active ingredient compris In some embodiments , the pharmaceutical composition ing one or more analgesic agents and an a -blocker . In yet comprises ( 1) one or more analgesic agents selected from other embodiments , at least one of the subcomponents in the the group consisting of aspirin , ibuprofen , naproxen , first component or the second component comprises an naproxen sodium , indomethacin , nabumetone and acet active ingredient comprising one or more analgesic agents aminophen in an amount of 50-400 mg per agent, ( 2 ) one or 45 and an 5a - reductase inhibitor. In yet other embodiments , at more a -blockers , or one or more 5a -reductase inhibitors , or least one of the subcomponents in the first component or the both , and ( 3 ) one or more spasmolytics selected from the second component comprises an active ingredient compris group consisting of carisoprodol, benzodiazepines , ing one or more analgesic agents, and an a -blocker and a baclofen , cyclobenzaprine , metaxalone, methocarbamol, 5a - reductase inhibitor . clonidine , clonidine analog , and dantrolene in a total amount 50 In some related embodiments , the second component is of 50-500 mg, wherein the pharmaceutical composition is coated with an enteric coating . formulated for extended release with a two- phase release In some related embodiments , the second component is profile in which 20-60 % of the active ingredients are formulated to release the subcomponents after a lag time of released within 2 hours of administration , and the remainder 0.1-12 hours, 0.5-12 hours, 1-12 hours , 2-12 hours, 1-4 are released continuously , or at a steady rate , in a period of 55 hours , 2-4 hours , 4-6 hours , 4-8 hours or 4-12 hours fol 5-24 hours , 5-8 hours , 8-16 hours or 16-24 hours . lowing oral administration . As used herein , " pharmaceutically acceptable carrier” In some related embodiments , the extended - release sub includes any and all solvents , dispersion media , coatings, component in the first component is formulated to release its antibacterial and antifungal agents , isotonic and absorption active ingredient over a time interval of about 2-10 hours . delaying agents, sweeteners and the like. The pharmaceuti- 60 In some related embodiments , the extended -release sub cally acceptable carriers may be prepared from a wide range component in the second component is formulated to release of materials including, but not limited to , flavoring agents , its active ingredient over a time interval of about 2-10 hours . sweetening agents and miscellaneous materials such as In some related embodiments , the active ingredient in the buffers and absorbents that may be needed in order to immediate - release subcomponent and the extended - release prepare a particular therapeutic composition . The use of 65 subcomponent in the first component further comprises an such media and agents with pharmaceutically active sub antimuscarinic agent. In some embodiments , the active stances is well known in the art . Except insofar as any ingredient in the immediate - release subcomponent and the US 10,596,127 B2 41 42 extended - release subcomponent in the second component subcomponent, wherein the second component is formulated further comprises an antimuscarinic agent. In some embodi to release its subcomponent after gastric emptying, wherein ments , the active ingredient in the immediate- release sub the immediate - release subcomponent and the extended - re component and the extended -release subcomponent in both lease subcomponent in the second component each com the first and the second component further comprises an 5 prises an active ingredient comprising one or more agents antimuscarinic agent. selected from the group consisting of analgesic agents , In some related embodiments , the active ingredient in the a -blockers and 5a - reductase inhibitors . immediate -release subcomponent and the extended - release In some related embodiments , the second component is subcomponent in the first component further comprises an formulated to release the subcomponents after a lag time of antidiuretic agent. In some embodiments , the active ingre- 10 2-12 hours , 2-4 hours , 2-6 hours, 2-8 hours or 4-8 hours dient in the immediate -release subcomponent and the following oral administration . extended - release subcomponent in the second component In some related embodiments , the active ingredient in the further comprises an antidiuretic agent. In some embodi immediate -release subcomponent and the extended - release ments , the active ingredient in the immediate- release sub subcomponent of the second component comprises one or component and the extended -release subcomponent in both 15 more analgesic agents . the first and the second component further comprises an In some related embodiments , the first component further antidiuretic agent. comprises an extended - release subcomponent, wherein the In some related embodiments , the active ingredient in the extended -release subcomponent comprises an active ingre immediate - release subcomponent and the extended - release dient comprising one or more agents selected from the group subcomponent in the first component further comprises a 20 consisting of analgesic agents, a - blockers and 5a - reductase spasmolytic . In some embodiments , the active ingredient in inhibitors. In some embodiments , the one or more agents the immediate - release subcomponent and the extended - re comprise an analgesic agent selected from the group con lease subcomponent in the second component further com sisting of aspirin , ibuprofen , naproxen , naproxen sodium , prises a spasmolytic . In some embodiments, the active indomethacin , nabumetone , and acetaminophen . ingredient in the immediate - release subcomponent and the 25 In some embodiments , the immediate - release subcompo extended - release subcomponent in both the first and the nent and the extended -release subcomponent in the second second component further comprises a spasmolytic . component each comprises tamsulosin . In some related In some related embodiments , the immediate -release sub embodiments, the immediate - release subcomponent and the component and the extended -release subcomponent in the extended - release subcomponent in the second component first component each comprises an analgesic agent, such as 30 each comprises finasteride . In some related embodiments , acetaminophen , in an amount of 5-2000 mg. In some the immediate -release subcomponent and the extended -re embodiments , the immediate - release subcomponent and the lease subcomponent in the second component each com extended - release subcomponent in the second component prises tamsulosin and finasteride . each comprises an analgesic agent, such as acetaminophen , In some related embodiments , at least one of the active in an amount of 5-2000 mg. In some embodiments , the 35 ingredients in the immediate - release subcomponent and / or active ingredient in the immediate - release subcomponent the extended - release subcomponent of the first and the and the extended - release subcomponent in both the first and second components further comprises an agent selected the second component each comprises an analgesic agent, from the group consisting of antimuscarinic agents , antidi such as acetaminophen, in an amount of 5-2000 mg. uretic agents and spasmolytics . In some related embodiments , the immediate - release sub- 40 In some related embodiments , the active ingredient in the component and the extended - release subcomponent in the immediate -release subcomponent and /or the extended - re first component each comprises tamsulosin . In some related lease subcomponent of the first component further com embodiments , the immediate - release subcomponent and the prises an agent selected from the group consisting of anti extended - release subcomponent in the first component each muscarinic agents, antidiuretic agents and spasmolytics. comprises finasteride. In some related embodiments , the 45 In some related embodiments , the active ingredient in the immediate - release subcomponent and the extended - release immediate -release subcomponent and /or the extended - re subcomponent in the first component each comprises tam lease subcomponent of the second component further com sulosin and finasteride . prises an agent selected from the group consisting of anti In some related embodiments , the active ingredient in the muscarinic agents , antidiuretic agents and spasmolytics . immediate - release subcomponent of the first component and 50 Another aspect of the present application relates to a the active ingredient in the immediate -release subcompo pharmaceutical composition the comprises a first component nent of the second component both comprise an analgesic comprising an immediate - release subcomponent and an agent, such as acetaminophen . In some embodiments , the extended -release subcomponent, wherein the first compo active ingredient in the immediate - release subcomponent of nent is formulated to release the subcomponents immedi the first component and the active ingredient in the imme- 55 ately after administration , and a second component com diate -release subcomponent of the second component com prising an immediate -release subcomponent and an prise different analgesic agents. extended -release subcomponent, wherein the second com Another aspect of the present application relates to a ponent is formulated for a delayed - release of the subcom pharmaceutical composition that comprises a first compo ponents , wherein the immediate - release subcomponent and nent comprising an immediate -release subcomponent , 60 the extended - release subcomponent in the first component wherein the immediate - release subcomponent comprises an each comprises an active ingredient comprising ( 1 ) one or active ingredient comprising one or more agents selected more analgesic agents , and ( 2 ) an a - blocker, a 5a -reductase from the group consisting of analgesic agents , a -blockers inhibitor or both , and wherein the immediate - release sub and 5a - reductase inhibitors , wherein the first component is component and the extended - release subcomponent in the formulated to release its subcomponent immediately after 65 second component each comprises an active ingredient oral administration ; and a second component comprising an comprising ( 1 ) one or more analgesic agents , and ( 2 ) an immediate - release subcomponent and an extended - release a -blocker , a 5a - reductase inhibitor or both , wherein the US 10,596,127 B2 43 44 pharmaceutical composition reduces the frequency of uri component and an extended -release component is formu nation in patients in need thereof. In some embodiments , the lated into an orally disintegrating tablet . one or more analgesic agents are selected from the group As used herein , the term " orally disintegrating tablet ” or consisting of aspirin , ibuprofen , naproxen , naproxen “ orally disintegrating formulation ” refers to drug tablet or sodium , indomethacin , nabumetone, and acetaminophen . In 5 formulation that rapidly disintegrates or dissolves in the oral some embodiments , the one or more analgesic agents com cavity . Orally disintegrating formulations differ from tradi prise acetaminophen , the a -blocker is tamsulosin and the tional tablets in that they are designed to be dissolved on the 5a -reductase inhibitor is finasteride. tongue rather than swallowed whole . In some embodiments , In other embodiments , the pharmaceutical composition the orally disintegrating formulations are designed to com comprises a pair of analgesic agents . Examples of such 10 pletely disintegrate or dissolve in the oral cavity without the paired analgesic agents include , but are not limited to , aid of additional water ( i.e. , in saliva only ) in 5 , 10 , 20 , 30 , acetaminophen and an NSAID , acetylsalicylic acid and 60 , 90 , 120 , 180 , 240 or 300 seconds. ibuprofen , acetylsalicylic acid and naproxen sodium , ace In some embodiment, the pharmaceutical composition tylsalicylic acid and nabumetone, acetylsalicylic acid and with an immediate - release component and an extended acetaminophen , acetylsalicylic acid and indomethancin , ibu- 15 release component is formulated into a liquid form for oral profen and naproxen sodium , ibuprofen and nabumetone , administration . Examples of the liquid form formulation ibuprofen and acetaminophen , ibuprofen and indomethan include , but are not limited to , gels , emulsions and particle cin , naproxen sodium and nabumetone , naproxen sodium suspensions . For example , the extended -release component and acetaminophen , naproxen sodium and indomethancin , may be formulated into a gel form that solidified in stomach . nabumetone and acetaminophen , nabumetone and indo- 20 In some embodiment, the pharmaceutical composition with methancin , and acetaminophen and indomethancin . The an immediate - release component and an extended -release paired analgesic agents are mixed at a weight ratio in the component is formulated into a pixie pack of powder that range of 0.1: 1 to 10 : 1, 0.2 : 1 to 5 : 1 or 0.3 : 1 to 3 : 1 with a can quickly melt on the tongue . In some embodiments , the combined dose or single dose ( i.e. , the dose for each immediate - release component or the extended release com analgesic ) in the range of 5 mg to 2000 mg, 20 mg to 2000 25 ponent or both further comprise one or more additional mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to agents selected from the group consisting of antimuscarinic 2000 mg, 5 mg to 1500 mg, 20 mg to 1500 mg, 100 mg to agents , spasmolytics and antidiuretic agents . 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg to Method of Manufacture 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg Another aspect of the present application relates to meth to 500 mg, 250 mg to 1000 mg, 250 mg to 1500 mg, 500 mg 30 ods of manufacturing extended -release pharmaceutical com to 1000 mg, 500 mg to 1500 mg, 1000 mg to 1500 mg, and positions for reducing the frequency of urination . In some 1000 mg to 2000 mg. In one embodiment, the paired embodiments , the method comprises the steps of forming a analgesic agents are mixed at a weight ratio of 1 : 1 . first mixture having a first active ingredient formulated for Another aspect of the present application relates to a immediate release and a second active ingredient formulated pharmaceutical composition that comprises an immediate- 35 for extended release ; coating the first mixture with a delayed release component and an extended -release component. release coating to form a core structure; and then coating the Each component comprises a pair of analgesic agents as core structure with a second mixture comprising a third described above and at least one of the components com active ingredient formulated for immediate release and a prises an agent selected from the group consisting of fourth active ingredient formulated for extended release. In a -blockers and 5a -reductase inhibitors. In some embodi- 40 one embodiment , at least one of the first, second , third and ments , the immediate - release component and the extended fourth active ingredients comprises an analgesic agent and at release component comprise different pairs of analgesic least one of the first , second , third and fourth active ingre agents . In some embodiments , the immediate -release com dients comprises an a -blocker , a 5a - reductase inhibitor or ponent and the extended - release component comprise the both . same pair of analgesic agents . In some embodiments, the 45 In some embodiments , the analgesic agent is selected immediate - release component and the extended - release from the group consisting of aspirin , ibuprofen , naproxen , component each comprises acetaminophen and an NSAID . naproxen sodium , indomethacin , nabumetone and acet In some embodiments , the immediate -release component aminophen , and wherein at least one of the first, second , and the extended -release component each comprises acet third and fourth active ingredients comprises 5 mg to 2000 aminophen and ibuprofen . In some embodiments , the imme- 50 mg of the analgesic agent. diate -release component and the extended -release compo In some embodiments, at least one of the first, second , nent each consists of acetaminophen , ibuprofen and an agent third and fourth active ingredients comprises ( 1) an analge selected from the group consisting of a -blockers and 5a - re sic agent selected from the group consisting of aspirin , ductase inhibitors . In some embodiments , the agent is tam ibuprofen , naproxen , naproxen sodium , indomethacin , nabu sulosin . In other embodiments , the agent is finasteride. 55 metone, and acetaminophen , and ( 2 ) an a -blocker . In some In some embodiments , the extended -release component is embodiments , the analgesic agent is acetaminophen and the formulated for extended release over a period of 0.5-24 , 2-6 , a -blocker is tamsulosin . 6-10 , 10-14 or 14-18 hours . In some embodiments , the In some embodiments , the at least one of the first , second , extended - release component is formulated for extended third and fourth active ingredients comprises ( 1 ) an analge release over a period of about 8 hours . In some embodi- 60 sic agent selected from the group consisting of aspirin , ments , the extended -release component is coated with a ibuprofen , naproxen , naproxen sodium , indomethacin , nabu delayed -release coating. In some embodiments , the delayed metone, and acetaminophen , and (2 ) an 5a -reductase inhibi release coating delays the release of the extended - release tor. In some embodiments , the analgesic agent is acetamino component for a period of 0.1-12 , 0.5-12 , 1-12 , 1-4 , 2-4 , 4-8 phen and the 5a -reductase inhibitor is finasteride . or 8-12 hours . In some embodiments , the delayed - release 65 In some embodiments , the at least one of the first , second , coating is an enteric coating . In some embodiment, the third and fourth active ingredients comprises ( 1 ) an analge pharmaceutical composition with an immediate - release sic agent selected from the group consisting of aspirin , US 10,596,127 B2 45 46 ibuprofen , naproxen , naproxen sodium , indomethacin , nabu value of 4.0 , 3.5 , 3.0 , 2.5 , 2.0 , 1.5 , 1.0 or lower . In some metone , and acetaminophen , (2 ) an a -blocker and (3 ) a embodiments , the enteric coating comprises one or more 5a - reductase inhibitor. pH -dependent polymers and one or more polysaccharides In some embodiments , the at least one of the first, second , that are resistant to erosion in both the stomach and intestine, third and fourth active ingredients comprises an agent 5 thus allowing the release of the first mixture only in colon . selected from the group consisting antimuscarinic agents , In some embodiment, the delayed release coating comprises antidiuretic agents and spasmolytics . two or more layers of coating. In some embodiment, the In some embodiments , the delayed release coating is an delayed release coating comprises a swelling layer and an enteric coating. In some embodiments , the enteric coating outer semi- permeable polymer layer that covers the swelling comprises a pH - dependent polymer. 10 layer. In some embodiments , the delayed release coating com In the next step , the coated core structure is re -coated with prises a swelling layer covered by an outer semi- permeable a second mixture that comprises a third active ingredient polymer layer. formulated for immediate release and a fourth active ingre In some embodiments , the delayed release coating is dient formulated for extended release . In some embodi formulated to release the coated material after a lag time of 15 ments , the second mixture is prepared by mixing the third 0.1-12 hours, 0.5-12 hours , 1-12 hours, 2-12 hours , 1-4 active ingredient in liquid or powder form with the fourth hours, 2-4 hours , 2-6 hours , 2-8 hours , 4-6 hours or 4-8 active ingredient , which is formulated for extended release . hours after oral administration . The fourth active ingredient may be formulated in an In some embodiments , the second active ingredient, or the extended release formulation having an active core com fourth active ingredient or both comprise an active core 20 prised of one or more inert particles, each in the form of a comprising an extended- release coating or a polymeric bead , pellet, pill , granular particle , microcapsule , micro matrix effecting diffusion controlled release. sphere ,microgranule , nanocapsule , or nanosphere coated on In some embodiments , the first mixture is prepared by its surfaces with drugs in the form of e.g. , a drug - containing mixing the first active ingredient in liquid or powder form coating or film - forming composition using , for example , with the second active ingredient , which is formulated for 25 fluid bed techniques or other methodologies known to those extended release. As described above , the second active of skill in the art. The inert particle can be of various sizes, ingredient may be formulated in an extended release for so long as it is large enough to remain poorly dissolved . mulation having an active core comprised of one or more Alternatively , the active core may be prepared by granulat inert particles, each in the form of a bead , pellet, pill , ing and milling and/ or by extrusion and spheronization of a granular particle , microcapsule ,microsphere , microgranule , 30 polymer composition containing the drug substance. In nanocapsule , or nanosphere coated on its surfaces with some embodiments , the active core comprises an extended drugs in the form of e.g. , a drug - containing coating or release coating or a polymeric matrix effecting diffusion film - forming composition using, for example , fluid bed controlled ease , as described in more detail earlier. In techniques or othermethodologies known to those of skill in some embodiments , the polymeric matrix is a water soluble the art . The inert particle can be of various sizes, so long as 35 or water- swellable matrix . In some embodiments , the fourth it is large enough to remain poorly dissolved . Alternatively , active ingredient is simply mixed with the third active the active core may be prepared by granulating and milling ingredient . Either ingredient or both ingredients may be in and / or by extrusion and spheronization of a polymer com the form ofbead , pellet , granular particle , pill, microcapsule , position containing the drug substance . In some embodi microsphere , microgranule , nanocapsule or nanosphere as a ments , the active core comprises a extended -release coating 40 powder or as a liquid suspension . or a polymeric matrix effecting diffusion controlled release , In other embodiments , the coated core structure is re as described in more detail earlier. In some embodiments , coated first with the fourth active ingredient, and then coated the polymeric matrix is a water soluble or water -swellable with the third active ingredient . In some embodiments , the matrix . In some embodiments , the second active ingredient fourth active ingredient is formulated to release the active is simply mixed with the first active ingredient. Either 45 ingredient over a period of 2-4 hours , 2-6 hours , 2-8 hours ingredient or both ingredients may be in the form of bead , or 2-10 hours . pellet, granular particle , pill , microcapsule , microsphere , In some embodiments , the fourth active ingredient is kept microgranule , nanocapsule or nanosphere as a powder or as in a compartment partially or completely separated from the a liquid suspension . In other embodiments , the second active third active ingredient. In other embodiments , the second ingredient forms an active core that is coated with the first 50 mixture is formed by keeping the fourth active ingredient in active ingredient . In some embodiments , the second active a compartment partially or completely separated from the ingredient in the first mixture is formulated to release the third active ingredient . active ingredient over a period of 2-4 hours , 2-6 hours , 2-8 In other embodiments , the method comprises the steps of hours or 2-10 hours . forming a core structure comprising a first active ingredient In some embodiments , the second active ingredient is 55 formulated for immediate release and a second active ingre kept in a compartment partially or completely separated dient formulated for extended release , coating the core from the first active ingredient. In other embodiments , the structure with a delayed release coating to form a coated first mixture is formed by keeping the second active ingre core structure , and mixing the coated core structure with a dient in a compartment partially or completely separated third active ingredient formulated for immediate release and from the first active ingredient. 60 a fourth active ingredient formulated for extended release to The first mixture is then coated with a delayed release form a final mixture . The first, second , third and fourth coating to form a core structure. In some embodiments , the active ingredients can be the active ingredients described delayed release coating is an enteric coating . In some above . In one embodiment, the first, second , third and fourth embodiments , the enteric coating comprises a pH -dependent active ingredients each comprises an analgesic agent. In polymer thatmaintains its structure integrity at low pH , such 65 some embodiments , the analgesic agent is selected from the as the pH in the stomach ( normally in the range of 1.5-3.5 ) . group consisting of aspirin , ibuprofen , naproxen , naproxen In some embodiments , the term “ low pH ” refers to a pH sodium , indomethacin , nabumetone and acetaminophen. In US 10,596,127 B2 47 48 some embodiments , the method further comprises the step In some embodiments , at least one of the first, second and of preparing a dosage form with the final mixture . In some third active ingredients comprises : ( 1 ) acetaminophen ; and embodiments , the dosage form is in a tablet form . In some ( 2 ) an a -blocker , a 5a -reductase inhibitor or both . embodiments , the dosage form is in an orally disintegrating In some embodiments , the at least one of the first, second form , e.g., orally disintegrating tablet form . In some 5 and third active ingredients comprises an agent selected from the group consisting antimuscarinic agents , antidiuretic embodiments , the dosage form is in a beads -in - a - capsule agents and spasmolytics . form . In some embodiments , the dosage form is in a liquid Another aspect of the present application relates to a ( e.g., emulsion ) form . method for manufacturing a pharmaceutical composition for In other embodiments , the method comprises the steps of 10 reducing the frequency of urination . The method comprises forming a core structure comprising a first active ingredient the steps of forming a core structure comprising a first pair formulated for immediate release and a second active ingre of analgesic agents formulated for extended -release , and dient formulated for extended release, coating the core coating the core structure with a coating layer comprising a structure with a delayed release coating to form a coated second pair of analgesics, wherein the second pair of anal core structure , mixing the coated core structure with a third 15 gesics is formulated for immediate release and wherein ingredient formulated for immediate release and a fourth either the core structure or the coating layer or both further ingredient formulated for extended release . comprise an agent selected from the group consisting of Another aspect of the present application relates to a a -blockers and 5a - reductase inhibitors . method for manufacturing a pharmaceutical composition for In some embodiments , the core structure is first coated reducing the frequency of urination . The method comprises 20 with a delayed -release coating and then coated with a the step of forming a core structure comprising a first active coating layer comprising a second pair of analgesics , ingredient formulated for immediate release and a second wherein the second pair of analgesics is formulated for active ingr nt formulated for extended release ; coating immediate release . the core structure with a delayed release coating to form a In some embodiments , the method comprises the steps of coated core structure ; mixing the coated core structure with 25 forming a first mixture comprising a first pair of analgesic a third active ingredient formulated for immediate release agents formulated for extended -release , forming a second mixture comprising a second pair of analgesic agents for and a fourth active ingredient formulated for extended mulated for immediate - release , and combining the first release to form a final mixture , and compressing the final mixture and the second mixture to form a final mixture , mixture into a tablet. In some embodiments , at least one of 30 wherein either the first mixture or the second mixture or both the first, second , third and fourth active ingredients com further comprise an agent selected from the group consisting prises an analgesic agent and at least one of the first , second , of a - blockers and 5a -reductase inhibitors . third and fourth active ingredients comprises an a -blocker , In some embodiments , the first mixture , the second mix a 5a -reductase inhibitor or both . ture and the final mixture are mixtures of solid materials . In In some embodiments , the analgesic agent is selected 35 some embodiments , the final mixture is in a powder or from the group consisting of aspirin , ibuprofen , naproxen , granulate form . In some embodiments , the method further naproxen sodium , indomethacin , nabumetone and acet comprises the step of pressing the final mixture into a tablet aminophen and wherein at least one of the first, second , third form . In some embodiments , the finalmixture is in a liquid , and fourth active ingredients comprises 5-2000 mg of the gel or emulsion form . analgesic agent. 40 Examples of paired analgesic agents include , but are not In some embodiments , the at least one of the first , second , limited to , acetaminophen and an NSAID , acetylsalicylic third and fourth active ingredients comprises : ( 1 ) acetamino acid and ibuprofen , acetylsalicylic acid and naproxen phen ; and ( 2) an a -blocker , a 5a - reductase inhibitor or both . sodium , acetylsalicylic acid and nabumetone , acetylsalicylic In some embodiments , the at least one of the first, second , acid and acetaminophen , acetylsalicylic acid and indometh third and fourth active ingredients comprises an agent 45 ancin , ibuprofen and naproxen sodium , ibuprofen and nabu selected from the group consisting antimuscarinic agents , metone , ibuprofen and acetaminophen , ibuprofen and indo antidiuretic agents and spasmolytics . methancin , naproxen sodium and nabumetone , naproxen Another aspect of the present application relates to a sodium and acetaminophen , naproxen sodium and indo method for manufacturing a pharmaceutical composition for methancin , nabumetone and acetaminophen , nabumetone reducing the frequency of urination . The method comprises 50 and indomethancin , and acetaminophen and indomethancin . the steps of forming a core structure comprising a first active In some embodiments , the first pair of analgesic agents is ingredient formulated for immediate release and a second different from the second pair of analgesic agents . In other active ingredient formulated for extended release ; coating embodiments , the first pair of analgesic agents is the same the core structure with a delayed release coating to form a as the second pair of analgesic agents . In one embodiment, coated core structure ; coating the coated core structure with 55 the first pair of analgesic agents and the second pair of a third active ingredient formulated for immediate release to analgesic agents are both acetaminophen and ibuprofen . form a double -coated core structure . In some embodiments , For example , the extended -release component may be wherein at least one of the first , second and third active formulated into a gel form that solidified in stomach . In ingredients comprises an analgesic agent and at least one of some embodiment, the pharmaceutical composition with an the first , second and third active ingredients comprises an 60 immediate - release component and an extended -release com a -blocker , a 5a - reductase inhibitor or both . ponent is formulated into a pixie pack of powder that can In some embodiments , the analgesic agent is selected quickly melt on the tongue. In some embodiments , the from the group consisting of aspirin , ibuprofen , naproxen , pharmaceutical composition with an immediate -release naproxen sodium , indomethacin , nabumetone and acet component and an extended -release component is formu aminophen and wherein at least one of the first, second and 65 lated into an orally disintegrating tablet using loose com third active ingredients comprises 5-2000 mg of the anal pression tableting . In loose compression , orally disintegrat gesic agent. ing formulation is compressed at much lower forces (4-20 US 10,596,127 B2 49 50 kN ) than traditional tablets . In some embodiments , the orally Macrophages are subjected to short term ( 1-2 hrs ) or long disintegrating formulation contains some form of sugar, term (24-48 hrs ) stimulation with : such as mannitol, to improve mouth feel . In some embodi 1 ) Each analgesic agent alone at various doses . ments , the orally disintegrating tablet is produced using ( 2 ) Each analgesic agent at various doses in the presence lyophilized orally disintegrating formulation . 5 of LPS . The present invention is further illustrated by the follow ( 3 ) Each analgesic agent at various doses in the presence ing example which should not be construed as limiting. The of carbachol or acetylcholine . contents of all references , patents and published patent ( 4 ) Each analgesic agent at various doses in the presence applications cited throughout this application are incorpo of AA , DGLA , or EPA . 10 ( 5 ) Botulinum neurotoxin A alone at various doses. rated herein by reference . ( 6 ) Botulinum neurotoxin A at various doses in the presence of LPS . Example 1 : Inhibition of the Urge to Urinate ( 7 ) Botulinum neurotoxin A at various doses in the presence of carbachol or acetylcholine . Twenty volunteer subjects , both male and female were 15 ( 8 ) Botulinum neurotoxin A at various doses in the enrolled , each of which experienced premature urge or presence of AA , DGLA , or EPA . desire to urinate , interfering with their ability to sleep for a ( 9 ) Each antimuscarinic agent alone at various doses . sufficient period of time to feel adequately rested . Each ( 10 ) Each antimuscarinic agent at various doses in the subject ingested 400-800 mg of ibuprofen as a single dose presence of LPS. prior to bedtime. At least 14 subjects reported that they were 20 ( 11 ) Each antimuscarinic agent at various doses in the able to rest better because they were not being awakened as presence of carbachol or acetylcholine. frequently by the urge to urinate . ( 12 ) Each antimuscarinic agent at various doses in the Several subjects reported that after several weeks of presence of AA , DGLA , or EPA . nightly use of ibuprofen , the benefit of less frequent urges to The cells are then analyzed for the release of PGH2, PGE , urinate was no longer being realized. However , all of these 25 PGE2, Prostacydin , Thromboxane , IL - 1B , IL -6 , TNF - a , the subjects further reported the return of the benefit after COX2 activity , the production of cAMP and CGMP, the several days of abstaining from taking the dosages . production of IL - 1B , IL - 6 , TNF - a and COX2 mRNA , and surface expression of CD80 , CD86 and MHC class II Example 2 : Effect of Analgesic Agents , Botulinum molecules . Neurotoxin and Antimuscarinic Agents on 30 Materials and Methods Macrophage Responses to Inflammatory and Macrophage Cells Non - Inflammatory Stimuli Murine RAW264.7 or J774 macrophage cells (obtained from ATCC ) were used in this study. Cells were maintained Experimental Design in a culture medium containing RPMI 1640 supplemented This study is designed to determine the dose and in vitro 35 with 10 % fetal bovine serum (FBS ) , 15 mM HEPES , 2 mM efficacy of analgesics and antimuscarinic agents in control L - glutamine , 100 U /ml penicillin , and 100 ug/ ml of strep ling macrophage response to inflammatory and non - inflam tomycin . Cells were cultured at 37 ° C. in a 5 % CO2 matory stimuli mediated by COX1 and /or COX2 and pros atmosphere and split (passages ) once a week . taglandins (PGE , PGH , etc. ) . It establishes baseline (dose In Vitro Treatment of Macrophage Cells with Analgesics and kinetic ) responses to inflammatory and non -inflamma- 40 RAW264.7 macrophage cells were seeded in 96 -well tory effectors in bladder cells . Briefly , cultured cells are plates at a cell density of 1.5x10 cells per well in 100 ul of exposed to analgesic agents and / or antimuscarinic agents in the culture medium . The cells were treated with ( 1 ) various the absence or presence of various effectors. concentrations of analgesic (acetaminophen , aspirin , ibupro The effectors include : lipopolysaccharide (LPS ), an fen or naproxen ), (2 ) various concentrations of lipopolysac inflammatory agent and COX1/ 2 inducer, as inflammatory 45 charide (LPS ) , which is an effector of inflammatory stimuli stimuli ; carbachol or acetylcholine, a stimulator of smooth to macrophage cells , ( 3 ) various concentrations of carbachol muscle contraction , as non - inflammatory stimuli ; botulinum or acetylcholine , which are effectors of non - inflammatory neurotoxin A , a known inhibitor of acetylcholine release , as stimuli, ( 4 ) analgesic and LPS or ( 5 ) analgesic and carbachol positive control; and arachidonic acid ( AA ) , gamma lino or acetylcholine. Briefly , the analgesics were dissolved in lenic acid (DGLA ) or eicosapentaenoic acid (EPA ) as pre- 50 FBS- free culture medium ( i.e., RPMI 1640 supplemented cursors of prostaglandins, which are produced following the with 15 mM HEPES , 2 mM L -glutamine , 100 U /ml peni sequential oxidation ofAA , DGLA or EPA inside the cell by cillin , and 100 ug /ml of streptomycin ), and diluted to desired cyclooxygenases (COX1 and COX2 ) and terminal prosta concentrations by serial dilution with the samemedium . For glandin synthases. cells treated with analgesic in the absence of LPS , 50 ul of The analgesic agents include: Salicylates such as aspirin , 55 analgesic solution and 50 ul of FBS - free culture medium iso - butyl- propanoic -phenolic acid derivative ( ibuprofen ) were added to each well. For cells treated with analgesic in such as Advil , Motrin , Nuprin , and Medipren , naproxen the presence of LPS , 50 ul of analgesic solution and 50 ul of sodium such as Aleve , Anaprox , Antalgin , Feminax Ultra , LPS ( from Salmonella typhimurium ) in FBS - free culture Flanax , Inza , Midol Extended Relief, Nalgesin , Naposin , medium were added to each well . All conditions were tested Naprelan , Naprogesic , Naprosyn , Naprosyn suspension , EC- 60 in duplicates . Naprosyn , Narocin , Proxen , Synflex and Xenobid , acetic After 24 or 48 hours of culture , 150 ul of culture super acid derivative such as indomethacin ( Indocin ) , 1 -naphtha natants were collected , spun down for 2 min at 8,000 rpm at leneacetic acid derivative such as nabumetone or relafen , 4 ° C. to remove cells and debris and stored at -70 ° C. for N - acetyl- para -aminophenol (APAP ) derivative such as acet analysis of cytokine responses by ELISA . The cells were aminophen or paracetamol ( Tylenol ) and Celecoxib . 65 collected and washed by centrifugation (5 min at 1,500 rpm The antimuscarinic agents include : oxybutynin , solifena at 4 ° C.) in 500 ul of Phosphate buffer (PBS ) . Half of the cin , darifenacin and atropine. cells were then snap frozen in liquid nitrogen and stored at US 10,596,127 B2 51 52 -70 ° C. The remaining cells were stained with fluorescent dase- labelled goat anti- biotin mAb (Vector Laboratories) . monoclonal antibodies and analyzed by flow cytometry . The colorimetric reaction was developed by the addition of Flow Cytometry Analysis of Co - Stimulatory Molecule 2,2 '- azino - bis( 3 ) -ethylbenzylthiazoline - 6 - sulfonic acid Expression ( ABTS ) substrate and H2O2 ( Sigma) and the absorbance For flow cytometry analysis , macrophages were diluted in 5 measured(PerkinElmer at 415) . nm with a Victor® V multilabel plate reader 100 ul of FACS buffer (phosphate buffered saline (PBS ) with Determination of COX2 Activity and the Production of 2 % bovine serum albumin (BSA ) and 0.01 % NaN3) and CAMP and cGMP stained 30 min at 4 ° C. by addition of FITC - conjugated The COX2 activity in the cultured macrophages is deter anti- CD40 , PE - conjugated anti - CD80 , PE - conjugated anti mined by sequential competitive ELISA ( R & D Systems) . CD86 antibody, anti MHC class II ( I - A ) PE (BD Biosci 10 The production of CAMP and CGMP is determined by the ence ). Cells were then washed by centrifugation (5 min at CAMP assay and cGMP assay . These assays are performed 1,500 rpm at 4 ° C.) in 300 ul of FACS buffer. After a second routinely in the art. wash , cells were re -suspended in 200 ul of FACS buffer and Results the percentage of cells expressing a given marker ( single Table 1 summarizes the experiments performed with Raw positive ), or a combination of markers (double positive ) 15 264 macrophage cell line and main findings in terms of the were analyzed with the aid of an Accuri C6 flow cytometer effects of analgesics on cell surface expression of costimu (BD Biosciences ) . latory molecules CD40 and CD80 . Expression of these Analysis of Cytokine Responses by ELISA molecules is stimulated by COX1/ 2 and inflammatory sig Culture supernatants were subjected to cytokine -specific nals and thus , was evaluated to determine functional con ELISA to determine IL - 1B , IL - 6 and TNF - a responses in 20 sequences of inhibition of COX1/ 2 . cultures of macrophages treated with analgesic , LPS alone As shown in Table 2 , acetaminophen , aspirin , ibuprofen or a combination of LPS and analgesic . The assays were and naproxen inhibit basal expression of co - stimulatory performed on Nunc MaxiSorp Immunoplates (Nunc ) coated molecules CD40 and CD80 by macrophages at all the tested overnight with 100 ul of anti -mouse IL -6 , TNF - a mAbs (BD doses ( i.e., 5x10 nM , 5x10 + nM , 5x10 nM , 5x102 nM , 50 Biosciences ) or IL - 1ß mAb (R & D Systems) in 0.1 M 25 nM and 5 nM ), except for the highest dose ( i.e. , 5x10 nM ), sodium bicarbonate buffer ( pH 9.5 ) . After two washes with which appears to enhance , rather than inhibit, expression of PBS (200 ul per well) , 200 ul of PBS 3 % BSA were added the co - stimulatory molecules . As shown in FIGS. 1A and in each well (blocking ) and the plates incubated for 2 hours 1B , such inhibitory effect on CD40 and CD50 expression at room temperature . Plates were washed again two times by was observed at analgesic doses as low as 0.05 nM (i.e. , addition of 200 ul per well , 100 ul of cytokine standards and 30 0.00005 uM ) . This finding supports the notion that a con serial dilutions of culture supernatants were added in dupli trolled release of small doses of analgesic may be preferable cate and the plates were incubated overnight at 4 ° C. Finally , to acute delivery of large doses. The experiment also the plates were washed twice and incubated with 100 ul of revealed that acetaminophen , aspirin , ibuprofen and secondary biotinylated anti -mouse IL - 6 , TNFa mAbs (BD naproxen have a similar inhibitory effect on LPS induced Biosciences ) or IL - 1B ( R & D Systems) followed by peroxi expression of CD40 and CD80 . TABLE 1 Summary of experiments

LPS Salmonella Control typhimurium Acetaminophen Aspirin Ibuprophen Naproxen

TESTS

X 2 X Dose responses ( 0 , 5 , 50 , 1000 ) ng/mL 3 X Dose responses ( 0,5 , 50 , 500 , 5 x 103, 5 x 104, 5 x 105, 5 x 104) nM 4 X X (5 ng /mL ) Dose responses X ( 50 ng /mL (0 , 5 , 50 , 500, 5 x 103, 5 x 104,5 x 105, 5 x 106) X ( 1000 ng/mL ) nM ANALYSIS

? . Characterization of activation stimulatory is : Flow cytometry analysis of CD40 , CD80 , CD86 and MHC class II b Mediators of inflammatory responses : ELISA analysis of IL - 1B , IL - 6 , TNF - a US 10,596,127 B2 53 54 TABLE 2 Summary of main findings Negative LPS Effectors % Positive Control 5 ng/ ml 5 x 10° 5 x 10 5 x 10+ 5 x 103 500 50 5 Dose analgesic (nM ) CD40 + CD80 + 20.6 77.8 CD40 + CD80 + 20.6 77.8 Acetaminophen CD40 + CD80 + 63 18 12 9.8 8.3 9.5 7.5 Aspirin CD40 + CD80 + 44 11 10.3 8.3 8 10.5 7.5 Ibuprophen CD40 + CD80 + ND * 6.4 7.7 7.9 6.0 4.9 5.8 Naproxen CD40 + CD80 + 37 9.6 7.7 6.9 7.2 6.8 5.2 Analgesic plus LPS Acetaminophen CD40 + CD80 + 95.1 82.7 72.4 68.8 66.8 66.2 62.1 Aspirin CD40 + CD80 + 84.5 80 78.7 74.7 75.8 70.1 65.7 Ibuprophen CD40 + CD80 + ND 67 77.9 72.9 71.1 63.7 60.3 Naproxen CD40 + CD80 + 66.0 74.1 77.1 71.0 68.8 72 73 * ND : not done (toxicity ) 20 Table 3 summarizes the results of several studies that ( 4 ) Each analgesic agent at various doses in the presence measured serum levels of analgesic after oral therapeutic of AA , DGLA , or EPA . doses in adult humans . As shown in Table 3 , the maximum ( 5 ) Botulinum neurotoxin A alone at various doses . serum levels of analgesic after an oral therapeutic dose are (6 ) Botulinum neurotoxin A at various doses the in the range of 104 to 10 % nM . Therefore , the doses of 25 presence of LPS . analgesic tested in vitro in Table 2 cover the range of ( 7 ) Botulinum neurotoxin A at various doses in the concentrations achievable in vivo in humans. presence of carbachol or acetylcholine . TABLE 3 Serum levels of analgesic in human blood after oral therapeutic doses Maximum serum levels after oral Molecular therapeutic doses Analgesic drug weight mg/L nM References Acetaminophen 151.16 11-18 7.2 x 104- BMC Clinical Pharmacology . 2010 , 10 : 10 ( Tylenol) 1.19 x 105 Anaesth Intensive Care . 2011, 39 : 242 Aspirin 181.66 30-100 1.65 105- Disposition of Toxic Drugs and Chemicals in (Acetylsalicylic 5.5 x 105 Man , 8th Edition , Biomedical Public , Foster acid ) City , CA , 2008 , pp . 22-25 J Lab Clin Med . 1984 June; 103 : 869 Ibuprofen 206.29 24-32 1.16 x 109- BMC Clinical Pharmacology2010 , 10:10 ( Advil , Motrin ) 1.55 x 105 J Clin Pharmacol. 2001, 41 : 330 Naproxen 230.26 Up to Up to J Clin Pharmacol. 2001, 41 : 330 (Aleve ) 60 2.6 x 105

Example 3 : Effect of Analgesic Agents , Botulinum ( 8 ) Botulinum neurotoxin A at various doses in the Neurotoxin and Antimuscarinic Agents on Mouse presence of AA , DGLA , or EPA . Bladder Smooth Muscle Cell Responses to ( 9 ) Each antimuscarinic agent alone at various doses. Inflammatory and Non - Inflammatory Stimuli 50 ( 10 ) Each antimuscarinic agent at various doses in the Experimental Design presence of LPS . This study is designed to characterize how the optimal ( 11) Each antimuscarinic agent at various doses in the doses of analgesics determined in Example 2 affect bladder presence of carbachol or acetylcholine. smooth muscle cells in cell culture or tissue cultures, and to 55 ( 12 ) Each antimuscarinic agent at various doses in the address whether different classes of analgesics can synergize presence of AA , DGLA , or EPA . to more efficiently inhibit COX2 and PGE2 responses . The cells are then analyzed for the release of PGH2, PGE, The effectors, analgesic agents and antimuscarinic agents PGE2, Prostacydin , Thromboxane, IL -1B , IL -6 , TNF - a , the are described in Example 2 . COX2 activity , the production of cAMP and CGMP, the Primary culture ofmouse bladder smooth muscle cells are 60 production of IL - 1B, IL - 6 , TNF - a and COX2 mRNA , and subjected to short term ( 1-2 hrs ) or long term (24-48 hrs ) surface expression of CD80 , CD86 and MHC class II stimulation with : molecules . ( 1) Each analgesic agent alone at various doses . Materials and Methods ( 2 ) Each analgesic agent at various doses in the presence Isolation and Purification of Mouse Bladder Cells of LPS . 65 Bladder cells were removed from euthanized animals ( 3 ) Each analgesic agent at various doses in the presence C57BL /6 mice (8-12 weeks old ) and cells were isolated by of carbachol or acetylcholine . enzymatic digestion followed by purification on a Percoll US 10,596,127 B2 55 56 gradient. Briefly , bladders from 10 mice were minced with Other Assays scissors to fine slurry in 10 ml of digestion buffer (RPMI The release of PGH2, PGE , Prostacydin , Thromboxane , 1640 , 2 % fetal bovine serum , 0.5 mg/ ml collagenase , 30 IL - 1B , IL -6 , and TNF - a , the production of CAMP and ug /ml DNase ). Bladder slurries were enzymatically digested CGMP, the production of IL - 1B , IL - 6 , TNF - a and COX2 for 30 minutes at 37° C. Undigested fragments were further 5 mRNAclass II, molecules and surface are expression determined of asCD80 described , CD86 in andExample MHC dispersed through a cell- trainer . The cell suspension was 2 . pelleted and added to a discontinue 20 % , 40 % and 75 % Analgesics Inhibit COX2 Responses of Mouse Bladder Percoll gradient for purification on mononuclear cells . Each Cells to an Inflammatory Stimulus experiment used 50-60 bladders. Several analgesics ( acetaminophen , aspirin, ibuprofen After washes in RPMI 1640 , bladder cells were resus 10 and naproxen ) were tested on mouse bladder cells at the pended RPMI 1640 supplemented with 10 % fetal bovine concentration of 5 uM or 50 uM to determine whether the serum , 15 mM HEPES , 2 mM L - glutamine , 100 U /ml analgesics could induce COX2 responses . Analysis of penicillin , and 100 ug/ ml of streptomycin and seeded in 24 -hour cultures showed that none of the analgesics tested induced COX2 responses in mouse bladder cells in vitro . clear- bottom black 96 -well cell culture microculture plates 15 The effect of these analgesics on the COX2 responses of at a cell density of 3x104 cells per well in 100 ul. Cells were mouse bladder cells to carbachol or LPS stimulation in vitro cultured at 37° C. in a 5 % CO2 atmosphere . was also tested . As indicated in Table 1 , the dose of In Vitro Treatment of Cells with Analgesics carbachol tested has no significant effect on COX2 levels in Bladder cells were treated with analgesic solutions (50 mouse bladder cells . On the other hand , LPS significantly well ) either alone or together with carbachol (10 -Molar , 50 20 increased total COX2 levels. Interestingly , acetaminophen , ul/ well ), as an example of non - inflammatory stimuli , or aspirin , ibuprofen and naproxen could all suppress the effect lipopolysaccharide (LPS ) of Salmonella typhimurium ( 1 of LPS on COX2 levels . The suppressive effect of the ug /ml , 50 ul/ well ) , as an example of non -inflammatory analgesic was seen when these drugs were tested at either 5 stimuli . When no other effectors were added to the cells , 50 uM or 50 uM ( Table 4 ) . ul of RPMI 1640 without fetal bovine serum were added to 25 the wells to adjust the final volume to 200 ul. TABLE 4 After 24 hours of culture , 150 ul of culture supernatants COX2 expression by mouse bladder cells after in were collected , spun down for 2 min at 8,000 rpm at 4 ° C. vitro stimulation and treatment with analgesic to remove cells and debris and stored at -70 ° C. for analysis of Prostaglandin E2 (PGE2 ) responses by ELISA . Cells were 30 Total COX2 levels fixed , permeabilized and blocked for detection of Cyclooxy Stimulus Analgesic ( Normalized RFUS) genase - 2 ( COX2) using a fluorogenic substrate . In selected None None 158 + 18 Carbachol (mm ) None 149 + 21 experiment cells were stimulated 12 hours in vitro for LPS (1 ug /ml ) None 420 + 26 analysis of COX2 responses 35 LPS ( 1 ug /ml ) Acetaminophen (5 UM ) 275 + 12 Analysis of COX2 Responses LPS ( 1 ug /ml ) Aspirin ( 5 UM ) 240 17 LPS (1 ug/ ml ) Ibuprofen ( 5 uM ) ) 253 32 COX2 responses were analyzed by a Cell -Based ELISA LPS ( 1 ug/ml ) Naproxen ( 5 uM ) 284 11 using Human /mouse total COX2 immunoassay ( R & D Sys LPS ( 1 ug/ ml ) Acetaminophen (50 uM ) 243 + 15 tems) , following the instructions of the manufacturer. LPS (1 ug /ml ) Aspirin ( 50 UM ) 258 + 21 Briefly , after cells fixation and permeabilization , a mouse 40 LPS (1 ug /ml ) Ibuprofen (50 UM ) 266 + 19 anti - total COX2 and a rabbit anti - total GAPDH were added LPS (1 ug /ml ) Naproxen (50 UM ) 279 + 23 to the wells of the clear - bottom black 96 - well cell culture microculture plates . After incubation and washes, an HRP Analgesics Inhibit PGE2 Responses ofMouse Bladder Cells conjugated anti- mouse IgG and an AP -conjugated anti to an Inflammatory Stimulus rabbit IgG were added to the wells . Following another 45 The secretion of PGE2 in culture supernatants of mouse incubation and set of washes, the HRP- and AP - fluorogenic bladder cells was measured to determine the biological substrates were added . Finally , a Victor® V multilabel plate significance of the alteration of mouse bladder cell COX2 reader (PerkinElmer ) was used to read the fluorescence levels by analgesics . As shown in Table 5 , PGE2 was not emitted at 600 nm (COX2 fluorescence ) and 450 nm detected in the culture supernatants of unstimulated bladder (GAPDH fluorescence ). Results are expressed as relative 50 cells or bladder cells cultured in the presence of carbachol . levels of total COX2 as determined by relative fluorescence Consistent with COX2 responses described above , stimula unit (RFUs ) and normalized to the housekeeping protein tion of mouse bladder cells with LPS induced the secretion GAPDH . of high levels of PGE2. Addition of the analgesics acet Analysis of PGE2 Responses aminophen , aspirin , ibuprofen and naproxen suppressed the Prostaglandin E2 responses were analyzed by a sequential 55 effect of LPS on PGE2 secretion and no difference was seen competitive ELISA (R & D Systems) . More specifically, cul between the responses of cells treated with the 5 or 50 uM ture supernatants or PGE2 standards were added to the wells dose of analgesic . of a 96 -well polystyrene microplate coated with a goat anti- mouse polyclonal antibody. After one hour incubation TABLE 5 on a microplate shaker, an HRP - conjugated PGE2 was 60 added and plates incubated for an additional two hours at PGE2 secretion by mouse bladder cells after in room temperature . The plates were then washed and HRP vitro stimulation and treatment with analgesic . substrate solution added to each well . The color was allowed PGE2 levels to develop for 30 min and the reaction stopped by addition Stimulus Analgesic (pg /ml ) sulfuric acid before reading the plate at 450 nm with 65 None None < 20.5 wavelength correction at 570 nm . Results are expressed as Carbachol (mm ) None < 20.5 mean pg /ml of PGE2. US 10,596,127 B2 57 58 TABLE 5 - continued tissue are used . Bladder smooth muscle cell contractions are recorded with a Grass polygraph ( Quincy Mass ., USA ) . PGE2 secretion by mouse bladder cells after in vitro stimulation and treatment with analgesic . Example 5 : Effect of Oral Analgesic Agents and PGE2 levels 5 Antimuscarinic Agents on COX2 and PGE2 Stimulus Analgesic (pg /ml ) Responses of Mouse Bladder Smooth Muscle Cells LPS ( 1 ug/ ml ) None 925 + 55 LPS (1 ug/ ml ) Acetaminophen ( 5 uM ) 619 = 32 Experimental Design : LPS ( 1 ug /ml ) Aspirin ( 5 uM ) 588 + 21 Normal mice and mice with over active bladder syndrome LPS (1 ug /ml ) Ibuprofen (5 UM )) 593 + 46 LPS ( 1 ug /ml ) Naproxen ( 5 uM ) 597 + 19 10 are given oral doses of aspirin , naproxen sodium , ibuprofen , LPS ( 1 ug/ ml ) Acetaminophen ( 50 uM ) 600 + 45 Indocin , nabumetone , Tylenol, Celecoxib , oxybutynin , solif LPS ( 1 ug /ml ) Aspirin ( 50 UM ) 571 1 53 enacin , darifenacin , atropine and combinations thereof. Con LPS (1 ug/ ml ) Ibuprofen (50 UM ) 568 + 32 trol groups include untreated normal mice and untreated LPS ( 1 ug/ ml ) Naproxen (50 uM ) 588 + 37 OAB mice with over active bladder syndrome. Thirty ( 30 ) 15 minutes after last doses , the bladders are collected and In summary , these data show that the analgesics alone at stimulated ex vivo with carbachol or acetylcholine. In 5 uM or 50 uM do not induce COX2 and PGE2 responses selected experiments , the bladders are treated with botuli num neurotoxin A before stimulation with carbachol. Ani in mouse bladder cells . The analgesics at 5 uM or 50 uM , mals are maintained in metabolic cages and frequency (and however , significantly inhibit COX2 and PGE2 responses of 20 volume) of urination are evaluated . Bladder outputs are mouse bladder cells stimulated in vitro with LPS (1 ug/ ml ) . determined by monitoring water intake and cage litter No significant effect of analgesics was observed on COX2 weight. Serum PGH2, PGE , PGE2, Prostacydin , Thrombox and PGE2 responses ofmouse bladder cells stimulated with ane , IL - 16 , IL -6 , TNF -a , MP, and cGMP levels are carbachol ( 1 mM ). determined by ELISA . CD80 , CD86 , MHC class II expres 25 sion in whole blood cells are determined by flow cytometry . Example 4 : Effect of Analgesic Agents, Botulinum At the end of the experiment, animals are euthanized and Neurotoxin and Antimuscarinic Agents on Mouse ex vivo bladder contractions are recorded with a Grass Bladder Smooth Muscle Cell Contraction polygraph . Portions of bladders are fixed in formalin , and COX2 responses are analyzed by immunohistochemistry . Experimental Design 30 Cultured mouse or rat bladder smooth muscle cells and Example 6 : Effect of Analgesic Agents , Botulinum mouse or rat bladder smooth muscle tissue are exposed to Neurotoxin and Antimuscarinic Agents on Human inflammatory stimuli and non - inflammatory stimuli in the Bladder Smooth Muscle Cell Responses to presence of analgesic agent and /or antimuscarinic agent at Inflammatory and Non - Inflammatory Stimuli various concentrations . The stimuli - induced muscle contrac- 35 tion is measured to evaluate the inhibitory effect of the Experimental Design analgesic agent and / or antimuscarinic agent . This study is designed to characterize how the optimal The effectors , analgesic agents and antimuscarinic agents doses of analgesic determined in Examples 1-5 affect human are described in Example 2 . bladder smooth muscle cells in cell culture or tissue cultures , Primary cultures of mouse bladder smooth muscle cells 40 and to address whether different classes of analgesics can are subjected to short term ( 1-2 hrs ) or long term (24-48 hrs ) synergize to more efficiently inhibit COX2 and PGE2 stimulation with : responses . ( 1) Each analgesic agent alone at various doses . The effectors, analgesic agents and antimuscarinic agents presence are described in Example 2 . ( 2 ) Each analgesic agent at various doses in the 45 Human bladder smooth muscle cells are subjected to short of LPS . term ( 1-2 hrs ) or long term (24-48 hrs ) stimulation with : ( 3 ) Each analgesic agent at various doses in the presence ( 1 ) Each analgesic agent alone at various doses . of carbachol or acetylcholine . ( 2 ) Each analgesic agent at various doses in the presence (4 ) Each analgesic agent at various doses in the presence of LPS . of AA , DGLA , or EPA . 50 ( 3 ) Each analgesic agent at various doses in the presence ( 5 ) Botulinum neurotoxin A alone at various doses . of carbachol or acetylcholine. (6 ) Botulinum neurotoxin A at various doses in the (4 ) Each analgesic agent at various doses in the presence presence of LPS . of AA , DGLA , or EPA . (7 ) Botulinum neurotoxin A at various doses in the ( 5 ) Botulinum neurotoxin A alone at various doses . presence of carbachol or acetylcholine. 55 ( 6 ) Botulinum neurotoxin A at various doses in the ( 8 ) Botulinum neurotoxin A at various doses in the presence of LPS . presence of AA , DGLA , or EPA . ( 7 ) Botulinum neurotoxin A at various doses in the (9 ) Each antimuscarinic agent alone at various doses . presence of carbachol or acetylcholine . ( 10 ) Each antimuscarinic agent at various doses in the (8 ) Botulinum neurotoxin A at various doses in the presence of LPS . 60 presence of AA, DGLA , or EPA . ( 11) Each antimuscarinic agent at various doses in the ( 9 ) Each antimuscarinic agent alone at various doses . presence of carbachol or acetylcholine . ( 10 ) Each antimuscarinic agent at various doses in the ( 12 ) Each antimuscarinic agent at various doses in the presence of LPS. presence of AA , DGLA , or EPA . ( 11 ) Each antimuscarinic agent at various doses in the Materials and Methods 65 presence of carbachol or acetylcholine . Primary mouse bladder cells are isolated as described in ( 12 ) Each antimuscarinic agent at various doses in the Example 3. In selected experiments , cultures of bladder presence of AA , DGLA , or EPA . US 10,596,127 B2 59 60 The cells are then analyzed for the release of PGH2, PGE, in 100 ul were treated with analgesic solutions ( 50 ul/ well ) PGE , Prostacydin , Thromboxane, IL - 1B , IL -6 , TNF- a , the either alone or together carbachol ( 10 -Molar , 50 ul/ well ) , as COX2 activity , the production of cAMP and CGMP, the an example of non - inflammatory stimuli, or lipopolysaccha production of IL - 1B , IL - 6 , TNF - a and COX2 mRNA , and ride (LPS ) of Salmonella typhimurium ( 1 ug /ml , 50 ul/ well ) , surface expression of CD80 , CD86 and MHC class II 5 as an example of non - inflammatory stimuli. When no other molecules . effectors were added to the cells, 50 ul of RPMI 1640 without fetal bovine serum were added to the wells to adjust Example 7 : Effect of Analgesic Agents , Botulinum the final volume to 200 ul. Neurotoxin and Antimuscarinic Agents on Human After 24 hours of culture , 150 ul of culture supernatants Bladder Smooth Muscle Cell Contraction 10 were collected , spun down for 2 min at 8,000 rpm at 4 ° C. to remove cells and debris and stored at -70 ° C. for analysis Experimental Design of Prostaglandin E2 (PGE2 ) responses by ELISA . Cells were Cultured human bladder smooth muscle cells are exposed fixed , permeabilized and blocked for detection of COX2 to inflammatory stimuli and non - inflammatory stimuli in the using a fluorogenic substrate . In selected experiment cells presence of an analgesic agent and /or antimuscarinic agent 15 were stimulated 12 hours in vitro for analysis of COX2 , at various concentrations . The stimulus - induced muscle con PGE2 and cytokine responses. traction is measured to evaluate the inhibitory effect of the Analysis of COX2 , PGE2 and Cytokine Responses analgesic agent and/ or antimuscarinic agent. COX2 and PGE2 responses were analyzed as described in The effectors , analgesic agents and antimuscarinic agents Example 3. Cytokine responses were analyzed as described are described in Example 2 . 20 in Example 2 . Human bladder smooth muscle cells are subjected to short Results term ( 1-2 hrs ) or long term (24-48 hrs) stimulation with : Analgesics Inhibit COX2 Responses of Normal Human ( 1 ) Each analgesic agent alone at various doses . Bladder Smooth Muscle Cells to Inflammatory and Non ( 2 ) Each analgesic agent at various doses in the presence Inflammatory Stimuli of LPS . 25 Analysis of cells and culture supernatants after 24 hours ( 3 ) Each analgesic agent at various doses in the presence of cultures showed that none of the analgesics tested alone of carbachol or acetylcholine . induced COX2 responses in normal human bladder smooth ( 4 ) Each analgesic agent at various doses in the presence muscle cells . However , as summarized in Table 6 , carbachol of AA , DGLA , or EPA . induced low , but significant COX2 responses in normal ( 5 ) Botulinum neurotoxin A alone at various doses. 30 human bladder smooth muscle cells. On the other hand , LPS (6 ) Botulinum neurotoxin A at various doses in the treatment resulted in higher levels of COX2 responses in presence of LPS. normal human bladder smooth muscle cells. Acetamino (7 ) Botulinum neurotoxin A at various doses in the phen , aspirin , ibuprofen and naproxen could all suppress the presence of carbachol or acetylcholine . effect of carbachol and LPS on COX2 levels . The suppres (8 ) Botulinum neurotoxin A at various doses in the 35 sive effect of the analgesics was seen on LPS - induced presence of AA , DGLA , or EPA . responses when these drugs were tested at either 5 uM or 50 ( 9 ) Each antimuscarinic agent alone at various doses . UM . ( 10 ) Each antimuscarinic agent at various doses in the presence of LPS . TABLE 6 ( 11) Each antimuscarinic agent at various doses in the 40 COX2 expression by normal human bladder smooth muscle presence of carbachol or acetylcholine . cells after in vitro stimulation with inflammatory and ( 12 ) Each antimuscarinic agent at various doses in the non- inflammatory stimuli and treatment with analgesic presence of AA , DGLA , or EPA . Bladder smooth muscle cell contractions are recorded Total COX2 Total COX2 45 levels levels with a Grass polygraph ( Quincy Mass ., USA ). (Normalized (Normalized RFUS) RFUS) Example 8 : Effect of Analgesic Agents on Normal Stimulus Analgesic subject 1 subject 2 Human Bladder Smooth Muscle Cell Responses to None None 230 199 Inflammatory and Non Inflammatory Signals Carbachol 10-3M None (50 UM ) 437 462 50 Carbachol 10-3 M Acetaminophen (50 UM ) 298 310 Experimental Design Carbachol 10-3 M Aspirin (50 UM ) 312 297 Culture of Normal Human Bladder Smooth Muscle Cells Carbachol 10-3 M Ibuprofen (50 UM ) 309 330 Carbachol 10-3 M Naproxen (50 UM ) 296 354 Normal human bladder smooth muscle cells were isolated LPS (10 ug/ml ) None 672 633 by enzymatic digestion from macroscopically normal pieces LPS ( 10 ug/ml ) Acetaminophen (5 uM ) 428 457 of human bladder . Cells were expended in vitro by culture 55 LPS ( 10 ug/ ml ) Aspirin ( 5 UM ) 472 491 LPS ( 10 ug/ ml ) Ibuprofen ( 5 uM ) 417 456 at 37 ° C. in a 5 % CO2 atmosphere in RPMI 1640 supple LPS ( 10 ug/ ml ) Naproxen (5 uM 458 501 mented with 10 % fetalbovine serum , 15 mM HEPES, 2 mM LPS ( 10 ug /ml ) Acetaminophen ( 50 UM ) 399 509 L - glutamine , 100 U /ml penicillin , and 100 mg/ ml of strep LPS (10 ug /ml ) Aspirin (50 UM ) 413 484 tomycin and passage once a week by treatment with trypsin LPS (10 ug/ ml ) Ibuprofen (50 UM ) 427 466 to detach cells followed by reseeding in a new culture flask . 60 LPS ( 10 ug/ ml ) Naproxen (50 UM ) 409 458 The first week of culture, the culture medium was supple mented with 0.5 ng /ml epidermal growth factor, 2 ng/ ml #Data are expressed as mean of duplicates fibroblast growth factor, and 5 ug /ml insulin . Analgesics Inhibit PGE2 Responses of Normal Human Treatment of Normal Human Bladder Smooth Muscle Cells Bladder Smooth Muscle Cells to Inflammatory and Non with Analgesics In Vitro 65 Inflammatory Stimuli Bladder smooth muscle cells trypsinized and seeded in Consistent with the induction of COX2 responses microculture plates at a cell density of 3x104 cells per well described above , both carbachol and LPS induced produc US 10,596,127 B2 61 62 tion of PGE2 by normalhuman bladder smooth muscle cells . TABLE 9 Acetaminophen , aspirin , ibuprofen and naproxen were also IL - 6 secretion by normal human bladder smooth muscle cells found to suppress the LPS - induced PGE2 responses at either after in vitro stimulation with inflammatory and non 5 uM or 50 uM ( Table 7 ) . inflammatory stimuli and treatment with analgesic 5 TABLE 7 IL - 6 IL - 6 (pg / ml ) * (pg / ml ) PGE2 secretion by normal human bladder smooth muscle cells Stimulus Analgesic Subject 1 Subject 2 after in vitro stimulation with inflammatory and non inflammatory stimuli and treatment with analgesic None None 10 Carbachol 10-3 M None 232 278 PGE2 levels PGE2 levels Carbachol 10-3 M Acetaminophen (50 uM ) 119 135 (pg /ml ) (pg /ml ) Carbachol 10-3 M Aspirin ( 50 UM ) 95 146 Stimulus Analgesic Subject 1 Subject 2 Carbachol 10-3 M Ibuprofen (50 uM ) 107 118 Carbachol 10-3M Naproxen (50 UM ) 114 127 None None < 20.5 < 20.5 LPS (10 ug/ ml ) None 4838 4383 Carbachol 10-3M None 129 104 15 LPS (10 ug /ml ) Acetaminophen ( 5 uM ) 2012 2308 Carbachol 10-3M Acetaminophen (50 UM ) 76 62 LPS ( 10 ug /ml ) Aspirin ( 5 UM ) 2199 2089 Carbachol 10-3 M Aspirin ( 50 UM ) 89 59 LPS (10 ug/ ml ) Ibuprofen ( 5 uM ) 2063 2173 Carbachol 10-3M Ibuprofen (50 UM ) 84 73 LPS (10 ug/ ml ) Naproxen ( 5 uM 2077 2229 Carbachol 10-3 M Naproxen (50 UM ) 77 66 LPS ( 10 ug/ml ) Acetaminophen (50 uM ) 2018 1983 LPS ( 10 ug /ml ) None 1125 998 LPS ( 10 ug/ ml ) Aspirin ( 50 uM ) 1987 2010 Ibuprofen (50 UM ) 2021 1991 LPS ( 10 ug /ml ) Acetaminophen ( 5 UM ) 817 542 20 LPS ( 10 ug/ml ) LPS ( 10 ug/ ml ) Aspirin ( 5 MM ) 838 598 LPS ( 10 ug/ ml ) Naproxen ( 50 UM ) 2102 2028 LPS ( 10 ug /ml ) Ibuprofen ( 5 uM ) 824 527 LPS ( 10 ug/ ml ) Naproxen ( 5 UM 859 506 #Data are expressed as mean of duplicates. LPS ( 10 ug/ml ) Acetaminophen ( 50 UM ) 803 540 LPS (10 ug /ml ) Aspirin (50 uM ) 812 534 Primary normal human bladder smooth muscle cells were LPS (10 ug /ml ) Ibuprofen (50 UM ) 821 501 isolated , cultured and evaluated for their responses to anal LPS (10 ug /ml ) Naproxen (50 UM ) 819 523 25 gesics in the presence of non - inflammatory (carbachol ) and Data are expressed as mean of duplicates inflammatory (LPS ) stimuli . The goal of this study was to determine whether or not normal human bladder smooth Analgesics Inhibit Cytokine Responses of Normal Human muscle cells recapitulate the observations previously made Bladder Cells to Inflammatory Stimuli with murine bladder cells . Analysis of cells and culture supernatants after 24 hours 30 The above -described experiment will be repeated with of culture showed that none of the analgesics tested alone analgesic agents and / or antimuscarinic agents in delayed induced IL - 6 or TNFa secretion in normal human bladder release , or extended -release formulation or delayed -and extended - release formulations . smooth muscle cells . As shown in Tables 8 and 9 , the doses The above description is for the purpose of teaching the of carbachol tested induced low , but significant TNFa and 35 person of ordinary skill in the art how to practice the present IL - 6 responses in normal human bladder smooth muscle invention , and it is not intended to detail all those obvious cells . On the other hand , LPS treatment resulted in massive modifications and variations of it which will become appar induction of these proinflammatory cytokines . Acetamino ent to the skilled worker upon reading the description . It is phen , aspirin , ibuprofen and naproxen suppress the effect of intended , however, that all such obvious modifications and carbachol and LPS on TNFa and IL -6 responses. The 40 variations be included within the scope of the present suppressive effect of the analgesics on LPS - induced invention , which is defined by the following claims. The responses was seen when these drugs were tested at either 5 claims are intended to cover the claimed components and uM or 50 ?M . steps in any sequence which is effective to meet the objec tives there intended , unless the context specifically indicates TABLE 8 45 the contrary . TNFa secretion by normal human bladder smooth muscle What is claimed is : cells after in vitro stimulation with inflammatory and 1. A method for manufacturing a pharmaceutical compo non- inflammatory stimuli and treatment with analgesic sition for reducing the frequency of urination , comprising : TNFa TNFa 50 forming a first mixture comprising a first active ingredient (pg /ml ) * (pg /ml ) formulated for immediate release and a second active Stimulus Analgesic Subject 1 Subject 2 ingredient formulated for extended release ; None None coating the first mixture with a delayed release coating to Carbachol 10-3M None 350 286 form a core structure ; Carbachol 10-3 M Acetaminophen (50 UM ) 138 164 55 Carbachol 10-3 M Aspirin ( 50 uM ) 110 142 coating the core structure with a second mixture compris Carbachol 10-3 M Ibuprofen (50 UM ) 146 121 ing a third active ingredient formulated for immediate Carbachol 10-3 M Naproxen (50 uM ) 129 137 release and a fourth active ingredient formulated for LPS ( 10 ug/ml ) None 5725 4107 extended release , LPS ( 10 ug/ml ) Acetaminophen ( 5 uM ) 2338 2267 wherein at least one of the first, second , third and fourth LPS ( 10 ug/ml ) Aspirin (5 UM ) 2479 2187 LPS (10 ug/ ml ) Ibuprofen ( 5 uM ) 2733 2288 60 active ingredients comprises acetaminophen and at LPS ( 10 ug /ml ) Naproxen ( 5 uM 2591 2215 least one of the first, second , third and fourth active LPS ( 10 ug /ml ) Acetaminophen (50 UM ) 2184 2056 ingredients comprises ibuprofen , and further wherein at LPS ( 10 ug /ml ) Aspirin (50 uM ) 2266 2089 least one of the first , second , third and fourth active LPS (10 ug/ ml ) Ibuprofen (50 UM ) 2603 1997 LPS ( 10 ug/ml ) Naproxen (50 UM ) 2427 2192 ingredients comprises an a -blocker , a 5a - reductase 65 inhibitor or both . #Data are expressed as mean of duplicates . 2. The method of claim 1 , wherein at least one of the first, second , third and fourth active ingredients comprises 5 mg US 10,596,127 B2 63 64 to 2000 mg per agent of acetaminophen and at least one of ingredients comprises ibuprofen , and at least one of the the first, second , third and fourth active ingredients com first , second , third and fourth active ingredients com prises 5 mg to 2000 mg per agent of ibuprofen . prises an a -blocker , a 5a -reductase inhibitor or both . 14. The method of claim 13 , wherein at least one of the second3. The, third method and of fourth claim 1active , wherein ingredients at least onecomprises of the first (1 ), 5 first, second, third and fourth active ingredients comprises ibuprofen , ( 2 ) acetaminophen , and ( 3 ) an a -blocker . 5-2000 mg per agent of acetaminophen and at least one of 4. The method of claim 3 , wherein the a - blocker is the first, second, third and fourth active ingredients com tamsulosin . prises 5 mg to 2000 mg per agent of ibuprofen . 5. The method of claim 1 , wherein at least one of the first , 15. The method of claim 13 , wherein at least one of the second , third and fourth active ingredients comprises (1 ) 10 first( 1, ) secondacetaminophen, third and ; andfourth active ingredients comprises: ibuprofen , ( 2 ) acetaminophen , and ( 3 ) an 5a - reductase ( 2 ) ibuprofen ; and inhibitor . ( 3 ) an a -blocker , a 5a -reductase inhibitor or both . 6. The method of claim 5 , wherein the 5a -reductase 16. The method of claim 13 , wherein at least one of the inhibitor7. The methodis finasteride of claim . 1 , wherein at least one of the first, 15 first, second , third and fourth active ingredients further second , third and fourth active ingredients comprises ( 1 ) comprises an agent selected from the group consisting ibuprofen , (2 ) acetaminophen , ( 3) an a -blocker and ( 4 ) a antimuscarinic agents , antidiuretic agents and spasmolytics . 5a -reductase inhibitor. 17. A method for manufacturing a pharmaceutical com 8. The method of claim 1 , wherein at least one of the first, position for reducing the frequency of urination , comprising : second, third and fourth active ingredients comprises an 20 forming a core structure comprising a first active ingre agent selected from the group consisting antimuscarinic dient formulated for immediate release and a second agents , antidiuretic agents and spasmolytics. active ingredient formulated for extended release ; 9. The method of claim 1 , wherein the delayed release coating the core structure with a delayed release coating coating is an enteric coating . to form a coated core structure ; 10. The method of claim 9 , wherein the enteric coating 25 coating the coated core structure with a third active comprises a pH -dependent polymer. ingredient formulated for immediate release to form 11. The method of claim 1 , wherein the delayed release double - coated core structure , coating comprises a swelling layer covered by an outer wherein at least one of the first , second and third active semi-permeable polymer layer . ingredients comprises acetaminophen and at least one 12. The method of claim 1 , wherein the second active 30 of the first, second and third active ingredients com ingredient, or the fourth active ingredient or both comprise prises ibuprofen and at least one of the first , second and an active core comprising an extended -release coating or a third active ingredients comprises an a - blocker , or a polymeric matrix effective diffusion controlled release . 5a - reductase inhibitor. 13. A method for manufacturing a pharmaceutical com 18. The method of claim 17 , wherein at least one of the position for reducing the frequency of urination , comprising : 35 first, second and third active ingredients - comprises 5-2000 forming a core structure comprising a first active ingre mg per agent of acetaminophen and at least one of the first , dient formulated for immediate release and a second second , and third active ingredients comprises 5 mg to 2000 active ingredient formulated for extended release ; mg per agent of ibuprofen . coating the core structure with a delayed release coating 19. The method of claim 17 , wherein at least one of the to form a coated core structure ; 40 first , second , and third active ingredients comprises: mixing the coated core structure with a third active ( 1 ) acetaminophen ; and ingredient formulated for immediate release and a ( 2 ) ibuprofen ; and fourth active ingredient formulated for extended ( 3 ) an a -blocker , or a 5a -reductase inhibitor. release to form a final mixture, and 20. The method of claim 17, wherein at least one of the preparing a dosage form with the final mixture , 45 first, second , and third active ingredients further comprises wherein at least one of the first, second , third and fourth an agent selected from the group consisting antimuscarinic active ingredients comprises acetaminophen and at agents , antidiuretic agents and spasmolytics . least one of the first , second , third and fourth active