HUNHAM USUN 20170348263A1TALA NA NA NA NA NANA ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0348263 A1 OHLSTEIN et al. (43 ) Pub . Date : Dec . 7 , 2017 (54 ) COMPOSITIONS AND METHODS OF USING A61K 9 / 00 ( 2006 . 01) MODIFIED RELEASE SOLABEGRON FOR A61K 9 / 16 (2006 .01 ) LOWER URINARY TRACT SYMPTOMS A61K 9 / 50 (2006 . 01) (71 ) Applicant: VELICEPT THERAPEUTICS, INC . , A61K 9 /24 (2006 .01 ) MALVERN , PA (US ) (52 ) U . S. CI. (72 ) Inventors: Eliot OHLSTEIN , Glennmoore , PA CPC ...... A61K 31/ 196 ( 2013 . 01 ) ; A61K 9 / 5084 (US ) ; Raymond E . STEVENS , JR ., ( 2013 .01 ) ; A61K 9 /209 ( 2013 .01 ) ; A61K West Chester , PA (US ); H . Jeffrey 9 /0053 ( 2013 .01 ) ; A61K 9 / 1676 ( 2013 .01 ) ; WILKINS, Sellersville , PA (US ) A61K 9 /2081 ( 2013 .01 ) (21 ) Appl. No. : 15 /614 ,577 (22 ) Filed : Jun . 5, 2017 (57 ) ABSTRACT Related U . S . Application Data This application relates to pharmaceutical compositions , (60 ) Provisional application No. 62 /345 ,388 , filed on Jun . comprising solabegron that are useful for the treatment of 3 , 2016 , provisional application No . 62 / 345 , 519 , filed lower urinary tract symptoms such as, for example , overac on Jun . 3 , 2016 . tive bladder and prostate disorders . Additionally, this appli cation relates to methods for treating lower urinary tract PublicPublication Classification symptoms utilizing the pharmaceutical compositions, com (51 ) Int. Cl. prising solabegron . In some embodiments , the pharmaceu A61K 31 / 196 ( 2006 . 01 ) tical compositions, comprising solabegron comprise a dual A61K 9 / 20 ( 2006 .01 ) release drug delivery system .
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COMPOSITIONS AND METHODS OF USING a first target Cmax , a second target Cmax , a first target Cmin MODIFIED RELEASE SOLABEGRON FOR between the first target Cmax and the second target Cmax , and LOWER URINARY TRACT SYMPTOMS a second target Cmin after the second target Cmor . [0006 ] Some embodiments describe a pharmaceutical [0001 ] The present application claims the benefit of U . S . composition comprising a therapeutically effective amount Provisional Application No. 62 /345 ,388 , filed Jun . 3 , 2016 ; of the amorphous form of solabegron and at least one and U . S . Provisional Application No. 62 /345 , 519 , filed Jun . pharmaceutically acceptable carrier or diluent. 3 , 2016 ; the disclosures of which are hereby incorporated by [0007 ) Further embodiments are directed to the use of reference in their entirety . such pharmaceutical compositions for the treatment of dis eases , including , but not limited to , lower urinary tract SUMMARY symptoms (hereinafter “ TAUS” ) , obesity , type 2 diabetes , [0002 ] Agonist -induced desensitization of G - protein heart failure , irritable bowel syndrome and similar gastro coupled receptors (GPCRs ) of the beta - 3 adrenoceptor is not intestinal disorders , pre - term labor, depression and anxiety . well studied . For many disease processes , GPCR desensiti In embodiments , LUTS may be overactive bladder and / or zation is thought to contribute to the disease process or limit prostate disorders . the effect of therapeutic agents . Prolonged exposure of the [0008 ] Some embodiments describe a method of treating receptor system molecule to a drug may result in receptor LUTS , obesity , type 2 diabetes , heart failure , irritable bowel down- regulation . Down- regulation occurs when there is a syndrome, gastrointestinal disorders , pre -term labor , depres decrease in the number of receptor system molecules on the sion and anxiety in a subject in need thereof, comprising cell, thus decreasing the response to continued administra administering to the subject , a pharmaceutical composition tion of the therapeutic agent. In addition , more drug may for the delivery of solabegron , comprising an immediate often be needed over time to achieve the same therapeutic release composition , comprising solabegron and at least one response . Pharmaceutical compositions of beta - 3 adreno pharmaceutically acceptable carrier or diluent ; and a modi ceptor agonists that can minimize desensitization would be fied release composition , comprising solabegron and at least expected to increase therapeutic response and therefore be one pharmaceutically acceptable carrier or diluent. beneficial in treating subjects when compared with pharma [0009 ] Some embodiments are directed to a method of ceutical compositions that do not minimize desensitization . treating LUTS , obesity , type 2 diabetes , heart failure , irri The present invention describes pharmaceutical composi table bowel syndrome and similar gastrointestinal disorders , tions that increase the therapeutically effective properties of pre -term labor, depression and anxiety in a subject in need solabegron , while otherwise minimizing such desensitiza thereof, comprising administering a pharmaceutical compo tion and methods of using these pharmaceutical composi sition to the subject, comprising a therapeutically effective tions for the treatment of diseases . amount of solabegron , wherein the pharmaceutical compo [0003 ] Various embodiments described herein relate to sition releases at least two releases of solabegron , wherein a pharmaceutical compositions comprising a therapeutically first release of solabegron achieves a first target Cmar , a effective amount of solabegron that achieves a first target second release of solabegron achieves a second target Cmoremax Cmax of solabegron , a second target Cmax of solabegron , a a first target Cmin is achieved between the first release and first target Cmin of solabegron between the first target Cmax the second release and a second Cminmin is achieved after the and the second target Cmor and a second min of solabegron second release . after the second target Cmar . In embodiments , the pharma [ 0010 ] Some embodiments are directed to a method for ceutical compositions reduce desensitization of the beta - 3 treating overactive bladder in a patient in need thereof adrenoceptor , particularly when compared to an immediate comprising orally administering once a day , to the patient , a release formulation of solabegron that may be given , for pharmaceutical composition comprising : an immediate example , twice daily . release drug layer comprising about 75 mg to about 250 mg [0004 ] In embodiments, the pharmaceutical compositions solabegron and at least one pharmaceutically acceptable achieve a plasma concentration [ C ] of solabegron of about carrier or diluent; and a delayed release core comprising 1 ug/ mL or below for a period of time of about 6 hours to about 100 mg to about 400 mg solabegron and at least one about 9 hours during a 24 hour period . In embodiments , the pharmaceutically acceptable carrier or diluent, wherein the pharmaceutical compositions achieve an AUC of about immediate release drug layer is coated on the delayed 5 ,000 ng. hr /mL to about 30 ,000 ng .hr /mL over a 24 hour release core period . In embodiments the pharmaceutical compositions are administered once a day to a subject in need thereof. BRIEF DESCRIPTION OF THE FIGURES [0005 ] Further embodiments are directed to a pharmaceu [ 0011] FIG . 1 — Graphical Illustration of a dual- release tical composition for the delivery of solabegron , comprising pharmaceutical composition that achieves a first target Cmary ( a ) at least one immediate release composition , comprising provides a period at a first target Cming achieves a second solabegron and at least one pharmaceutically acceptable target Cmax and finally provides a period at a second target carrier or diluent; and ( b ) at least one modified release Cmin composition , comprising solabegron and at least one phar [0012 ] FIG . 2 — Cumulative concentration response maceutically acceptable carrier or diluent. In some embodi curves (CCRC ) to solabegron performed after a one hr ments the pharmaceutical composition may have any of the incubation to the EC , concentration of solabegron and a Cmax , Cmin , Tmax , or Tmin described herein . Some embodi period ofwashout using PSS . Two -way ANOVA to compare ments herein are directed to a pharmaceutical composition the curves gives p < 0 .001 , with a Bonferroni post hoc test to comprising a multiparticulate formulation of mini- tablets compare individual points with comparable points on the each comprising a therapeutically effective amount of sol vehicle incubation curve ( black triangles) . * = p < 0 .05 , abegron , wherein the pharmaceutical composition achieves * * = p < 0 .01 , * * * = p < 0 . 001 . US 2017 /0348263 A1 Dec . 7 , 2017
[0013 ] FIG . 3 — Cumulative concentration response [0026 ] FIG . 16 — Graphical illustration of a dissolution curves ( CCRC ) to solabegron performed after a three hr study of solabegron composition C (See Example 23 ) plot incubation to the EC9o concentration of solabegron and a ted as a percent of solabegron in solution as a function of period of washout using PSS . Two -way ANOVA to compare time . the curves gives p < 0 . 001 , with a Bonferroni post hoc test to 10027 ) FIG . 17 _ Graphical illustration of a dissolution compare individual points with comparable points on the study of solabegron composition D (See Example 23 ) plot ted as a percent of solabegron in solution as a function of vehicle incubation curve (black triangles ). * = p < 0 . 05 , time. * * = p < 0 .01 , * * * = p < 0 . 001 . [0028 ] FIG . 18 _ Graphical illustration of immediate [ 0014 ] FIG . 4 Cumulative concentration response release /modified release PK profile for 50 mg immediate curves (CCRC ) to CL -316 , 243 performed after a three hr release solabegron combined with 200 mg modified release incubation to the EC , concentration of CL - 316 , 243 and a solabegron plotted as ng /mL as a function of time . period of washout using PSS . Two - way ANOVA to compare [0029 ] FIG . 19 __ Graphical illustration of immediate the curves gives p < 0 .001 , with a Bonferroni post hoc test to release /modified release PK profile for interpolated 75 mg compare individual points with comparable points on the immediate release solabegron combined with 200 mg modi vehicle incubation curve (black triangles ). * = p < 0 . 05 , fied release solabegron plotted as ng /mL as a function of * * = p < 0 . 01 , * * * = p < 0 . 001 . time. [0015 ) FIG . 5 _ Graphical illustration of a tablet that is an [0030 ] FIG . 20 — _ Graphical illustration of immediate immediate release formulation and a tablet that is a modified release /modified release PK profile for 100 mg immediate release formulation enclosed in a capsule . release solabegron combined with 200 mg modified release [ 0016 ] FIG . 6 Graphical illustration of a dissolution solabegron plotted as ng /mL as a function of time. study of solabegron -polymer formulation plotted as a con [0031 ] FIG . 21 - Graphical illustration of immediate centration of solabegron in solution as a function of time. release /modified release PK profile for interpolated 125 mg [0017 ] FIG . 7 – Fourier - transform infrared spectroscopy immediate release solabegron combined with 200 mgmodi (FTIR ) scans of solabegron API, a spray - dried 20 : 80 sol fied release solabegron plotted as ng/ mL as a function of abegron to polyvinyl pyrrolidine (PVPK30 ) formulation , a time. physical mixture of 20 : 80 solabegron to polyvinyl pyrroli [0032 ] FIG . 22 —_ Graphical illustration of immediate dine ( PVPK30 ) and the PVPK30 carrier. The solabegron release /modified release PK profile for 150 mg immediate API displays amine ( N - H ) peaks at about 3400 and 3250 release solabegron combined with 200 mg modified release cm - and carbonyl peaks at 1593 cm - 7 . The PVPK30 carrier solabegron plotted as ng /mL as a function of time. displays a carbonyl peak at about 1670 cm - 1. The observed [0033 ] FIG . 23 — Table representing time and events for changes in the amine and carbonyl peaks in the solabegron screening through end of the study described in Example 25 PVPK30 formulation is absent in the physical mixture . The by study day . observed changes are indicative of the amorphous form of [0034 ] FIG . 24 — Table representing time and events for solabegron . screening before and after dosing in the study described in 10018 ] FIG . 8 Graphical illustration of a tablet that is a Example 25 by hour. modified release solabegron core (solabegron with a modi [0035 ] FIG . 25Graphical illustration of the PK data for fied (MR ) release coating ), that is coated in a matrix of the solabegron 200 mg total dose DR - 4 from Example 25 immediate / early release solabegron and a polymer . plotted as ng/ mL of solabegron as a function of time. [ 00191 FIG . 9 Graphical illustration of a dissolution 10036 ] FIG . 26 Graphical illustration of the PK data for study of solabegron composition A (See Example 22 ) plotted the solabegron 200 mg total dose DR -4 from Example 25 as a percent of solabegron in solution as a function of time. plotted as ng/ mL of solabegron as a function of time in log [0020 ] FIG . 10 — _ Graphical illustration of a dissolution study of solabegron composition B (See Example 22 ) plot scale . ted as a percent of solabegron in solution as a function of DETAILED DESCRIPTION time. [0037 ] Solabegron (3 '- [ (2 - { [( 2R )- 2 -( 3 -chlorophenyl ) - 2 [0021 ] FIG . 11 — Graphical illustration of a dissolution hydroxyethyl?amino } ethypamino ]biphenyl - 3 -carboxylic study of solabegron composition C (See Example 22 ) plot acid ) is a beta - 3 adrenoceptor agonist, with the following ted as a percent of solabegron in solution as a function of structure : time . [0022 ] FIG . 12 — Graphical illustration of a dissolution study of solabegron composition E (See Example 22 ) plotted as a percent of solabegron in solution as a function of time . [ 0023 ] FIG . 13 — Graphical illustration of a dissolution OH study of 75 mg immediate release solabegron coated delayed release placebo core in 500 mL of FaSSGF (See Example 22 ) plotted as a percent of solabegron in solution as a function of time. [0024 ] FIG . 14Graphical illustration of a dissolution OH study of solabegron composition A (See Example 23) plotted 1111 as a percent of solabegron in solution as a function of time . [0025 ] FIG . 15 _ Graphical illustration of a dissolution NH study of solabegron composition B (See Example 23 ) plot ted as a percent of solabegron in solution as a function of time. US 2017 /0348263 A1 Dec . 7 , 2017
It is further described in U . S . Pat. No . 6 , 251, 925 , U . S . Pat. [0043 ] Administration of a drug to treat such disease could No. 8 ,642 ,661 and United States Patent Publication No. be by the oral or parenteral routes of administration . For the 2013 / 0172277A1 (now U . S . Pat. No . 9 ,522 , 129 ), PCT oral route of administration , a pharmaceutical composition Application No . US2015 / 38583 filed Jun . 30 , 2015 ; PCT is described that releases drug for systemic absorption at the Application No. PCT/ US2015 /63795 , and PCT Application desired time- points and releases the desired systemic plasma No . US2016 /058516 . Solabegron has been demonstrated to drug levels . significantly reduce the symptoms of overactive bladder (hereinafter “ OAB ' ) in women with moderate to severe Definitions OAB , showing that solabegron is safe , well -tolerated , and [0044 ] As used herein , the term “ about” means plus or does not demonstrate significant differences in adverse minus 10 % of a given value . For example , " about 50 % " events as compared to placebo . means in the range of 45 % - 55 % . [0038 ] The use of a beta - 3 adrenoceptor agonist may be [0045 ] As used herein the term “ agonist ” refers to a limited by beta - 3 receptor desensitization . It is conceivable compound , the presence of which results in a biological that like the beta - 2 adrenoceptor in airway smooth muscle , activity of a receptor that is the same as the biological continuous , prolonged administration of a beta - 3 adrenocep activity resulting from the presence of a naturally occurring tor agonist will elicit beta - 3 receptor desensitization in ligand for the receptor. bladder smooth muscle . Prolonged exposure of a beta - 3 [0046 ] The terms " amorphous form ", amorphous solid ” adrenoceptor agonist may possibly result in a decrease in the and amorphous solabegron ” refer to a solabegron solid that number of beta - 3 receptors , a decrease binding affinity or does not have a definite geometric or crystalline shape. It is diminish post -receptor signal transduction mechanisms and a solid in which there is no long -range order in the positions second messenger signaling, resulting in a diminished thera of the atoms that is characteristic or a crystal. peutic response . [0047 ] As used herein the terms “ area under the curve” [0039 ] To prevent or reduce beta - 3 adrenoceptor desensi and " AUC ” is the area under the curve (mathematically tization , it is described herein that the therapeutic adminis known as a definite integral) in a pharmacokinetic plot of the tration of a beta - 3 adrenoceptor agonist occurs in a manner concentration of a drug against time. such that drug occupancy at the receptor occurs at levels that [0048 ] As used herein the terms “ BID ” and “ b .i .d .” mean do not elicit significant receptor desensitization and phar twice a day ( from the Latin bis in die ) . maceutical compositions that achieve the same. [ 0049 ] As used herein the terms “ Cmat ” , “ Cmin ” , “ Tmar ” , [0040 ] It is well established in the GPCR field that pro and “ T , ” are terms used in pharmacokinetic analyses of the longed occupancy of a receptor by an agonist can result in concentration of a drug against time. Cmax is a term that receptor desensitization . A method to limit this is to have the refers to the maximum ( or peak ) plasma concentration that agonist off the receptor, and allow the receptor to recover a drug achieves in a specified compartment or test area of the from agonist occupancy . When examining an entire popu body after the drug has been administrated and prior to the lation of receptors , the entire population of receptors does administration of a second dose . Cmor771 X is the opposite of not need to be unoccupied ; fractional occupancy of the Cmin , which is the minimum ( or trough ) concentration that entire receptor population can still result in prevention of a drug achieves after dosing . Tnor is the term used in receptor desensitization and preservation of function . In pharmacokinetics to describe the time at which the Cmay12 is other words , anything lower than 100 % receptor occupancy observed and Tmin is the term used in pharmacokinetics to may still allow some percentage of receptor resensitization . describe the time atwhich the Cmin is observed after the drug 10041 ] The pharmaceutical compositions and methods of has been administered and prior to the administration of a administration as described herein will not produce signifi second dose .T is the time it takes for the peak plasma cant receptor desensitization , while ensuring the method of concentration to reach half of its original value after admin administration will optimize for the beta - 3 adrenoceptor istration to a subject . stimulation , thus enabling the target tissue to benefit fully [ 0050 ] The term “ delayed release ” as used herein is a from the administered therapeutic agent. The therapeutic dosage form that releases a drug at a time other than agent, in the present application , is the beta - 3 adrenoceptor immediately upon administration . agonist solabegron The pharmaceutical compositions may 10051] As used herein , the term " desensitization ” refers to have a selected amplitude and duration so that the beta - 3 a state wherein a receptor, specifically in the present appli adrenoceptor will not down - regulate and the binding affinity cation a beta - 3 adrenoceptor, has been overexposed to an of the receptor system molecule will not be diminished . agonist for an extended period of time and an increased [0042 ] Embodiments of the present application describe dosage of agonist must be administered to achieve a similar pharmaceutical compositions comprising a therapeutically physiological response . It is a process whereby after pro effective amount of solabegron in a succession of at least longed agonist exposure , the receptor is uncoupled from its two releases , wherein each release is optimized to provide a signaling cascade , and thus the biological effect of receptor therapeutically effective plasma concentration [ C ] that opti activation is attenuated . Desensitization occurs when the mizes the tissue response while also providing a lower beta - 3 adrenoceptor is not otherwise responsive to an ago plasma concentration [ C ] between the first and second nist ( or antagonist ), is less responsive to an agonist (or release as well as between the second release and the antagonist ) , or the target tissue (e .g ., the bladder ) is not subsequent administration of the pharmaceutical composi otherwise responsive or is less responsive to an agonist (or tion to allow for a sufficient recovery time for the beta -3 antagonist ). adrenoceptors and methods of using the same to treat [0052 ] As used herein the phrase “ drug delivery system ” diseases . An exemplary embodiment of such a pharmaceu refers to any physical form , vehicle or composition that may tical composition and its release profile is provided in (FIG . be formulated to administer a therapeutic agent to a subject 1 ) . in need thereof such as , for example but not limited to the US 2017 /0348263 A1 Dec . 7 , 2017 following : tablets , capsules, granules, powders , liquids, sus zensulfonate , p - toluenesulfonate and pamoate (i . e ., 1, 1' pensions, suppositories , ointments, creams and aerosols . methylene -bis - ( 2 -hydroxy - 3 - naphthoate ) ) salts . Certain 10053 ] As used herein , the term “ effective amount” refers compounds of the application can form pharmaceutically to an amount that results in measurable inhibition of at least acceptable salts with various amino acids. Suitable base salts one symptom or parameter of a specific disorder or patho include , but are not limited to , aluminum , calcium , lithium , logical process . magnesium , potassium , sodium , zinc, iron and dietha 10054 ] The term " extended release " or " sustained release " nolamine salts . Pharmaceutically acceptable base addition as used herein is a dosage form that makes a drug available salts are also formed with amines , such as organic amines . over an extended period of time afteradministration . Examples of suitable amines are N , N - dibenzylethylenedi [0055 ] As used herein the term “ immediate release ” refers amine , chloroprocaine, choline, diethanolamine , dicyclo to pharmaceutical compositions that release the active ingre hexylamine, ethylenediamine , N -methylglucamine , and pro dient within a short period of time, typically less than 30 caine . minutes . 10061 ] As used herein the terms “ QD ” and “ q . d .” mean [0056 ] As used herein the phrase " lower urinary tract once a day ( from the Latin quaque die ) . symptoms” or “ LUTS ” refers to a group of medical symp [0062 ] As used herein the terms, “ release ” , “ releases ” , toms comprising increased frequency of urination , increased " delivery ” , “ pulsatile delivery device” , refer to pharmaceu urinary urgency of urination , painful urination , excessive tical compositions and methods of treatment wherein a passage of urine at night ( nocturia ), poor stream , overactive therapeutic agent is delivered rapidly within a short , prede bladder, hesitancy, terminal dribbling , incomplete voiding , termined period of time, as a result of a biological or external and overflow incontinence . Subjects with LUTS may have trigger or after a specific lag time The terms can also refer one or more of these symptoms. to pharmaceutical compositions and methods of treatment [0057 ] As used herein the term “ modified release” refers wherein a therapeutic agent is delivered within a predeter to pharmaceutical compositions that does not otherwise mined period of time. release the active ingredient immediately , for example it 10063] The term solabegron refers to ( 3 ' - [ ( 2 - { [ ( 2R ) - 2 - ( 3 may release the active ingredient at a sustained or controlled chlorophenyl) - 2 -hydroxyethyl ] amino } ethyl) amino ] biphe rate over an extended period of time such as , for example , nyl- 3 - carboxylic acid ) is a beta - 3 adrenoceptor agonist, with 4 hours , 8 hours , 12 hours , 16 hours , and 24 hours or release the following structure : the pharmaceutical dosage after a set time such as , for example, enteric - coated compositions that release the dos age in the intestinal track . Modified release includes , extended release , sustained release and delayed release . [0058 ] As used herein the phrase " overactive bladder " or OH " OAB ” refers to a group of medical symptoms comprising urinary urgency , frequent urination , nocturia , urinating unin tentionally and urge incontinence . Subjects with OAB may have one or more of these symptoms. [0059 ] The phrase " pharmaceutically acceptable ” refers to OH molecular entities and compositions that are generally Ilille regarded as safe and nontoxic . In particular, pharmaceuti cally acceptable carriers, diluents or other excipients used in NH the pharmaceutical compositions of this application are physiologically tolerable , compatible with other ingredients , and do not typically produce an allergic or similar untoward reaction ( e . g . , gastric upset, dizziness and the like ) when Solabegron is solabegron or a pharmaceutically acceptable administered to a subject. Preferably , as used herein , the salt thereof In embodiments , solabegron is amorphous , term “ pharmaceutically acceptable ” means approved by a zwitterion or the free base . In embodiments , a pharmaceu regulatory agency of the Federal or a state government or tically acceptable salt thereof may include , but is not limited listed in the U . S . Pharmacopoeia or other generally recog to , hydrochloride , hydrobromide , hydroiodide , nitrate , sul nized pharmacopoeia for use in animals , and more particu fate , bisulfate , phosphate , acid phosphate , isonicotinate , larly in humans. acetate , lactate, salicylate , citrate , tartrate , pantothenate , [ 0060 ] The phrase " pharmaceutically acceptable salt( s )” , bitartrate , ascorbate , succinate , maleate , gentisinate , fumar as used herein , includes those salts of compounds of the ate , gluconate , glucaronate , saccharate , formate , benzoate , application that are safe and effective for use in mammals glutamate , methanesulfonate , ethanesulfonate , benzensul and that possess the desired biological activity . Pharmaceu fonate , p - toluenesulfonate and pamoate ( i. e ., 1 , 1 ' -methyl tically acceptable salts include salts of acidic or basic groups ene - bis - ( 2 -hydroxy - 3 -naphthoate ) ) , various amino acids , present in compounds of the application or in compounds aluminum , calcium , lithium , magnesium , potassium , identified pursuant to the methods of the application . Phar sodium , zinc , iron , diethanolamine, amines, such as organic maceutically acceptable acid addition salts include , but are amines, N , N -dibenzyl ethylenediamine , chloroprocaine , not limited to , hydrochloride , hydrobromide, hydroiodide , choline, diethanolamine, dicyclohexylamine , ethylenedi nitrate , sulfate, bisulfate , phosphate , acid phosphate , isoni amine, N -methylglucamine , and procaine. Solabegron may cotinate , acetate , lactate , salicylate , citrate , tartrate , pantoth - exist in any physical form known to one of skill in the art enate , bitartrate , ascorbate , succinate , maleate , gentisinate , such as , for example , nanoparticles, crystalline solids , amor fumarate , gluconate , glucaronate , saccharate , formate , ben phous solids , polymorphs, ionic solids such as , for example , zoate , glutamate , methanesulfonate , ethanesulfonate , ben cations, anions and zwitterions, pharmaceutically acceptable US 2017 /0348263 A1 Dec . 7 , 2017 salts , hydrates , solvates, stereoisomers , solutions and sus that had or would become abnormal . For the purposes of this pensions . Crystalline solids have regular ordered arrays of application , beneficial or desired clinical results include , but components held together by uniform intermolecular forces, are not limited to , alleviation of symptoms; diminishment of whereas the components of amorphous solids are not the extent or vigor or rate of development of the condition , arranged in regular arrays. Hydrates are substances that disorder or disease ; stabilization ( i . e . , not worsening ) of the incorporate at least one water molecule into their crystalline state of the condition , disorder or disease ; delay in onset or matrix . Solvates are substances that incorporate at least one slowing of the progression of the condition , disorder or solvent molecule into their crystalline matrix . Polymorphs disease ; amelioration of the condition , disorder or disease exhibit different crystalline structures for molecules that state ; and remission (whether partial or total) , whether or not have the same molecular formula and sequence of bonded it translates to immediate lessening of actual clinical symp atoms . Stereoisomers are isomeric molecules that have the toms, or enhancement or improvement of the condition , same molecular formula and sequence of bonded atoms disorder or disease . Treatment seeks to elicit a clinically ( constitution ) , but that differ only in the three - dimensional significant response without excessive levels of side effects . orientations of their atoms in space . In some embodiment solabegron is the amorphous solid form of solabegron . In Pharmaceutical Compositions some embodiments , solabegron is solabegron hydrochlo [0070 ] In one embodiment, the present application ride . In some embodiments the solabegron is the zwitterion describes a pharmaceutical composition comprising a thera form of solabegron . peutically effective amount of solabegron , wherein the phar [0064 ] The terms “ subject, ” “ individual” or “ patient” are maceutical composition achieves a first target Cmax , a sec used interchangeably and as used herein are intended to ond target Cmax , a first target Cmin between the first target include human and non -human animals . Non - human ani Cmar and the second target Cmax , and a second target Cmin mals includes all vertebrates , e . g . mammals and non -mam after the second target Cmar mals , such as non -human primates , sheep , dogs , cats , cows , [0071 ] In embodiments , the first target Cmax is about 0 . 5 horses , chickens , amphibians , and reptiles, although mam ug/ mL to about 4 . 0 ug /mL . In embodiments , the first target mals are preferred , such as non - human primates, sheep , Cmor is about 1 . 0 ug /mL to about 3 . 5 ug /mL . In embodi dogs , cats , cows and horses. Preferred subjects include ments, the first target Cmax is about 1 ug/ mL to about 2. 0 humans in need of treatment. The methods are particularly ug /mL . In embodiments , the first target Cmor is about 1 . 5 suitable for treating humans having a disease or disorder ug /mL to about 3 . 5 ug/ mL . In embodiments , the first target described herein . Cmor is about 1 . 5 ug /mL to about 3 . 0 ug /mL . In embodi [ 0065 ] As used herein , the term “ therapeutic ” means an ments , the first target Cmax is about 2 .0 ug/ mL to about 3 . 5 agent utilized to treat, combat , ameliorate , protect against or ug/ mL . In embodiments, the first target Cmar is about 2 . 0 improve an unwanted condition or disease of a subject. ug /mL to about 3 . 0 ug /mL . In embodiments , the first target [0066 ] The term “ therapeutic benefit” means having an Cmax is about 1. 0 ug /mL to about 4 .0 ug /mL . In embodi effect that results in a beneficial outcome. For example , the ments , the first target Cmoy is about 1 . 5 ug /mL to about 4 . 0 beneficial outcome can be a minimize desensitization of the ug /mL . In embodiments , the first target Cmax is about 2 .0 beta - 3 adrenoceptor ; an increase therapeutic response ; ame ug /mL to about 4 . 0 ug /mL . In embodiments , the first target lioration , protection against or improvement of an unwanted Cmor is about 2 . 5 ug/ mL to about 4 . 0 ug /mL . In embodi condition or disease ; alleviation of symptoms; diminishment ments , the first target Cmax is about 3 . 0 ug/ mL to about 4 .0 of the extent or vigor or rate of development of the condi ug /mL . In embodiments , the first target C is about 3 . 5 tion , disorder or disease ; stabilization ( i . e ., not worsening ) of ug /mL to about 4 .0 ug /mL . In embodiments , the first target the state of the condition , disorder or disease ; delay in onset Cmor is about 0 . 5 ug /mL to about 3 . 5 ug/ mL . In embodi or slowing of the progression of the condition , disorder or ments , the first target C is about 2 . 5 ug/ mL to about 3 . 5 disease ; and remission of a disorder or disease . The thera ug/ mL . In embodiments , the first target Cmax is about 3 . 0 peutic benefit may be objective (i . e . , measurable by some ug /mL to about 3 . 5 ug /mL . In embodiments, the first target test or marker ) or subjective (i . e. , subject gives an indication Cmor is about 0 . 5 ug /mL to about 3 . 0 ug /mL . In embodi of or feels an effect or physician observes a change ) . ments , the first target Cmax is about 1 . 0 ug /mL to about 3 . 0 [ 0067 ] As used herein the term “ therapeutically effective ug/ mL . In embodiments , the first target Cmor is about 2 . 5 amount of compositions of the application is an amount , ug/ mL to about 3 . 0 ug /mL . In embodiments , the first target which confers a therapeutic effect on the treated subject, at Cmax is about 0 . 5 ug /mL to about 2 .5 ug/ mL . In embodi a reasonable benefit / risk ratio applicable to any medical ments , the first target Cmax is about 1 . 0 ug/ mL to about 2 . 5 treatment. The therapeutic effect may be objective ( i . e ., ug /mL . In embodiments , the first target Cmax is about 1 .5 measurable by some test or marker ) or subjective (i . e ., ug/ mL to about 2 . 5 ug/ mL . In embodiments , the first target subject gives an indication of or feels an effect or physician Cmax is about 2 . 0 ug/ mL to about 2 . 5 ug /mL . In embodi observes a change ). ments , the first target Cmax is about 0 . 5 ug /mL to about 2 .0 [ 0068 ] As used herein the terms “ TID ” and t. i. d . ” mean ug /mL . In embodiments , the first target Cmax is about 1 . 5 three times a day ( from the Latin ter in die ) . ug/ mL to about 2 . 0 ug /mL . In embodiments , the first target [0069 ] As used herein the terms " treat” , “ treated ” , or Cmor is about 0 . 5 ug /mL to about 1 . 5 ug /mL . In embodi “ treating ” refer to both therapeutic treatment and prophy ments , the first target Cmax is about 1 . 0 ug/ mL to about 1 . 5 lactic or preventative measures , wherein the object is to ug /mL . In embodiments , the first target Cmor is about 0 . 5 protect against ( partially or wholly ) or slow down ( e . g ., ug /mL to about 1 . 0 ug /mL . lessen or postpone the onset of) an undesired physiological [0072 ] In embodiments , the first target Cmin is about 0 .25 condition , disorder or disease, or to obtain beneficial or ug /mL to about 1 . 5 ug /mL . In embodiments , the first target desired clinical results such as partial or total restoration or Cmin is about 0 .25 ug /mL to about 1 ug /mL . In embodiments , inhibition in decline of a parameter , value, function or result the first target Cmin is about 0 . 5 ug/ mL to about 1 . 5 ug/ mL . US 2017 /0348263 A1 Dec . 7 , 2017
In embodiments , the first target Cmin is about 0 . 5 ug/ mL to the second target Cmin is about 0 .05 ug/ mL to about 0 . 75 about 1. 0 ug /mL . In embodiments , the first target Cmin is ug /mL . In embodiments , the second target Cmin is about 0 . 1 about 0 .75 ug/ mL to about 1 . 5 ug /mL . In embodiments , the ug /mL to about 0 .75 ug /mL . In embodiments , the second first target my is about 0 .25 ug /mL to about 1 . 25 ug /mL . In target C is about 0 .25 ug /mL to about 0 .75 ug /mL . In embodiments , the first target Cmin is about 1 . 0 ug /mL to embodiments , the second target Cmin is about 0 . 5 ug /mL to about 1 . 5 ug/ mL . In embodiments , the first target Cmin is about 0 .75 ug /mL . In embodiments , the second target Cmin about 1 .25 ug /mL to about 1 . 5 ug /mL . In embodiments , the is about 0 . 01 ug /mL to about 0 . 5 ug /mL . In embodiments , first target Cmin is about 0 . 5 ug /mL to about 1 . 25 ug /mL . In the second target Cmin is about 0 .05 ug /mL to about 0 . 5 embodiments , the first target Cmin is about 0 .75 ug /mL to ug /mL . In embodiments , the second target Cmin is about 0 . 1 about 1. 25 ug /mL . In embodiments , the first target Cmin is ug/ mL to about 0 . 5 ug/ mL . In embodiments , the second about 1 .0 ug/ mL to about 1 .25 ug /mL . In embodiments , the target Cmin is about 0 .25 ug /mL to about 0 . 5 ug /mL . In first target Cmin is about 0 . 75 ug /mL to about 1 ug/ mL . In embodiments , the second target Cmin is about 0 . 01 ug/ mL to embodiments , the first target Cmin is about 0 . 25 ug /mL to about 0 . 25 ug /mL . In embodiments , the second target Cmin about 0 .75 ug /mL . In embodiments, the first target Cmin is is about 0 . 05 ug /mL to about 0 .25 ug /mL . In embodiments , about 0 . 5 ug /mL to about 0 . 75 ug /mL . In embodiments , the the second target Cmin is about 0 . 1 ug /mL to about 0 .25 first target Cmin is about 0 .25 ug /mL to about 0 .5 ug /mL . ug /mL . In embodiments , the second target Cmin is about 0 .01 [0073 ] In embodiments , the second target Cmax is about ug /mL to about 0 . 1 ug /mL . In embodiments , the second 1 . 5 ug/ mL to about 4 . 0 ug /mL . In embodiments , the second target Cmin is about 0 .05 ug /mL to about 0 . 1 ug /mL . In target Cmax is about 1. 5 ug /mL to about 3. 0 ug /mL . In embodiments , the second target Cmin is about 0 .01 ug /mL to embodiments , the second target Cmax is about 2 . 5 ug/ mL to about 0 .05 ug/ mL . about 4 . 0 ug /mL . In embodiments , the second target Cmar is [0075 ]. In embodiments , the first target Cmormn is achieved at about 2 . 0 ug /mL to about 4 . 0 ug /mL . In embodiments, the about 0 .75 to about 4 hours ( i . e . , first Tmax) after adminis second target Cmax is about 2 . 0 ug /mL to about 3 .0 ug/ mL . tration of the pharmaceutical composition . In embodiments , In embodiments , the second target Cmax is about 3 . 0 ug /mL the first target Cmar is achieved at about 1 .5 to about 3 hours to about 4 . 0 ug/ mL . In embodiments , the second target Cmax ( i . e . , first Tmor) after administration of the pharmaceutical is about 0 . 5 ug /mL to about 4 . 0 ug /mL . In embodiments , the composition . In embodiments, the first target Cmor is second target Cmax is about 1 . 0 ug/ mL to about 4 . 0 ug/ mL . achieved at about 1 . 0 to about 4 hours ( i. e ., first Tmax ) after In embodiments , the second target Cmax is about 3 . 5 ug /mL administration of the pharmaceutical composition . In to about 4 .0 ug/ mL . In embodiments , the second target Cmax embodiments , the first target Cmax is achieved at about 1 . 5 to is about 0 . 5 ug/ mL to about 3 . 5 ug /mL . In embodiments , the about 4 hours ( i. e . , first Tm ) after administration of the second target Cmax is about 1 .0 ug/ mL to about 3 .5 ug/ mL . pharmaceutical composition . In embodiments , the first tar In embodiments , the second target Cmor is about 1 . 5 ug /mL get Cmax is achieved at about 2 .0 to about 4 hours (i . e . , first to about 3 . 5 ug/ mL . In embodiments , the second target Cmax Tmar ) after administration of the pharmaceutical composi is about 2 . 0 ug /mL to about 3 .5 ug /mL . In embodiments , the tion . In embodiments , the first target Cmor is achieved at second target Cmor is about 2 . 5 ug /mL to about 3 . 5 ug /mL . about 2 . 5 to about 4 hours ( i. e ., first Tmax ) after administra In embodiments , the second target Cmax is about 3 . 0 ug /mL tion of the pharmaceutical composition . In embodiments , the to about 3 . 5 ug /mL . In embodiments , the second target Cmaxmax first target Cmor is achieved at about 3 . 0 to about 4 hours is about 0 .5 ug /mL to about 3 .0 ug /mL . In embodiments , the ( i . e . , first Tmax ) after administration of the pharmaceutical second target Cmax is about 1 . 0 ug /mL to about 3 .0 ug/ mL . composition . In embodiments, the first target Cmor is In embodiments , the second target Cmax is about 2 .5 ug /mL achieved at about 3. 5 to about 4 hours (i . e. , first Tmarmax) after to about 3 . 0 ug /mL . In embodiments , the second target Cmax administration of the pharmaceutical composition . In is about 0 . 5 ug /mL to about 2 . 5 ug /mL . In embodiments , the embodiments , the first target Cmor is achieved at about 0 . 75 second target Cmar is about 1 . 0 ug/ mL to about 2 . 5 ug /mL . to about 3 . 5 hours ( i . e . , first Tor ) after administration of the In embodiments , the second target Cmax is about 1 . 5 ug/ mL pharmaceutical composition . In embodiments , the first tar to about 2 .5 ug /mL . In embodiments , the second target Cmax get Cmar is achieved at about 1. 0 to about 3 .5 hours (i . e. , first is about 2 .0 ug /mL to about 2 . 5 ug /mL . In embodiments , the TO ) after administration of the pharmaceutical composi second target Cmax is about 0 . 5 ug/ mL to about 2 .0 ug/ mL . tion . In embodiments , the first target Cmax is achieved at In embodiments , the second target Cmor is about 1 . 0 ug /mL about 1 . 5 to about 3 . 5 hours ( i . e ., first Tmor ) after adminis to about 2 .0 ug/ mL . In embodiments , the second target Cmax tration of the pharmaceutical compositionmax . In embodiments , is about 1. 5 ug/ mL to about 2 .0 ug /mL . In embodiments , the the first target Cmax is achieved at about 2 . 0 to about 3 . 5 second target Cmax is about 0 . 5 ug/ mL to about 1 . 5 ug/ mL . hours (i . e. , first Tmar) after administration of the pharma In embodiments , the second target Cmax is about 1 .0 ug /mL ceutical composition . In embodiments , the first target Cmax to about 1. 5 ug/ mL . In embodiments , the second target Cmax is achieved at about 2 .5 to about 3 . 5 hours ( i. e ., first Tmar ) is about 0 .5 ug /mL to about 1 .0 ug /mL . after administration of the pharmaceutical composition . In [0074 ] In embodiments , the second target Cmin is about 0 . 1 embodiments , the first target Cmax is achieved at about 3 . 0 to ug /mL to about 1 . 0 ug /mL . In embodiments, the second about 3 . 5 hours ( i. e . , first Tmar ) after administration of the target Cmin is about 0 .25 ug /mL to about 1. 0 ug /mL . In pharmaceutical composition . In embodiments , the first tar embodiments , the second target Cmin is about 0 . 5 ug /mL to get mor is achieved at about 0 .75 to about 3 . 0 hours ( i . e . , about 1 . 0 ug /mL . In embodiments , the second target Cmin is first Tmax) after administration of the pharmaceutical com about 0 . 75 ug/ mL to about 1. 0 ug/ mL . In embodiments , the position . In embodiments , the first target Cmax is achieved at second target Cmin is about 0 .05 ug /mL to about 1 . 0 ug /mL . about 1 . 0 to about 3 . 0 hours ( i . e ., first Tmor ) after adminis In embodiments , the second target Cmin is about 0 .01 ug /mL tration of the pharmaceutical composition . In embodiments , to about 1 . 0 ug /mL . In embodiments , the second target Cmin the first target Cmor is achieved at about 2 . 0 to about 3 . 0 is about 0 .01 ug/ mL to about 0 .75 ug/ mL . In embodiments , hours ( i. e . , first Tmax ) after administration of the pharma US 2017 /0348263 A1 Dec . 7 , 2017 ceutical composition . In embodiments , the first target Cmax about 7 . 5 hours ( i. e ., first Tmin ) after administration of the is achieved at about 2 . 5 to about 3 . 0 hours ( i. e . , first Tmar ) pharmaceutical composition . In embodiments , the first tar after administration of the pharmaceutical composition . In get min is achieved at about 6 . 5 to about 7 . 5 hours ( i. e ., first embodiments , the first target Cmor is achieved at about 0 .75 Tin ) after administration of the pharmaceutical composi to about 2 . 5 hours ( i. e . , first Tmar ) after administration of the tion . In embodiments , the first target Cmin is achieved at pharmaceutical composition . In embodiments , the first tar about 7 . 0 to about 7 . 5 hours ( i . e . , first Tuinmy ) after adminis get Cmax71 27 is achieved at about 1 . 0 to about 2 . 5 hours ( i. e . , first tration of the pharmaceutical composition . In embodiments , Tar) after administration of the pharmaceutical composi the first target Cmin is achieved at about 4 to about 7 .0 hours tion . In embodiments , the first target Cmax is achieved at ( i. e ., first Tmin ) after administration of the pharmaceutical about 1 . 5 to about 2 .5 hours (i .e ., first Tmax) after adminis composition . In embodiments , the first target Cmin is tration of the pharmaceutical composition . In embodiments, achieved at about 4 . 5 to about 7 . 0 hours ( i . e . , first Tmin after the first target Cmax is achieved at about 2 . 0 to about 2 .5 administration of the pharmaceutical composition . In hours ( i . e . , first Timor ) after administration of the pharma embodiments, the first target Cmin is achieved at about 5 to ceutical composition . In embodiments, the first targetCor max about 7 . 0 hours ( i . e ., first Tmin ) after administration of the is achieved at about 0 .75 to about 2 . 0 hours (i . e. , first Tmax ) pharmaceutical composition . In embodiments , the first tar after administration of the pharmaceutical composition . In get mi is achieved at about 5 . 5 to about 7 . 0 hours ( i . e . , first embodiments , the first target Cmar is achieved at about 1 . 0 to Tmin ) after administration of the pharmaceutical composi about 2 . 0 hours ( i .e ., first Tmor ) after administration of the tion . In embodiments , the first target Cmin is achieved at pharmaceutical composition . In embodiments , the first tar about 6 to about 7 . 0 hours ( i . e ., first Tmin ) after administra get Cmax is achieved at about 1 . 5 to about 2 . 0 hours (i . e . , first tion of the pharmaceutical composition . In embodiments , the TW ) after administration of the pharmaceutical composi first target Cmi is achieved at about 6 . 5 to about 7 . 0 hours tion . In embodiments , the first target Cmax is achieved at i. e ., first Tminmin /) after administration of the pharmaceutical about 0 .75 to about 1 . 5 hours ( i .e . , first Tor ) after admin composition . In embodiments , the first target Cmin is istration of the pharmaceutical composition . In embodi achieved at about 4 to about 6 . 5 hours ( i. e ., first Twin ) after ments , the first target Cmar is achieved at about 1 . 0 to about administration of the pharmaceutical composition . In 1 . 5 hours ( i. e . , first Tmor ) after administration of the phar embodiments , the first target Cmin is achieved at about 4 . 5 to maceutical composition . In embodiments , the first target about 6 .5 hours ( i. e ., first Tmin ) after administration of the Cmor is achieved at about 0 .75 to about 1 . 0 hours ( i . e . , first pharmaceutical composition . In embodiments , the first tar Tmax ) after administration of the pharmaceutical composi get min is achieved at about 5 to about 6 .5 hours (i .e . , first tion . Tmin ) after administration of the pharmaceutical composi tion . In embodiments, the first target Cmin is achieved at [0076 ] In embodiments , the first target Cmin is achieved at about 5 . 5 to about 6 . 5 hours ( i. e . , first Tmin ) after adminis about 4 to about 8 hours ( i. e . , first Tmin ) after administration tration of the pharmaceutical composition . In embodiments , of the pharmaceutical composition . In embodiments , the first the first target Cmi is achieved at about 6 to about 6 . 5 hours target Cmin is achieved at about 5 to about 6 hours ( i . e . , first ( i. e ., first Tmin ) after administration of the pharmaceutical ImTmnin ) after administration of the pharmaceutical composi composition . In embodiments , the first target Cmin is tion . In embodiments , the first target Cmin is achieved at min about 4 . 5 to about 8 hours ( i . e . , first Tmin ) after administra achieved at about 4 to about 6 . 0 hours ( i . e . , first Tuin ) after tion of the pharmaceutical composition . In embodiments , the administration of the pharmaceutical composition . In first target Cmin is achieved at about 5 to about 8 hours ( i . e . , embodiments , the first target Cmin is achieved at about 4 . 5 to first Tmin ) after administration of the pharmaceutical com about 6 . 0 hours (i . e ., first Tmin ) after administration of the position . In embodiments , the first target Cmin is achieved at pharmaceutical composition . In embodiments , the first tar about 5 . 5 to about 8 hours ( i . e ., first Tmin ) after administra get Cmin is achieved at about 5 . 5 to about 6 . 0 hours ( i. e ., first tion of the pharmaceutical composition . In embodiments , the Twin ) after administration of the pharmaceutical composi first target Cmin is achieved at about 6 to about 8 hours (i . e ., tion . In embodiments , the first target Cminmin is achieved at first Tmin ) after administration of the pharmaceutical com about 4 to about 5 .5 hours ( i. e ., first Tmin ) after administra position . In embodiments , the first target C is achieved at tion of the pharmaceutical composition . In embodiments , the about 6 .5 to about 8 hours ( i. e ., first Tmin ) after administra first target Cmin is achieved at about 4 . 5 to about 5 . 5 hours tion of the pharmaceutical composition . In embodiments , the ( i. e ., first Tmin ) after administration of the pharmaceutical first target Cmin is achieved at about 7 .0 to about 8 hours (i . e ., composition . In embodiments , the first target Cmin is first Tmin ) after administration of the pharmaceutical com achieved at about 5 to about 5 . 5 hours ( i. e . , first Tmin ) after position . In embodiments , the first target Cmin is achieved at administration of the pharmaceutical composition . In about 7 . 5 to about 8 hours ( i . e . , first Tmin ) after administra embodiments , the first target Cmin is achieved at about 4 to tion of the pharmaceutical composition . In embodiments , the about 5 . 0 hours ( i . e . , first Tmin ) after administration of the first target mi is achieved at about 4 to about 7 . 5 hours (i . e . , pharmaceutical composition . In embodiments , the first tar first Tmin ) after administration of the pharmaceutical com get Cmin is achieved at about 4 . 5 to about 5 .0 hours (i . e ., first position . In embodiments , the first target Cmin is achieved at Twin ) after administration of the pharmaceutical composi about 4 . 5 to about 7 . 5 hours ( i . e ., first Tmin ) after adminis tion . In embodiments , the first target Cmin7711 7 is achieved at tration of the pharmaceutical composition . In embodiments , about 4 to about 4 . 5 hours ( i. e . , first Tmin ) after administra the first target Cmin is achieved at about 5 to about 7 . 5 hours tion of the pharmaceutical composition . ( i. e ., first Tmin ) after administration of the pharmaceutical [0077 ] In embodiments , the second target Cmax is achieved composition . In embodiments , the first target Cmin is at about 12 to about 20 hours ( i. e ., second Tmax ) after achieved at about 5 . 5 to about 7 .5 hours (i . e . , first Tmin ) after administration of the pharmaceutical composition . In administration of the pharmaceutical composition . In embodiments , the second target Cmar is achieved at about 14 embodiments , the first target Cmin is achieved at about 6 to to about 16 hours (i . e ., second Tmar ) after administration of US 2017 /0348263 A1 Dec . 7 , 2017
the pharmaceutical composition . In embodiments , the sec the pharmaceutical composition . In embodiments , the sec ond target Cmax is achieved at about 2 .75 to about 16 hours ond target Cmax is achieved at about 2. 75 to about 6 hours ( i. e ., second Tmax ) after administration of the pharmaceutical (i . e. , second Tmar) after administration of the pharmaceutical composition . In embodiments , the second target Cmor is composition . In embodiments , the second target Cmax is achieved at about 4 to about 16 hours ( i. e ., second Tmax ) achieved at about 4 to about 6 hours (i .e ., second Tmax ) after after administration of the pharmaceutical composition . In administration of the pharmaceutical composition . In embodiments , the second target Cmax is achieved at about 6 embodiments , the second target Cmax is achieved at about to about 16 hours ( i. e ., second Tmax ) after administration of 2 . 75 to about 4 hours ( i . e . , second Tor ) after administration the pharmaceutical composition . In embodiments , the sec of the pharmaceutical composition . In embodiments , the ond target Cmar is achieved at about 8 to about 16 hours (i . e ., second target Cmax is achieved at about 16 , about 17 , about second Tmax ) after administration of the pharmaceutical 18 , about 19 or about 20 hours . composition . In embodiments , the second target Cmax is [0078 ] In embodiments , the second target Cmar is achieved achieved at about 10 to about 16 hours (i . e ., second Tmar) at about 2 to about 8 hours ( i. e . , second Tmax ) after the first after administration of the pharmaceutical composition . In target Cmin . In embodiments , the second target Cmax is embodiments , the second target Cmax is achieved at about 12 achieved at about 4 to about 6 hours ( i. e ., second Tmor ) after to about 16 hours ( i. e ., second Tor ) after administration of the first target Cmin . In embodiments , the second target Cmax the pharmaceutical composition . In embodiments , the sec is achieved at about 3 to about 8 hours ( i. e . , second Tmax ) after the first target Cmax . In embodiments , the second target ond target Cmor2 is achieved at about 2 . 75 to about 14 hours ( i. e ., second Tmax ) after administration of the pharmaceutical Cmor is achieved at about 4 to about 8 hours ( i . e . , second composition . In embodiments , the second target Cmax is Tmar ) after the first target Cmin . In embodiments , the second achieved at about 4 to about 14 hours ( i. e ., second Tmor ) target Cmor is achieved at about 5 to about 8 hours ( i . e . , after administration of the pharmaceutical composition . In second Tmax ) after the target first Cmin . In embodiments , the embodiments , the second target Cmax is achieved at about 6 second target Cmax is achieved at about 6 to about 8 hours to about 14 hours (i . e . , second Tmar ) after administration of (i . e ., second Tmar ) after the first target Cmin . In embodi the pharmaceutical composition . In embodiments , the sec ments , the second target Cmax is achieved at about 7 to about ond target Cmois achieved at about 8 to about 14 hours ( i. e ., 8 hours ( i. e ., second Tor) after the first target Cmim . In second Tor ) after administration of the pharmaceutical embodiments , the second target Cmax is achieved at about 2 mo composition . In embodiments, the second target CmorMax is to about 7 hours ( i. e ., second Tmax) after the first target Cmin . achieved at about 10 to about 14 hours ( i. e . , second Tmar) In embodiments , the second target Cmax is achieved at about after administration of the pharmaceutical composition . In 3 to about 7 hours ( i . e . , second Tor ) after the first target embodiments , the second target Cmax is achieved at about 12 Cmin . In embodiments , the second target C is achieved at to about 14 hours ( i . e . , second Tor) after administration of about 4 to about 7 hours ( i . e . , second Tmax7712X ) after the first the pharmaceutical composition . In embodiments , the sec target Cmiv . In embodiments , the second target Cmoris ond target Cmax is achieved at about 2 .75 to about 12 hours achieved at about 5 to about 7 hours ( i . e ., second Tmax ) after (i . e ., second Tmax ) after administration of the pharmaceutical the first target Cmin . In embodiments, the second target Cmor composition . In embodiments , the second target Cmax is is achieved at about 6 to about 7 hours (i . e . , second Tmaxmax ) achieved at about 4 to about 12 hours (i . e . , second Tmar ) after the first target Cmin . In embodiments , the second target after administration of the pharmaceutical composition . In Cmor is achieved at about 2 to about 6 hours ( i. e ., second embodiments , the second target Cmax is achieved at about 6 Tmax ) after the first target Cmin . In embodiments , the second to about 12 hours (i . e ., second Tmar ) after administration of target Cmor is achieved at about 3 to about 6 hours ( i . e . , the pharmaceutical composition . In embodiments , the sec second Tor ) after the first target Cmin . In embodiments, the ond target Cmax is achieved at about 8 to about 12 hours ( i. e . , second target Cmax is achieved at about 5 to about 6 hours second Tmax ) after administration of the pharmaceutical ( i . e . , second Tormax ) after the first target Cmim . In embodi composition . In embodiments , the second target Cmax is ments, the second target Cmor is achieved at about 2 to about achieved at about 10 to about 12 hours ( i. e . , second Tmax ) 5 hours (i . e ., second Tmar ) after the first target Cmin . In after administration of the pharmaceutical composition . In embodiments , the second target Cmax is achieved at about 3 embodiments , the second target Cmax is achieved at about to about 5 hours ( i. e ., second Tmar ) after the first target Cmin . 2 .75 to about 10 hours ( i. e ., second Tmor ) after administra In embodiments , the second target Cmor is achieved at about tion of the pharmaceutical composition . In embodiments , the 4 to about 5 hours ( i. e ., second Tmax ) after the first target second target Cmax is achieved at about 4 to about 10 hours Cmin . In embodiments , the second target Cmax is achieved at ( i. e . , second Tmar) after administration of the pharmaceutical about 2 to about 4 hours ( i . e . , second Tmax771AX , ) after the first composition . In embodiments , the second target Cmax is target Cmin . In embodiments , the second target Cmax is achieved at about 6 to about 10 hours (i . e. , second Tmar ) achieved at about 3 to about 4 hours (i . e. , second Tmar ) after after administration of the pharmaceutical composition . In the first target Cmin . In embodiments , the second target Cmax embodiments , the second target Cmax is achieved at about 8 is achieved at about 2 to about 3 hours (i . e ., second Tmax) to about 10 hours ( i. e . , second Tmar) after administration of after the first target Cmin . the pharmaceutical composition . In embodiments , the sec [0079 ] In embodiments , the time between the first target ond target Cmar is achieved at about 2 .75 to about 8 hours Cmax and the second target Cmax is about 2 to about 8 hours . (i . e ., second Tmax ) after administration of the pharmaceutical In embodiments, the time between the first target Cmorand composition . In embodiments , the second target Cmax is the second target Cmax is about 3 to about 7 hours . In achieved at about 4 to about 8 hours ( i . e . , second Tor ) after embodiments , the time between the first target Cmar and the administration of the pharmaceutical composition . In second target Cmax is about 4 to about 6 hours . In embodi embodiments , the second target Cmor is achieved at about 6 ments , the time between the first target Cmor and the second to about 8 hours ( i. e ., second Tmar777 X ) after administration of target Cmax777 X is about 3 to about 8 hours . In embodiments , the US 2017 /0348263 A1 Dec . 7 , 2017
time between the first target Cmax and the second target Cmax pharmaceutical composition is a single unit dose . In embodi is about 4 to about 8 hours. In embodiments , the time ments, the pharmaceutical composition is two unit doses . between the first target Cmar and the second target Cmax is [0082 ] In one embodiment, the present application about 5 to about 8 hours. In embodiments , the time between describes a pharmaceutical composition comprising a thera the first target Cmax and the second target Cmax is about 6 to peutically effective amount of the amorphous solid form of about 8 hours . In embodiments , the time between the first solabegron , wherein the pharmaceutical composition target Cmax and the second target Cmax is about 7 to about 8 achieves a first target Cmax, a second target Cmax , a first hours . In embodiments , the time between the first target target Cmin between the first target Cmax and the second Cmar and the second target Cmax is about 2 to about 7 hours . target Cmax, and a second target Cmin after the second target In embodiments , the timebetween the first target Cmax and Cmax , wherein the first target Cmax , the second target Cmax? the second target Cmor is about 4 to about 7 hours . In the first target Cming and second target Cmin are as described embodiments , the time between the first target Cmax and the previously . In one embodiment, the present application second target Cmax is about 5 to about 7 hours . In embodi describes a pharmaceutical composition comprising a thera ments , the timebetween the first target Cmor and the second peutically effective amount of the hydrochloride salt form of target Cmax is about 6 to about 7 hours . In embodiments , the solabegron , wherein the pharmaceutical composition time between the first target Cmor and the second target Cmox achieves a first target Cmax, a second target Cmar, a first is about 2 to about 6 hours . In embodiments, the time target Cmin between the first target Cmax and the second between the first target Cmar and the second target Cmar is target more and a second target Cmin after the second target about 3 to about 6 hours. In embodiments , the time between Cmax , wherein the first target Cmax , the second target Cmax? the first target Cmax and the second target Cmaxmax is about 5 to the first target Cming and second target Cmin are as described about 6 hours . In embodiments , the time between the first previously . In one embodiment, the present application target Cmor and the second target Cmor is about 2 to about 5 describes a pharmaceutical composition comprising a thera hours. In embodiments , the time between the first target peutically effective amount of the zwitterion form of sol CmorUn and the second target Cmor is about 3 to about 5 hours . abegron , wherein the pharmaceutical composition achieves In embodiments , the time between the first target Cmax and a first target Cmax , a second target Cmax , a first target Cmin the second target Cmax is about 4 to about 5 hours . In between the first target Cmax and the second target Cmax , and embodiments , the time between the first target Cmar and the a second target Cmin after the second target Cmar, wherein second target Cmor is about 2 to about 4 hours. In embodi the first target Cmax , the second target Cmax , the first target ments , the timebetween the first target Cmor and the second Cmin , and second target Cmin are as described previously . target Cmor is about 3 to about 4 hours . In embodiments , the Further embodiments describe pharmaceutical composi time between the first target Cmax and the second target Cmax tions, wherein said pharmaceutical composition achieves a is about 2 to about 3 hours . plasma concentration of about 1 ug /mL or less for about 6 [0080 ] In embodiments , the second target Cmin is achieved hours to about 9 hours during a twenty -four hour period . before about 24 hours ( i. e ., second Tmin ) after administration Further embodiments describe pharmaceutical composi of the pharmaceutical composition . In embodiments , the tions, wherein said pharmaceutical composition achieves a second target Cmin is achieved before about 20 hours ( i. e . , target AUC of about 5 ,000 ng hr /ml to about 30 ,000 ng second Tmin ) after administration of the pharmaceutical hr/ mL . Further embodiments describe pharmaceutical com composition . In embodiments , the second target Cmin is positions, further comprising two separate and distinct achieved before about 16 hours ( i . e . , second Tmin ) after releases of solabegron . Further embodiments describe phar administration of the pharmaceutical composition . In maceutical compositions , wherein the two releases are con embodiments the second target Cmin is achieved at about 24 tained within two separate and distinct drug delivery sys hours . In embodiments the second target Cmin is achieved at tems. Further embodiments describe pharmaceutical, about 23 hours . In embodiments the second target Cmin is wherein the two separate and distinct drug delivery systems achieved at about 22 hours. In embodiments the second are administered BID . Further embodiments describe phar target Cmin is achieved at about 21 hours . In embodiments maceutical compositions , wherein the BID administration is the second target Cmor is achieved at about 20 hours. In separated by a period ofbetween about 6 to about 18 hours . embodiments the second target Cmin is achieved at about 19 Further embodiments describe pharmaceutical composi hours . In embodiments the second target Cmin is achieved at tions, wherein the two releases are contained within the about 18 hours. In embodiments the second target Cmin is same drug delivery system . Further embodiments describe achieved at about 17 hours . In embodiments the second pharmaceutical compositions , wherein the delivery vehicle target Cmin is achieved at about 16 hours . is selected from the group consisting of: tablets ; bi- layer [0081 ] In embodiments , the first target Cmax may be tablets ; multilayer tablets , capsules ; spray dry formulations , achieved through a first release of solabegron and the second multi particulates; drug coated spheres /pellets ; matrix tab target Cmax may be achieved through a second release of lets ; and multi core tablets . Further embodiments describe solabegron . In embodiments , the first target Cmor may be pharmaceutical compositions , wherein the first target Cmoris achieved during or after a first release of solabegron ; that is achieved after the start of a first release of solabegron and the first target Cmax may be achieved after the start of the first the second target Cmor is achieved after the start of a second release . In embodiments , the second target Cmor may be release of solabegron . Further embodiments describe phar achieved during or after a second release of solabegron ; that maceutical compositions, wherein said first target Cmax is is the second target Cmar may be achieved after the start of about 0 . 5 ug /mL to about 3 . 5 ug/ mL . Further embodiments the second release . In embodiments , the first target Cmin may describe pharmaceutical compositions, wherein said second be achieved after the first target Cmax and before the second target Cmax is about 1 .5 ug .mL to about 4 ug/ mL . Further target Cmax . In embodiments , the second target Cmin may be embodiments describe pharmaceutical compositions , achieved after the second target Cmax . In embodiments , the wherein said first target Cmin is about 0 . 25 ug /mL to about US 2017 /0348263 A1 Dec . 7 , 2017
1 . 5 ug /mL . Further embodiments describe pharmaceutical target area under the curve of about 5 , 000 ng .hr / mL to about compositions, wherein said second target Cmin is about 0 .01 15 , 000 ng .hr /mL over a 24 hour period . In embodiments , the ug/ mL to about 1. 0 ug/ mL . Further embodiments describe pharmaceutical composition achieves a target area under the pharmaceutical compositions , wherein the time between the curve of about 10 , 000 ng .hr /mL to about 15 ,000 ng. hr / mL first target Cmax and the second target Cmax is about 2 to over a 24 hour period . In embodiments , the pharmaceutical about 8 hours . Further embodiments describe pharmaceuti composition achieves a target area under the curve of about cal compositions, wherein the first target Cmin777777 is achieved at 5 ,000 ng . hr /mL to about 10 ,000 ng .hr /mL over a 24 hour about 4 to about 8 hours after the first administration . period . In embodiments , the pharmaceutical composition Further embodiments describe pharmaceutical composi achieves a target area under the curve of about 5 , 000 tions , wherein the second target Cmin is achieved before ng . hr /mL over a 24 hour period ; about 6 , 000 ng .hr / mL over about 24 hours after administration of the pharmaceutical a 24 hour period ; about 7 ,000 ng .hr /mL over a 24 hour composition . Further embodiments describe pharmaceutical period ; about 8 ,000 ng .hr / mL over a 24 hour period ; about compositions, wherein the first target Cmor is achieved at 9 ,000 ng . hr /mL over a 24 hour period ; about 10 ,000 ng .hr / about 0 .75 to about 4 hours after the first administration . mL over a 24 hour period ; about 11 ,000 ng .hr /mL over a 24 Further embodiments describe pharmaceutical composi hour period ; about 12 ,000 ng .hr /mL over a 24 hour period ; tions, wherein the second target Cmor is achieved at about 2 about 13 ,000 ng .hr /mL over a 24 hour period , about 14 , 000 to about 8 hours after the first target Cmin . Further embodi ng .hr / mL over a 24 hour period , about 15 , 000 ng .hr / mL over ments describe pharmaceutical compositions, wherein the a 24 hour period ; about 16 , 000 ng. hr /mL over a 24 hour first release comprises about 30 mg to about 500 mg of period ; about 17 , 000 ng .hr /mL over a 24 hour period ; about solabegron . Further embodiments describe pharmaceutical 18 , 000 ng .hr /mL over a 24 hour period ; about 19 ,000 compositions, wherein the second release comprises about ng. hr / mL over a 24 hour period ; about 20 ,000 ng .hr / mL over 30 mg to about 500 mg of solabegron . Further embodiments a 24 hour period ; about 21, 000 ng .hr /mL over a 24 hour describe pharmaceutical compositions , further comprising period ; about 22 , 000 ng .hr /mL over a 24 hour period ; about one or more additional therapeutic agents selected from the 23 , 000 ng .hr /mL over a 24 hour period ; about 24 ,000 group consisting of: antimuscarinic agents ; alpha adreno ng. hr /mL over a 24 hour period; about 25 ,000 ng. hr / mL over ceptor blockers ; botulinum toxin ; purinergics ; cannabinoids ; a 24 hour period ; about 26 ,000 ng. hr / mL over a 24 hour transient receptor potential ( TRP ) protein inhibitors ; pros period ; about 27 , 000 ng .hr / mL over a 24 hour period ; about taglandins ; percutaneous tibial nerve stimulation ; 5 -alpha 28 , 000 ng .hr / mL over a 24 hour period ; about 29 ,000 reductase inhibitors; and phosphodiesterase - 5 inhibitors. ng .hr /mL over a 24 hour period ; or about 30 ,000 ng. hr/ mL [0083 ] In embodiments , the pharmaceutical composition over a 24 hour period . achieves a target area under the curve (herein after AUC ) of [0084 ] In embodiments , the plasma concentration [ C ] of about 5 , 000 ng. hr /mL to about 30 , 000 ng. hr /mL over a 24 solabegron is about 1 ug /mL or below for a period of time hour period . In embodiments , the pharmaceutical composi of about 6 hours to about 9 hours during a 24 hour period . tion achieves a target area under the curve of about 10 , 000 In embodiments , the plasma concentration [ C ] of solabegron ng .hr / mL to about 30 ,000 ng .hr / mL over a 24 hour period . is about 1 ug /mL or below for a period of time of about 7 In embodiments , the pharmaceutical composition achieves a hours to about 8 hours during a 24 hour period . In embodi target area under the curve of about 15 ,000 ng .hr / mL to ments , the plasma concentration [ C ] of solabegron is about about 30 ,000 ng .hr /mL over a 24 hour period . In embodi 1 ug/ mL or below for a period of time of about 7 hours to ments , the pharmaceutical composition achieves a target about 9 hours during a 24 hour period . In embodiments , the area under the curve of about 20 ,000 ng . hr /mL to about plasma concentration [ C ] of solabegron is about 1 ug/ mL or 30 ,000 ng. hr / mL over a 24 hour period . In embodiments , the below for a period of time of about 8 hours to about 9 hours pharmaceutical composition achieves a target area under the during a 24 hour period . In embodiments , the plasma curve of about 25 ,000 ng .hr / mL to about 30 ,000 ng. hr / mL concentration ( C ) of solabegron is about 1 ug /mL or below over a 24 hour period . In embodiments , the pharmaceutical for a period of time of about 6 hours to about 8 hours during composition achieves a target area under the curve of about a 24 hour period . In embodiments , the plasma concentration 5 ,000 ng . hr/ mL to about 25 ,000 ng .hr / mL over a 24 hour [ C ] of solabegron is about 1 ug /mL or below for a period of period . In embodiments , the pharmaceutical composition time of about 6 hours to about 7 hours during a 24 hour achieves a target area under the curve of about 10 ,000 period . ng. hr / mL to about 25 , 000 ng .hr / mL over a 24 hour period . [0085 ] In embodiments , the pharmaceutical composition In embodiments, the pharmaceutical composition achieves a provides a therapeutic benefit for about 15 to about 22 hours target area under the curve of about 15 ,000 ng .hr / mL to during a 24 hour period . In embodiments , the pharmaceu about 25 , 000 ng .hr / mL over a 24 hour period . In embodi tical composition provides a therapeutic benefit for about 15 ments , the pharmaceutical composition achieves a target hours during a 24 hour period . In embodiments , the phar area under the curve of about 20 ,000 ng .hr / mL to about maceutical composition provides a therapeutic benefit for 25 ,000 ng. hr / mL over a 24 hour period . In embodiments , the about 16 hours during a 24 hour period . In embodiments , the pharmaceutical composition achieves a target area under the pharmaceutical composition provides a therapeutic benefit curve of about 5 , 000 ng . hr/ mL to about 20 , 000 ng . hr /mL for about 17 hours during a 24 hour period . In embodiments , over a 24 hour period . In embodiments , the pharmaceutical the pharmaceutical composition provides a therapeutic ben composition achieves a target area under the curve of about efit for about 18 hours during a 24 hour period . In embodi 10 ,000 ng. hr / mL to about 20 ,000 ng. hr / mL over a 24 hour ments , the pharmaceutical composition provides a therapeu period . In embodiments , the pharmaceutical composition tic benefit for about 19 hours during a 24 hour period . In achieves a target area under the curve of about 15 ,000 embodiments , the pharmaceutical composition provides a ng .hr /mL to about 20 , 000 ng .hr /mL over a 24 hour period . therapeutic benefit for about 20 hours during a 24 hour In embodiments , the pharmaceutical composition achieves a period . In embodiments , the pharmaceutical composition US 2017 /0348263 A1 Dec . 7 , 2017 provides a therapeutic benefit for about 21 hours during a 24 500 mg. In embodiments , the first release of solabegron may hour period . In embodiments , the pharmaceutical composi be about 75 mg to about 400 mg. In embodiments , the first tion provides a therapeutic benefit for about 22 hours during release of solabegron may be about 75 mg to about 250 mg. a 24 hour period . In embodiments, the second release of solabegron may be [0086 ] In embodiments , the pharmaceutical composition about 30 mg to about 500 mg. In embodiments , the second provides a therapeutically effective [ C ] for about 15 hours to release of solabegron may be about 100 mg to about 400 mg. about 22 hours during a 24 period . In embodiments , the In embodiments , the first release and the second release of pharmaceutical composition provides a therapeutically solabegron may be about 125 mg. In embodiments , the first effective [ C ] for about 15 hours during a 24 period . In release and the second release of solabegron may be about embodiments , the pharmaceutical composition provides a 200 mg. In embodiments , the first release of solabegron may therapeutically effective [ C ] for about 16 hours during a 24 be about 125 mg and the second release of solabegron may period . In embodiments , the pharmaceutical composition be about 200 mg. In embodiments the first release of provides a therapeutically effective [ C ] for about 17 hours solabegron may be about 30 mg, about 35 mg, about 40 mg , during a 24 period . In embodiments , the pharmaceutical about 45 mg, about 50 mg, about 55 mg, about 60 mg, about composition provides a therapeutically effective [ C ] for 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 about 18 hours during a 24 period . In embodiments, the mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, pharmaceutical composition provides a therapeutically about 110 mg, about 115 mg, about 120 mg, about 125 mg, effective [C ] for about 19 hours during a 24 period . In about 130 mg, about 135 mg, about 140 mg , about 145 mg , embodiments , the pharmaceutical composition provides a about 150 mg, about 155 mg, about 160 mg, about 165 mg, therapeutically effective [ C ] for about 20 hours during a 24 about 170 mg, about 175 mg, about 180 mg, about 185 mg, period . In embodiments , the pharmaceutical composition about 190 mg, about 195 mg, about 200 mg , about 205 mg , provides a therapeutically effective [ C ] for about 21 hours about 210 mg, about 215 mg, about 220 mg, about 225 mg , during a 24 period . In embodiments , the pharmaceutical about 230 mg, about 235 mg, about 240 mg, about 245 mg, composition provides a therapeutically effective [ C ] for about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 22 hours during a 24 period . about 270 mg, about 275 mg, about 280 mg, about 285 mg , [ 0087 ] Further embodiments describe pharmaceutical about 290 mg, about 295 mg, about 300 mg, about 305 mg, compositions further comprising two separate and distinct about 310 mg, about 315 mg, about 320 mg , about 325 mg , releases of solabegron . Further embodiments describe phar about 330 mg, about 335 mg, about 340 mg, about 345 mg, maceutical compositions, wherein the first target Cmax is about 350 mg, about 355 mg, about 360 mg, about 365 mg, achieved after the start of a first release of solabegron and about 370 mg, about 375 mg, about 380 mg, about 385 mg, the second target Cmax is achieved after the start of a second about 390 mg, about 395 mg, about 400 mg, about 405 mg, release of solabegron . about 410 mg, about 415 mg, about 420 mg, about 425 mg, 10088 ] In embodiments , the first release of solabegron about 430 mg, about 435 mg, about 440 mg, about 445 mg, may be a pulsatile release of solabegron . In embodiments , about 450 mg, about 455 mg, about 460 mg, about 465 mg, the second release of solabegron may be a pulsatile release about 470 mg, about 475 mg, about 480 mg, about 485 mg , of solabegron . In embodiments , the first release of solabe about 490 mg, about 495 mg or about 500 mg. In embodi gron may be an immediate release of solabegron . In embodi ments the second release of solabegron may be 30 mg, about ments , the second release of solabegron may be an imme 35 mg, about 40 mg, about 45 mg , about 50 mg, about 55 diate release of solabegron . In embodiments , the first release mg, about 60 mg, about 65 mg, about 75 mg, about 75 mg, of solabegron may be modified release of solabegron . In about 80 mg, about 85 mg , about 90 mg, about 95 mg, about embodiments , the second release of solabegron may be a 100 mg, about 105 mg, about 110 mg, about 115 mg, about modified release of solabegron . In embodiments, the first 120 mg, about 125 mg , about 130 mg, about 135 mg, about release of solabegron may be an extended release of sol 140 mg, about 145 mg, about 150 mg, about 155 mg, about abegron . In embodiments, the second release of solabegron 160 mg , about 165 mg, about 170 mg, about 175 mg, about may be an extended release of solabegron . In embodiments , 180 mg, about 185 mg, about 190 mg, about 195 mg, about the first release of solabegron may be a delayed release of 200 mg , about 205 mg , about 210 mg , about 215 mg, about solabegron . In embodiments , the second release of solabe 220 mg, about 225 mg, about 230 mg, about 235 mg, about gron may be a delayed release of solabegron . In embodi 240 mg, about 245 mg, about 250 mg, about 255 mg, about ments , the first release of solabegron may be a multiparticu 260 mg, about 265 mg , about 270 mg , about 275 mg, about late formulation of solabegron . In embodiments, the second 280 mg, about 285 mg, about 290 mg, about 295 mg, about release of solabegron may be a multiparticulate formulation 300 mg , about 305 mg , about 310 mg , about 315 mg, about of solabegron . In embodiments , the first release of solabe 320 mg, about 325 mg, about 330 mg, about 335 mg, about gron may be a matrix formulation of solabegron . In embodi 340 mg, about 345 mg , about 350 mg, about 355 mg, about ments, the second release of solabegron may be a matrix 360 mg, about 365 mg , about 370 mg , about 375 mg, about formulation of solabegron . In embodiments , the first and 380 mg , about 385 mg, about 390 mg, about 395 mg, about second release of solabegron may be any combination of the 400 mg, about 405 mg, about 410 mg , about 415 mg, about foregoing . In embodiments the first release of solabegron 420 mg, about 425 mg, about 430 mg, about 435 mg, about and the second release of solabegron may be in a single 440 mg, about 445 mg, about 450 mg, about 455 mg, about pharmaceutical composition or in separate pharmaceutical 460 mg, about 465 mg, about 470 mg, about 475 mg, about compositions . 480 mg, about 485 mg, about 490 mg, about 495 mg or about [0089 ] In embodiments , the first release of solabegron and 500 mg . In embodiments the first release of solabegron and the second release of solabegron may be identical amounts the second release of solabegron may be in a single phar or may be different amounts of solabegron . In embodiments , maceutical composition or in separate pharmaceutical com the first release of solabegron may be about 30 mg to about positions . US 2017 /0348263 A1 Dec . 7 , 2017
[0090 ] In embodiments , the pharmaceutical compositions, release layer will release solabegron at a later time and lower further comprises one or more additional therapeutic agents in the GI tract. The modified release layer may be coated selected from the group consisting of : antimuscarinic agents ; with either a pH dependent coating or a time dependent alpha adrenoceptor blockers ; botulinum toxin ; purinergics ; coating so as to delay the second release of solabegron to the cannabinoids; transient receptor potential ( TRP ) protein desired position in the GI tract . It will be understood by one inhibitors ; prostaglandins ; percutaneous tibial nerve stimu of skill in the art that a bi- layer or multilayer tablet also lation ; 5 - alpha reductase inhibitors; and phosphodies encompasses a multi compartment tablet or capsule wherein terase - 5 inhibitors . In embodiments , the antimuscarinic the different regions of pharmaceutical compositions don ' t agent may be tolterodine, oxybutynin , trospium , solifenacin , have to be in layers , e . g beads compresses within a tablet darifenacin , propiverine , fesoterodine, and pharmaceutically formation . acceptable salts thereof. In embodiments , alpha adrenocep [ 0094 ] In embodiments , the pharmaceutical composition tor blockers may be tamuslosin , alfuzosin , and silodosin and may be a matrix tablet . In embodiments, the matrix tablet pharmaceutically acceptable salts thereof. In embodiments , may comprise a well -mixed composite of drug ( s ) with 5 - alpha reductase inhibitors may be finasteride , dutaseteride rate - controlling excipients . Numerous sustained and / or and pharmaceutically acceptable salts thereof. In embodi delayed release tablets such as membrane controlled system , ments , phosphodiesterase - 5 inhibitors may be sildenafil, matrices with water soluble / insoluble polymers , and osmotic tadaiafil, vardenafil , udenafil , avanafil and pharmaceutically systemsmay be utilized . The tablet may contain either the acceptable salts thereof amorphous form of solabegron , the crystalline form of [ 0091] In embodiments , the present application describes solabegron or any other form of solabegron . The delayed / a pharmaceutical composition comprising a multiparticulate sustained release can be achieved by applying a permeable formulation of mini -tablets each comprising a therapeuti or semipermeable membrane to the tablet core or by mixing cally effective amount of solabegron . In embodiments , the the drug with excipient that is either a hydrophilic polymer multiparticulate formulation may comprise at least two with high viscosity and gel forming capability or a hydro populations of pellets containing solabegron . In embodi phobic excipient that slows down the diffusion of drug ments , a first population of pellets is immediate release and molecule . An immediate release drug layer can be coated to a second population is delayed , sustained or modified the tablet that will be available for an early release in the GI release . In embodiments , the first population of pellets tract, while the delayed release core will be designed to release the solabegron immediately in the upper GI tract and delay the drug release after a time period in a designed the second population of pellets release the solabegron later region of the GI tract. In embodiments , the pharmaceutical in a lower portion of the GI tract. In embodiments , the composition is a single unit dose . In embodiments , the second population of pellets that are delayed , sustained or pharmaceutical composition is two unit doses . modified release may be coated with a pH dependent coating [ 0095 ] In embodiments , the pharmaceutical composition or a time dependent coating so as to delay the second release may be a multicore tablet. In embodiments the multicore of solabegron to the desired position in the GI tract. In tablet may comprise multiple discrete cores consisting of at embodiments, the pellets may be drug - layered and/ or least one immediate release core and at least one modified matrix - type pellets . release core contained within the same tablet . The at least [0092 ] In embodiments , the pharmaceutical composition one immediate release core will be available for an early may be a drug - coated sphere ( s ) formulation . In embodi release in the GI tract, while the at least one modified release ments , the formulation may comprise at least two popula core will be designed to delay the drug release after a time tions of drug - coated spheres containing solabegron . In period in a designed region of the GI tract . In embodiments , embodiments , a first population of drug - coated spheres the pharmaceutical composition is a single unit dose . In release the solabegron immediately in the upper GI tract and embodiments , the pharmaceutical composition is two unit the second population of drug - coated spheres release the doses. solabegron later in a lower portion of the GI tract. In [0096 ] In embodiments , the pharmaceutical composition embodiments , the second population of drug - coated spheres may be a gastroretentive oral delivery system . In embodi may be coated with a pH dependent coating or a time ments the gastroretentive oral delivery system may comprise dependent coating so as to delay the second release of a gastroretentive oral dosage form containing solabegron for solabegron to the desired position in the GI tract. In embodi the multiple releases of solabegron to a subject in need . The ments , the pharmaceutical composition is a single unit dose . formulation will contain a tablet or capsule having both an In embodiments , the pharmaceutical composition is two unit immediate release and modified release component. The doses. In further embodiments the spheres allow for a drug immediate layer will release solabegron immediately in the load of solabegron of greater than about 30 weight percent GI tract , wherein the modified release layer will release of the composition ; greater than about 35 weight percent of solabegron at a later time inside the GI tract. The gastrore the composition ; greater than about 40 weight percent of the tentive oral dosage form may utilize mucoadhesive , composition , greater than about 50 weight percent of the swellable , high density or floating technologies to prolong composition , greater than about 55 weight percent of the residence time in the stomach thereby allowing a prolonged composition or greater than about 60 weight percent of the period for release of both first and second releases in the composition . stomach or upper GI. Both releases may contain any physi 10093 ]. In embodiments , the pharmaceutical composition cal form of solabegron such as , for example , amorphous or may be a bi- layer tablet or a dual- encapsulated capsule . In crystalline solid . In embodiments , the pharmaceutical com embodiments , the bi- layer tablet may comprise an immedi position is a single unit dose . In embodiments , the pharma ate release layer and a delayed , sustained or modified release ceutical composition is two unit doses . layer. The immediate layer may release solabegron imme [0097 ] In one embodiment, the present application diately in the GI tract and the modified , delayed or sustained describes a pharmaceutical composition for the delivery of US 2017 /0348263 A1 Dec . 7 , 2017 solabegron , comprising at least one immediate release com about 185 mg, about 190 mg, about 195 mg, about 200 mg , position , comprising solabegron and at least one pharma about 205 mg, about 210 mg, about 215 mg, about 220 mg, ceutically acceptable carrier or diluent; and at least one about 225 mg, about 230 mg, about 235 mg , about 240 mg, modified release composition , comprising solabegron and at about 245 mg, about 250 mg, about 255 mg, about 260 mg, least one pharmaceutically acceptable carrier or diluent. about 265 mg, about 270 mg, about 275 mg, about 280 mg , Further embodiments describe pharmaceutical composi about 285 mg, about 290 mg, about 295 mg , about 300 mg, tions, wherein the at least one immediate release composi about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, tion comprises about 75 mg to about 400 mg solabegron . about 345 mg, about 350 mg, about 355 mg , about 360 mg , Further embodiments describe pharmaceutical composi about 365 mg, about 370 mg, about 375 mg, about 380 mg, tions, wherein the at least one modified release composition about 385 mg, about 390 mg, about 395 mg , about 400 mg , comprises about 100 mg to about 400 mg solabegron . about 405 mg, about 410 mg, about 415 mg , about 420 mg , Further embodiments describe pharmaceutical composi about 425 mg, about 430 mg, about 435 mg , about 440 mg, tions, wherein the at least one immediate release composi about 445 mg, about 450 mg, about 455 mg , about 460 mg , tion comprises about 100 mg to about 300 mg solabegron about 465 mg, about 470 mg, about 475 mg, about 480 mg, and the at least one modified release composition comprises about 485 mg, about 490 mg, about 495 mg or about 500 mg. about 100 mg to about 300 mg solabegron . Further embodi Further embodiments describe pharmaceutical composi ments describe pharmaceutical compositions , wherein the at tions , wherein the at least one immediate release composi least one immediate release composition comprises about tion achieves a blood plasma Cmax from about 0 . 5 ug /mL to 125 mg solabegron and the at least one modified release about 3 . 5 ug /mL . Further embodiments describe pharma composition comprises about 125 mg solabegron . Further ceutical compositions, wherein the at least one modified embodiments describe pharmaceutical compositions, release composition achieves a blood plasma Cmor from wherein the at least one immediate release composition about 1. 5 ug /mL to about 4 ug /mL . Further embodiments comprises about 200 mg solabegron and the at least one describe pharmaceutical compositions , wherein a Cmin from modified release composition comprises about 200 mg sol about 0 .25 ug /mL to about 1 . 5 ug/ mL is achieved in about abegron . Further embodiments describe pharmaceutical 4 to about 8 hours after administration to a subject in need compositions , wherein the at least one immediate release of treatment. Further embodiments describe pharmaceutical composition comprises about 125 mg solabegron and the at compositions , wherein a Cmin from about 0 .01 ug /mL to least one modified release composition comprises about 200 about 1 . 0 ug /mL is achieved before about 24 hours after mg solabegron . In embodiments , the immediate release of solabegron and the modified release of solabegron may be administration to a subject in need of treatment. identical amounts or may be different amounts of solabe [0098 ] Further embodiments describe pharmaceutical gron . In embodiments, the immediate release of solabegron compositions, wherein the at least one immediate release may be about 30 mg, about 35 mg, about 40 mg, about 45 composition achieves a blood plasma Cmor in about 0 . 75 to mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 4 hours after administration to a subject in need of about 70 mg, about 75 mg, about 80 mg, about 85 mg, about treatment. Further embodiments describe pharmaceutical 90 mg, about 95 mg, about 100 mg , about 105 mg , about 110 compositions, wherein the at least one modified release mg, about 115 mg, about 120 mg, about 125 mg, about 130 composition achieves a blood plasma Cmax in about 2 to mg, about 135 mg, about 140 mg, about 145 mg, about 150 about 8 hours after the first Cmim . Further embodiments mg, about 155 mg, about 160 mg, about 165 mg, about 170 describe pharmaceutical compositions, further comprising mg, about 175 mg, about 180 mg, about 185 mg, about 190 one or more additional therapeutic agents or treatments mg , about 195 mg, about 200 mg, about 205 mg, about 210 useful for the treatment of LUTS , obesity , type 2 diabetes , mg , about 215 mg, about 220 mg, about 225 mg, about 230 heart failure , irritable bowel syndrome and similar gastro mg , about 235 mg, about 240 mg, about 245 mg, about 250 intestinal disorders , pre - term labor, depression and anxiety , mg, about 255 mg, about 260 mg , about 265 mg, about 270 wherein the one more additional therapeutic agents or treat mg, about 275 mg, about 280 mg, about 285 mg, about 290 ments are selected from the groups consisting of: antimus mg, about 295 mg, about 300 mg, about 305 mg, about 310 carinic agents ; alpha adrenoceptor blockers ; botulinum mg, about 315 mg, about 320 mg, about 325 mg, about 330 toxin ; purinergics ; cannabinoids ; transient receptor potential mg, about 335 mg, about 340 mg, about 345 mg, about 350 ( TRP ) protein inhibitors ; prostaglandins ; percutaneous tibial mg, about 355 mg, about 360 mg, about 365 mg, about 370 nerve stimulation ; 5 - alpha reductase inhibitors ; and phos mg, about 375 mg, about 380 mg, about 385 mg, about 390 phodiesterase - 5 inhibitors . Further embodiments describe mg, about 395 mg, about 400 mg, about 405 mg, about 410 pharmaceutical compositions, wherein the one or more mg , about 415 mg, about 420 mg, about 425 mg, about 430 additional therapeutic agents may be administered prior to , mg, about 435 mg, about 440 mg, about 445 mg, about 450 simultaneously with , or following the administration of the mg, about 455 mg, about 460 mg, about 465 mg, about 470 pharmaceutical composition comprising solabegron . mg, about 475 mg, about 480 mg, about 485 mg, about 490 [ 0099 ] In one embodiment the present application mg , about 495 mg or about 500 mg. In embodiments the describes a pharmaceutical composition comprising a thera modified release of solabegron may be 30 mg, about 35 mg, peutically effective amount of solabegron , wherein the phar about 40 mg, about 45 mg , about 50 mg, about 55 mg , about maceutical composition releases at least two releases of 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 solabegron , wherein a first release of solabegron achieves a mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, first target Cmor11 (2X , a second release of solabegron achieves a about 105 mg, about 110 mg, about 115 mg, about 120 mg, second target Cmax , a first target Cmin is achieved between about 125 mg, about 130 mg, about 135 mg, about 140 mg, the first release and the second release and a second Cmin is about 145 mg, about 150 mg, about 155 mg, about 160 mg , achieved after the second release . Further embodiments of about 165 mg, about 170 mg, about 175 mg, about 180 mg, the present application describe pharmaceutical composi US 2017 /0348263 A1 Dec . 7 , 2017 14 . tions, wherein said first target Cmax is about 1 . 5 ug/ mL to treatment and a Cmin less than about 0 . 5 ug /mL is achieved about 4 ug /mL , wherein said first Cmin is about 0 . 5 ug/ mL to after about 12 hours after administration to a subject in need about 1 . 5 ug /mL , wherein said second target Cmax is about of treatment. Still other embodiments of the present appli 1 . 5 ug .mL to about 4 ug /mL and wherein said second min cation describe pharmaceutical compositions , further com is about 0 .01 ug /mL to about 0 . 5 ug /mL . Other embodiments prising one or more additional therapeutic agents or treat of the present application describe pharmaceutical, wherein ments useful for the treatment of LUTS , obesity , type 2 the first mox is achieved at about 1 to about 3 hours after the diabetes, heart failure , irritable bowel syndrome and similar first release , wherein the first Cmin is achieved at about 2 to gastrointestinal disorders , pre - term labor , depression and about 4 hours after the first release , wherein the time anxiety , wherein the one more additional therapeutic agents between the first target Cmax and the second target Cmar is or treatments are antimuscarinic agents , alpha adrenoceptor about 2 to about 8 hours , wherein the second Cmor is blockers , botulinum toxin , purinergics , cannabinoids , tran achieved at about 1 to about 3 hours after the second release sient receptor potential ( TRP ) protein inhibitors , prostaglan and wherein the second Cmin is achieved at about 3 to about dins , 5 - alpha reductase inhibitors , phosphodiesterase - 5 8 hours after the second release . Further embodiments of the inhibitors or percutaneous tibial nerve stimulation and the present application describe pharmaceutical compositions, one or more additional therapeutic agents may be adminis wherein the first release comprises about 100 mg to about tered prior to , simultaneously with , or following the admin 300 mg of solabegron and wherein the second release istration of the pharmaceutical composition comprising sol comprises about 100 mg to about 300 mg of solabegron . abegron . Other embodiments of the present application describe phar 0101] In one embodiment the present application maceutical compositions, wherein the concentration of sol describes a pharmaceutical composition for the delivery of abegron is about 0 . 5 ug /mL or below for a period of time solabegron , comprising at least one immediate release com from about 12 to about 18 hours . Still other embodiments of position , comprising solabegron and at least one pharma the present application describe pharmaceutical composi ceutically acceptable carrier or diluent; and at least one tions , further comprising one or more additional therapeutic modified release composition , comprising solabegron and at agents or treatments useful for the treatment of LUTS , least one pharmaceutically acceptable carrier or diluent . obesity , type 2 diabetes , heart failure, irritable bowel syn Further embodiments describe pharmaceutical composi drome and similar gastrointestinal disorders , pre - term labor , tions, wherein the at least one immediate release composi depression and anxiety , wherein the one more additional tion comprises about 75 mg to about 400 mg solabegron . therapeutic agents or treatments are antimuscarinic agents , Further embodiments describe pharmaceutical composi alpha adrenoceptor blockers , botulinum toxin , purinergics, tions , wherein the at least one modified release composition cannabinoids, transient receptor potential ( TRP ) protein comprises about 75 mg to about 400 mg solabegron . Further inhibitors , prostaglandins , 5 - alpha reductase inhibitors , embodiments describe pharmaceutical compositions , phosphodiesterase - 5 inhibitors or percutaneous tibial nerve wherein the at least one immediate release composition stimulation and the one or more additional therapeutic achieves a blood plasma Cmor in about 0 .75 to about 4 hours agents may be administered prior to , simultaneously with , or after administration to a subject in need of treatment. Further following the administration of the pharmaceutical compo embodiments describe pharmaceutical compositions , sition comprising solabegron . wherein the at least one modified release composition [0100 ] In one embodiment, the present application achieves a blood plasma Cmax in about 6 to about 16 hours describes a pharmaceutical composition for the delivery of after administration to a subject in need of treatment. Further solabegron , comprising at least one immediate release com embodiments describe pharmaceutical compositions , further position , comprising solabegron and at least one pharma comprising one or more additional therapeutic agents or ceutically acceptable carrier or diluent ; and at least one treatments useful for the treatment of LUTS , obesity , type 2 modified release composition , comprising solabegron and at diabetes , heart failure , irritable bowel syndrome and similar least one pharmaceutically acceptable carrier or diluent. gastrointestinal disorders , pre -term labor, depression and Additional embodiments describe pharmaceutical composi anxiety , wherein the one more additional therapeutic agents tions , wherein the at least one immediate release composi or treatments are selected from the groups consisting of: tion comprises about 100 mg to about 300 mg solabegron antimuscarinic agents ; alpha adrenoceptor blockers ; botuli and the modified release composition comprises about 100 num toxin ; purinergics; cannabinoids ; transient receptor mg to about 300 mg solabegron . Further embodiments potential ( TRP ) protein inhibitors ; prostaglandins; percuta describe pharmaceutical compositions , wherein at least one neous tibial nerve stimulation ; 5 - alpha reductase inhibitors ; immediate release composition achieves a blood plasma and phosphodiesterase - 5 inhibitors . Further embodiments Cmor in about 1 to about 3 hours after administration to a describe pharmaceutical compositions , wherein the one or subject in need of treatment and at least one modified release more additional therapeutic agents may be administered composition achieves a blood plasma Cmor in about 5 to prior to , simultaneously with , or following the administra about 11 hours after administration to a subject in need of tion of the pharmaceutical composition comprising solabe treatment. Other embodiments describe pharmaceutical gron . Further embodiments describe pharmaceutical com compositions, wherein the at least one immediate release positions, wherein the at least one immediate release composition achieves a blood plasma Cmax from about 1 . 5 composition achieves a blood plasma CmorMAX from about 1 . 0 ug /mL to about 4 ug /mL and the at least one modified release ug/ mL to about 3 . 5 ug /mL . Further embodiments describe composition achieves a blood plasma Cmar from about 1 .5 pharmaceutical compositions , wherein the at least one modi ug /mL to about 4 ug /mL . Still additional embodiments fied release composition achieves a blood plasma Cmor from describe pharmaceutical compositions, wherein a Cmin from about 1 . 5 ug /mL to about 4 ug /mL . Further embodiments about 0 . 5 ug /mL to about 1 . 5 ug /mL is achieved in about 3 describe pharmaceutical compositions , wherein a Cmin from to about 5 hours after administration to a subject in need of about 0 .25 ug /mL to about 1. 5 ug/ mL is achieved in about US 2017 /0348263 A1 Dec . 7 , 2017
4 to about 8 hours after administration to a subject in need Clear, Eudragit L30 D55 , and Plasacryl HTP20 . In embodi of treatment. Further embodiments describe pharmaceutical ments the matrix of solabegron and a polymer comprises compositions , wherein a Cmin from about 0 . 1 ug /mL to about solabegron and opadry . In further embodiments the solabe 1 . 0 ug/ mL is achieved at about 24 hours after administration gron is the HCl salt of solabegron . to a subject in need of treatment . Further embodiments [0104 ] In one embodiment , the present application describe pharmaceutical compositions , wherein the at least describes the amorphous form of solabegron . An amorphous one immediate release composition comprises about 125 mg form is a solid that does not have a definite geometric or solabegron and the at least one modified release composition crystalline shape . It is a solid in which there is no long -range comprises about 125 mg solabegron . Further embodiments order in the positions of the atoms that is characteristic or a describe pharmaceutical compositions , wherein the at least crystal. For certain compounds, the amorphous form of the one immediate release composition comprises about 200 mg compound exhibits desirable properties for purposes of solabegron and the at least one modified release composition formulation and bioavailability . Fourier - transform infrared comprises about 200 mg solabegron . Further embodiments spectroscopy (FTIR ) scans of solabegron API and a spray describe pharmaceutical compositions, wherein the at least dried 20 : 80 solabegron to polyvinyl pyrrolidine ( PVPK30 ) one immediate release composition comprises about 125 mg formulation were conducted . The solabegron API displays solabegron and the at least one modified release composition amine ( N - H ) peaks at about 3400 and 3250 cm - 1 and comprises about 200 mg solabegron . carbonyl peaks at 1593 cm - 7 . The spray - dried 20 : 80 sol [0102 ] In one embodiment, the present application abegron to polyvinyl pyrrolidine (PVPK30 ) formulation describes a pharmaceutical composition comprising a mul displays a broadening of both the amine and carbonyl peaks. tiparticulate formulation of mini- tablets each comprising a The observed changes in the amine and carbonyl peaks in therapeutically effective amount of solabegron , wherein the the solabegron -PVPK30 formulation are indicative of the pharmaceutical composition achieves a first target Cmax , a amorphous form of solabegron . second target Cmax , a first target Cmin between the first target [0105 ] In one embodiment, the present application Cmax and the second target Cmax , and a second target Cmin describes a pharmaceutical composition comprising a thera after the second target Cmax. Further embodiments describe peutically effective amount of the amorphous form of sol pharmaceutical compositions, further comprising at least abegron and at least one pharmaceutically acceptable carrier two separate populations of mini- tablets selected from the or diluent. Further embodiments describe pharmaceutical group consisting of: immediate release mini - tablets ; sus compositions, wherein the therapeutically effective amount tained -release mini- tablets ; delayed - release mini - tablets ; of amorphous solabegron is about 150 mg to about 850 mg. and modified - release mini - tablets . Further embodiments Further embodiments describe pharmaceutical composi describe pharmaceutical compositions , wherein the mini tions, wherein the pharmaceutical composition is prepared tablets are optionally coated . Further embodiments describe by spray - drying the therapeutically effective amount of pharmaceutical compositions, wherein the mini- tablets com amorphous solabegron with at least one pharmaceutically prise solabegron and at least one pharmaceutically accept acceptable polymer . Further embodiments describe pharma able polymer . Further embodiments describe pharmaceutical ceutical compositions, wherein the pharmaceutically accept compositions , wherein the pharmaceutically acceptable able polymer is selected from the group consisting of polymer is selected from the group consisting of hydroxy - hydroxypropylmethyl cellulose ; polyethylene glycol; propylmethyl cellulose ; polyethylene glycol; hydroxypropyl hydroxypropyl B -cyclodextrin ; polyvinyl pyrrolidine ; B - cyclodextrin ; polyvinyl pyrrolidine ; poloxamer; and poloxamer; and hydroxypropyl cellulose . Further embodi hydroxypropyl cellulose . Further embodiments describe ments describe pharmaceutical compositions, wherein the pharmaceutical compositions, wherein at least one popula pharmaceutical composition is prepared by hot- melt extrud tion of mini- tablets further comprises a controlled -release ing the therapeutically effective amount of amorphous sol excipient. Further embodiments describe pharmaceutical abegron with at least one pharmaceutically acceptable poly compositions , wherein at least one population of mini mer . Further embodiments describe pharmaceutical tablets further comprises an enteric release coating . Further compositions, wherein the pharmaceutically acceptable embodiments describe pharmaceutical compositions, polymer is selected from the group consisting of hydroxy wherein the multiparticulate formulation is contained within propylmethyl cellulose ; polyethylene glycol; hydroxypropyl a capsule . B -cyclodextrin ; polyvinyl pyrrolidine; poloxamer ; and [ 0103] In embodiments , the present application describes hydroxypropyl cellulose . a pharmaceutical composition comprising a modified release [0106 ] The pharmaceutical compositions of the present solabegron core that is coated in a matrix of immediate / early application can be administered transdermally , orally , by release solabegron and a polymer, comprising a therapeuti inhalation , nasally , or parenterally , such as subcutaneously cally effective amount of solabegron , wherein the pharma or intravenously , as well as sublingually to various mam ceutical composition achieves a first target Cmar , a second malian species known to be subject to such maladies , e . g . , target Cmax, a first target Cmin between the first target Cmax humans, in an effective amount up to about 1 gram , prefer and the second target Cmax, and a second target Cmin after the ably up to about 800 mg, more preferably up to about 600 second target Cmor . In further embodiments the modified mg in a once -a -day regimen . In some embodiments the release solabegron core comprises solabegron and at least pharmaceutical compositions of the present invention are one excipient surrounded by a delayed release layer. In administered in an effective up of about 175 mg to about 650 further embodiments the modified release core comprises mg. In some embodiments the pharmaceutical compositions micronized solabegron , mannitol, microcrystalline cellu of the present invention are administered in an effective up lose , croscarmellose sodium , citric acid , sodium lauryl sul of about 150 mg to about 500 mg. fate , colloidal SiO2, and sodium stearyl fumarate ; sur - (0107 ] The pharmaceutical compositions of the present rounded by a delayed release layer comprising Opadry application can be administered for any of the uses described US 2017 /0348263 A1 Dec . 7 , 2017 herein by any suitable means, for example , orally , such as in [ 0111 ] The compositions of the present application can the form of tablets , capsules, granules or powders ; sublin also be delivered through the oral cavity by sublingual gually ; bucally ; parenterally , such as by subcutaneous , intra and /or buccal administration . Molded tablets , compressed venous, intramuscular , or intrasternal injection or infusion tablets or freeze - dried tablets are exemplary forms which techniques ( e . g . , as sterile injectable aqueous or non -aque may be used . Exemplary compositions include those formu ous solutions or suspensions ); in dosage unit formulations lating the present beta -3 adrenoceptor agonists with fast containing non - toxic , pharmaceutically acceptable vehicles dissolving diluents such as mannitol, lactose , sucrose and /or or diluents . The present compositions can , for example , be cyclodextrins. administered in a form suitable for immediate release or extended release . Immediate release or extended release can [0112 ] The compositions of the present application may be achieved by the use of suitable pharmaceutical compo take the form of pulsatile delivery systems such as , for sitions comprising the present compounds, or , particularly in example , PULSINCAP® , MICROPUMP® , MEDUSATM , the case of extended release , by the use of devices such as PORT® system , CHRONOTROPIC® , TIME CLOCK® , subcutaneous implants or osmotic pumps . Other devices multilayered tablets, DiffuCORE® , rupturable tablets , include vaginal rings. The present compositions can also be ACCU -BREAK® system , DIFFUCAPS® , DIFFUTABS® , administered liposomally . Eurand MINITABS® , MICROCAPS® , SODAS® , [0108 ] The formulation for a beta -3 adrenoceptor agonist IPDAS® , OsDrC® , OptiDoseTM OptiMeltTM , ZYDIS® , can significantly modify the absorption profile . For example , CODAS® , PRODAS® , TMDS® , DMDS? , PMDS® , some compounds are differentially absorbed in different GEOCLOCK® , GEOMATRIX® , PULSYS® , OROS® regions of the GI tract . Some of the factors involved in INTELLIMATRIXTM and VERSETROLTM . Also included absorption can include pH - dependent solubility , particle in such formulations may be high molecular weight excipi size , lipophilicity , ionization , GI-motility or transporters . In ents such as celluloses (avicel ) or polyethylene glycols the current example for the absorption of solabegron , sol (PEG ) . Such formulations can also include an excipient to abegron demonstrates pH -dependent solubility and absorp aid mucosal adhesion such as hydroxy propyl cellulose tion . Accordingly, solabegron and pharmaceutical salts (HPC ) , hydroxy propyl methyl cellulose (HPMC ) , sodium thereof display the optimum absorption in the proximal GI carboxy methyl cellulose (SCMC ) , maleic anhydride copo tract . Pharmaceutical compositions are presented herein that lymer ( e . g ., Gantrez) , and agents to control release such as improve the pH - dependent solubility of solabegron in the polyacrylic copolymer (e . g . Carbopol 934 ) . Lubricants , gli distal GI tract . Under these improved conditions, a second dants , flavors, coloring agents and stabilizers may also be release of solabegron and absorption will result . Addition added for ease of fabrication and use . ally ,methods for the release of solabegron in the distal GI [0113 ] In some embodiments , the composition of the tract based on pH are presented herein . present invention comprises a modified release solabegron core that is coated in a matrix of solabegron and a polymer. 0109 ]. Another example of producing a delayed second In further embodiments the modified release solabegron core release is based on the transit time of the dosage form . This comprises solabegron and at least one excipient surrounded is achievable through the time -dependent erosion or disso by a delayed release layer. In further embodiments the lution of the dosage form coating . The GI transit time is well modified release core comprises micronized solabegron , understood , and the coatings are designed to erode within a mannitol, microcrystalline cellulose , croscarmellose specific time range that corresponds to a specific region sodium , citric acid , sodium lauryl sulfate, colloidal SiO2, within the GI tract. Pharmaceutical compositions and meth and sodium stearyl fumarate ; surrounded by a delayed ods of use are presented herein for the release of solabegron release layer comprising Opadry Clear , Eudragit L30 D55 , based on time- dependent erosion . and Plasacryl HTP20 . In embodiments the matrix of solabe [0110 ] Exemplary compositions for oral administration gron and a polymer comprises solabegron and Opadry . In include emulsions and suspensions which can contain , for further embodiments the solabegron is the HCl salt of example , microcrystalline cellulose for imparting bulk , alg solabegron . inic acid or sodium alginate as a suspending agent, meth ylcellulose as a viscosity enhancer , and sweeteners or fla [0114 ] In some embodiments the pharmaceutical compo voring agents such as those known in the art ; and immediate sition of the present invention comprises : release tablets which can contain , for example , microcrys talline cellulose , dicalcium phosphate , starch , magnesium Percent Chemical Name stearate and / or lactose and / or other excipients , binders , extenders , disintegrants , diluents and lubricants such as Tablet About 25 to about 40 weight % * Solabegron Core About 20 to about 50 weight % Diluent those known in the art. Surfactants , oils and co - solvents that About 5 to about 15 weight % Bulking Agent can be used in oral solabegron compositions include , but are About 0 to about 10 weight % 1st Surfactant / not limited to : Tween 80 , Span 80 , Cremophor EL , Solutol Wetting Agent HS15 , Vitamin E GTPS , Poloxamer 407 , Labrasol, Labra About 5 to about 15 weight % Disintegrant About 0 to about 5 weight % Solubilizer fils , Gelucire 44 / 14 , Lauroglycol, Capryol 90 , Ethanol, About 0 to about 5 weight % 2nd Surfactant/ Benzyl Alcohol , Proylene Glycol ( PG ), PEG400 , PEG1000 , Wetting Agent Poloxamer 188 , Glycerin , CapmulMCM , Peceol, Mannitol, About 0 to about 2 weight % Flow Enhancer Microcrystalline Cellulose , Kolliphor P188, Croscarmellose About 0 to about 5 weight % Lubricant Modified About 0 to about 5 weight % Coating Diluent Sodium , Citric Acid , Sodium Lauryl Sulfate , Colloidal Release About 3 to about 5 weight % > pH 5 . 5 Delayed SiO2, Sodium Stearyl Fumarate , Opadry Clear , Eudragit Layer Release Polymer L30 D55 , Plasacryl HTP20 , solabegron HCl, and Opadry About 0 to about 2 weight % Plasticizer Clear. US 2017 /0348263 A1 Dec . 7 , 2017 17
-continued [0116 ] In one embodiment the pharmaceutical composi tion comprises : Percent Chemical Name Immediate About 5 to about 15 weight % * Solabegron % w // w Chemical Name Release About 5 to about 15 weight % Coating Diluent Layer Tablet about 22 . 8 * Micronized Solabegron HCl Core (D90 = ~ 4 um ) * adjusted for HCl salt if the solabegron is the HCl salt form about 31 . 4 Mannitol about 7 . 6 Microcrystalline Cellulose about 0 to about 10 Poloxamer 188 (aka Kolliphor 188 ) It will be understood by one of skill in the art that the total about 5 to about 15 Croscarmellose Sodium of all of the components in the above composition must about 2 . 3 Citric Acid equal 100 % . In further embodiments the solabegron is the about 0 to about 5 Sodium Lauryl Sulfate solabegron salt. In further embodiments the solabegron in about 0 . 4 Colloidal SiO2 the immediate release layer is a micronized solabegron . In about 1 . 6 Sodium Stearyl Fumarate some embodiments the solabegron is about 25 weight % , DR about 2 . 3 Opadry Clear Layer about 3 . 8 Eudragit L30 D55 about 26 weight % , about 27 weight % , about 28 weight % , about 0 . 9 Plasacryl HTP20 about 29 weight % , about 30 weight % , about 31 weight % , IR about 8 . 5 * Solabegron HCl about 32 weight % , about 33 weight % , about 34 weight % , Layer about 8 . 5 Opadry Clear about 35 weight % , about 36 weight % , about 37 weight % , about 38 weight % , about 39 weight % , or about 40 weight * adjusted for HC1 salt % . In some embodiments the first surfactant/ wetting agent is O weight % , 1 weight % , 2 weight % , 3 weight % , 4 weight It will be understood by one of skill in the art that the total % , 5 weight % , 6 weight % , 7 weight % , 8 weight % , 9 of all of the components in the above composition must weight % or, 10 weight % . In some embodiments the second equal 100 % . surfactant/ wetting agent is O weight % , 1 weight % , 2 weight [0117 ] In one embodiment the pharmaceutical composi % , 3 weight % , 4 weight % , or 5 weight % . tion comprises : [0115 ] In some embodiments the pharmaceutical compo sition of the present invention comprises : % w / w Chemical Name Tablet About 22. 8 * Micronized Solabegron HCI Percent Chemical Name Core (D90 = ~ 4 um ) About 31. 4 Mannitol Tablet About 25 to about 40 weight % * Micronized Solabegron HCI About 7 . 6 Microcrystalline Cellulose Core (D90 = - 4 um . ) About 7 . 5 Croscarmellose Sodium About 20 to about 50 weight % Mannitol About 2 . 3 Citric Acid About 5 to about 15 weight % Microcrystalline Cellulose About 2 . 3 Sodium Lauryl Sulfate About 0 to about 10 weight % Kolliphor P188 (aka About 0 . 4 Colloidal SiO2 Poloxamer 188 ) Sodium Stearyl Fumarate About 5 to about 15 weight % Croscarmellose Sodium About 1 . 6 About 0 to about 5 weight % Citric Acid About 76 Sub - total About 0 to about 5 weight % Sodium Lauryl Sulfate DR About 2 . 3 Opadry Clear About 0 to about 2 weight % Colloidal SiO2 Eudragit L30 D55 About 0 to about 5 weight % Sodium Stearyl Fumarate Layer About 3 . 8 Modified About 0 to about 5 weight % Sub - total About 0 . 9 Plasacryl HTP20 Release About 3 to about 5 weight % Opadry Clear Layer About 0 to about 2 weight % Eudragit L30 D55 About 82 . 9 Sub - total Immediate About 5 to about 15 weight % * Solabegron HCI IR About 8 . 5 * Solabegron HCI Release About 5 to about 15 weight % Opadry Clear Layer About 8 . 5 Opadry Clear Layer * adiusted for HCl salt * adjusted for HCl salt It will be understood by one of skill in the art that the total It will be understood by one of skill in the art that the total of all of the components in the above composition must of all of the components in the above composition must equal 100 % . equal 100 % . In some embodiments the solabegron is about [0118 ] In one embodiment the pharmaceutical composi 25 weight % , about 26 weight % , about 27 weight % , about 28 weight % , about 29 weight % , about 30 weight % , about tion comprises: 31 weight % , about 32 weight % , about 33 weight % , about 34 weight % , about 35 weight % , about 36 weight % , about % w / w Chemical Name 37 weight % , about 38 weight % , about 39 weight % , or Tablet About 22 .7 * Micronized Solabegron HCI about 40 weight % . In some embodiments the kolliphor Core (D90 = - 4 um ) P188 is o weight % , 1 weight % , 2 weight % , 3 weight % , About 26 . 2 Mannitol 4 weight % , 5 weight % , 6 weight % , 7 weight % , 8 weight About 7 .6 Microcrystalline Cellulose About 7 . 6 Poloxamer 188 (aka Kolliphor 188 ) % , 9 weight % or, 10 weight % . In some embodiments the About 7 . 6 Croscarmellose Sodium sodium lauryl sulfate is 0 weight % , 1 weight % , 2 weight About 2 . 3 Citric Acid % , 3 weight % , 4 weight % , or 5 weight % . US 2017 /0348263 A1 Dec . 7 , 2017
- continued [0122 ] Exemplary compositions for delivery directly to the bladder include extended - release solid - drug core devices % w / w Chemical Name that are implanted via catheter. About 0 . 4 Colloidal SiO2 (0123 ]. The therapeutic agents in the pharmaceutical com About 1 . 6 Sodium Stearyl Fumarate positions of the present application may exist in any physical form known to one of skill in the art such as, for example , About 76 Sub - total nanoparticles, crystalline solids, amorphous solids, poly DR About 2 . 3 Opadry Clear Layer About 3 . 8 Eudragit L30 D55 morphs , ionic solids such as , for example , cations, anions About 0 . 9 Plasacryl HTP20 and zwitterions, pharmaceutically acceptable salts , hydrates , solvates , stereoisomers , solutions and suspensions . Crystal About 82 . 9 Sub -total line solids have regular ordered arrays of components held IR About 8 . 5 * Solabegron HCI together by uniform intermolecular forces, whereas the Layer About 8 . 5 Opadry Clear components of amorphous solids are not arranged in regular * adjusted for HCl salt arrays . Hydrates are substances that incorporate at least one water molecule into their crystalline matrix . Solvates are It will be understood by one of skill in the art that the total substances that incorporate at least one solvent molecule of all of the components in the above composition must into their crystalline matrix . Polymorphs exhibit different equal 100 % . crystalline structures for molecules that have the same [0119 ] In one embodiment the pharmaceutical composi molecular formula and sequence of bonded atoms. Stereoi tion comprises: somers are isomeric molecules that have the samemolecular formula and sequence of bonded atoms ( constitution ) , but that differ only in the three - dimensional orientations of their % w / w Chemical Name atoms in space . Tablet About 22 .7 * Micronized Solabegron HCI 10124 ]. Further , the therapeutic agents in the pharmaceu Core (D90 = - 4 um ) tical compositions of the present application may exist in About 23 . 9 Mannitol any isotopic form known to one of skill in the art such as , About 7 . 6 Microcrystalline Cellulose About 7 . 6 Poloxamer 188 ( aka Kolliphor 188 ) for example , deuterated , tritiated , 13C , 14C , etc . About 7 . 6 Croscarmellose Sodium [0125 ] The present application describes immediate About 2 . 3 Citric Acid release , extended release, delayed release , and modified About 2 . 3 Sodium Lauryl Sulfate release formulations of solabegron . Previously , both the About 0 . 4 Colloidal SiO2 About 1 . 6 Sodium Stearyl Fumarate HCL salt and the amorphous form of solabegron have been tested in clinical studies and based on the totality of the About 76 Sub - total in - vitro and clinical data there were found to be two impedi DR About 2 . 3 Opadry Clear ments to developing a solabegron QD formulation to pro Layer About 3 . 8 Eudragit L30 D55 vide the desired PK profile illustrated in FIG . 1 : 1 ) the pH About 0 . 9 Plasacryl HTP20 dependent and low solubility of solabegron and 2 ) the About 82. 9 Sub - total position of release of solabegron in the intestine . Composi IR About 8 . 5 * Solabegron HCl tions were prepared to overcome the above - described Layer About 8 . 5 Opadry Clear impediments in developing a solabegron QD formulation to * adjusted for HCl salt provide the desired PK profile of FIG . 1 . [0126 ] It will be understood that the specific dose level It will be understood by one of skill in the art that the total and frequency of dosage for any particular subject can be of all of the components in the above composition must varied and will depend upon a variety of factors including equal 100 % . the species , age, body weight, general health , gender and 10120 ] Exemplary compositions for parenteral administra diet of the subject, the mode and time of administration , rate tion include injectable solutions or suspensions which can of excretion , drug combination , and severity of the particular contain , for example , suitable non - toxic , parenterally condition . acceptable diluents or solvents , such as mannitol, 1 , 3 - bu (0127 ] The present application includes within its scope tanediol , water , polyethylene glycol, Ringer ' s solution , an pharmaceutical compositions comprising , a therapeutically isotonic sodium chloride solution , or other suitable dispers effective amount of solabegron , alone or in combination ing or wetting and suspending agents , including synthetic with a pharmaceutical carrier or diluent. Surfactants , oils mono - or diglycerides, and fatty acids, including oleic acid , and co - solvents that can be used in solabegron compositions or Cremaphor. include , but are not limited to : Tween 80 , Span 80 , Cremo [0121 ] Exemplary compositions for transdermal adminis phor EL , Solutol HS15 , Vitamin E GTPS , Poloxamer 407 , tration include transdermal therapeutic systems (hereinafter Labrasol, Labrafils, Gelucire 44 / 14 , Lauroglycol, Capryol “ TTS ” ) . TTS are patches having a layered structure and 90, Ethanol, Benzyl Alcohol, Proylene Glycol (PG ) , comprising at least one active pharmaceutical ingredient in PEG400 , PEG1000 , Poloxamer 188 , Glycerin , Capmul a reservoir layer . A distinction is made between matrix - type MCM , Peceol, Mannitol, Microcrystalline Cellulose , Kolli and reservoir - type TTS : in the first case the reservoir layer phor P188 , Croscarmellose Sodium , Citric Acid , Sodium containing the active pharmaceutical ingredient has a pres Lauryl Sulfate , Colloidal SiO2 , Sodium Stearyl Fumarate , sure - sensitive adhesive finish , and in the second case a Opadry Clear, Eudragit L30 D55 , Plasacryl HTP20 , solabe membrane which controls the rate of release of the active gron HCl, and Opadry Clear. pharmaceutical ingredient, and where appropriate an addi [0128 ] Optionally , the pharmaceutical compositions of the tional pressure - sensitive adhesive layer , are present. present invention can be used alone , or in combination with US 2017 /0348263 A1 Dec . 7 , 2017 19
other suitable therapeutic agents or treatments useful in the [ 0139 ] Examples of suitable therapeutics for preterm treatment of LUTS including: antimuscarinic agents, alpha labor : tocolytics , magnesium sulfate , corticosteroids, terb adrenoceptor blockers , botulinum toxin , purinergics , can utaline , ritodrine, nifedipine , oxytocin receptor antagonists nabinoids , transient receptor potential ( TRP ) protein inhibi ( Atosiban® ). tors, prostaglandins , percutaneous tibial nerve stimulation , [ 0140 ] Examples of suitable therapeutics for anxiety : esci 5 -alpha reductase inhibitors and phosphodiesterase - 5 inhibi talopram (Lexapro® ) , duloxetine (Cymbalta® ), venlafaxine tors . ( Effexor XR® ) and paroxetine (Paxil® ) , buspirone benzo [0129 ] Optionally , the pharmaceutical compositions of the diazepines alprazolam ( Xanax® ) , diazepam ( Valium® ) and present invention can be used alone , or in combination with lorazepam ( Ativan® ). other suitable therapeutic agents or treatments useful in the [0141 ] Examples of suitable therapeutics for depression : treatment of obesity, diabetes , heart failure , irritable bowel selective serotonin reuptake inhibitors (SSRI ), fluoxetine syndrome ( IBS ) , preterm labor, anxiety or depression . ( Prozac® ) , paroxetine (Paxil® , Pexeva® ) , sertraline [0130 ] Such other therapeutic agent( s ) may be adminis ( Zoloft® ) , citalopram ( Celexa® ), escitalopram (Lexapro® ) , tered prior to , simultaneously with , or following the admin serotonin -norepinephrine reuptake inhibitors ( SNRIS ) , istration of solabegron containing pharmaceutical composi duloxetine (Cymbalta® ) , venlafaxine (Effexor XR® ) , des tion in accordance with the invention . venlafaxine ( Pristiq® , Khedezla® ) , levomilnacipran [0131 ] Examples of suitable antimuscarinic agents for use ( Fetzima® ) , norepinephrine - dopamine reuptake inhibitors in combination with the pharmaceutical compositions of the (NDRIs ), bupropion (Wellbutrin® , Aplenzin® , Forfivo present application include tolterodine, oxybutynin , tros XL? ) , atypical antidepressants, trazodone and mirtazapine pium , solifenacin , darifenacin , propiverine , fesoterodine , (Remeron® ), vortioxetine ) (Brintellix® ) , vilazodone ) (Vii and pharmaceutically acceptable salts thereof. bryd® ), vilazodone , tricyclic antidepressants , imipramine [ 0132 ] Examples of suitable alpha adrenoceptor blockers ( Tofranil® ) , nortriptyline (Pamelor® ) , amitriptyline , dox for use in combination with the pharmaceutical composi epin , trimipramine (Surmontil® ) , desipramine (Nor tions of the present application include tamuslosin , alfu pramin® ), protriptyline (Vivactil® ), monoamine oxidase zosin , and silodosin . inhibitors (MAOIs ), tranylcypromine ( Parnate® ) , phenel [0133 ] Examples of suitable 5 - alpha reductase inhibitors zine (Nardil® ) and isocarboxazid (Marplan® ) . for use in combination with the pharmaceutical composi tions of the present application include finasteride , dutase teride and pharmaceutically acceptable salts thereof. Methods of Treatment [0134 ] Examples of suitable phosphodiesterase - 5 inhibi [0142 ] In embodiments , methods of treating a disease tors for use in combination with the pharmaceutical com comprising administering to a subject in need thereof a positions of the present application include sildenafil, tada pharmaceutical composition as described herein are pro lafil, vardenafil , udenafil , avanafil and pharmaceutically vided . In embodiments , the disease may be LUTS , obesity , acceptable salts thereof. type 2 diabetes, heart failure, irritable bowel syndrome and [0135 ] Examples of suitable therapeutics for obesity : orl similar gastrointestinal disorders, pre -term labor, depression istat (Xenical® ), lorcaserin (Belviq® ) , phentermine and and anxiety , combinations thereof . In embodiments , treating topiramate ( Qsymia® ), buproprion and naltrexone (Con LUTS may include treating or otherwise decreasing fre trave® ) , and uncertain mimetics such as liraglutide (Sax quency of urgency , decreasing nocturia , decreasing urinary enda® ). micturition frequency , decreasing urinary incontinence , [ 0136 ] Examples of suitable therapeutics for diabetes : increasing voided volume, decreasing post - void residual metformin , sulfonylureas (DiaBeta® , Glynase® ) , glipizide volume, and / or improving subject reporting outcomes . In (Glucotrol® ) glimepiride (Amaryl® ) , meglitinides , repa embodiments , the pharmaceutical composition may be glinide (Prandin® ), nateglinide ( Starlix® ) , thiazolidin administered once a day . In embodiments , the pharmaceu edione ( Actos® , Avandia® ) , DPP - 4 inhibitors , sitagliptin tical composition is administered every other day (COD ), ( Januvia® ) , saxagliptin (Onglyza® ) , linagliptin ( Trad once a day (QD ) , twice a day (BID ) or three times a day jenta® ), purinergics, GLP -1 receptor agonists exenatide ( TID ) to a subject in need thereof. (Byetta® ), liraglutide ( Victoza® ) , SGLT2 inhibitors, cana [0143 ] In embodiments , methods of treating such diseases gliflozin ( Invokana® ) , dapagliflozin ( Farxiga® ) and insulin . may further comprise administering a therapeutically effec [0137 ] Examples of suitable therapeutics for heart failure : tive amount of one or more additional therapeutic agents . In angiotensin - converting enzyme (ACE ) inhibitors, enalapril , embodiments , the one or more additional therapeutic agents lisinopril , angiotensin II receptor blockers , ( Losartan® , may be administered prior to , simultaneously with , or fol (Valsartan® ) , beta blockers) (Carvedilol® ) , metoprolol, lowing the administration of the pharmaceutical composi bisoprolol, diuretics ,hydrochlorthiazide , furosemide, aldos tion comprising solabegron . In embodiments , the one or terone antagonists , spironolactone, eplerenone ( Inspra® ), more additional therapeutic agents may be an antimuscarinic inotropes and digoxin agents , alpha adrenoceptor blockers , botulinum toxin , puri [0138 ] Examples of suitable therapeutics for IBS : alos nergics , cannabinoids , transient receptor potential ( TRP ) etron (Lotronex® ) , lubiprostone ( Amitiza® ) , eluxadoline protein inhibitors, prostaglandins , 5 - alpha reductase inhibi ( Viberzi® ), llinaclotide (Linzess® ), rifaximin (Xifaxan® ), tors , phosphodiesterase - 5 inhibitors or percutaneous tibial fiber supplements (OTC ) , psyllium (Metamucil® ) , methyl nerve stimulation . In embodiments , the antimuscarinic agent cellulose ( Citrucel® ) , anti -diarrheal medications , loper may be tolterodine, oxybutynin , trospium , solifenacin , amide ( Imodium® ) , bile acid binders , cholestyramine (Pre darifenacin , propiverine , fesoterodine, and pharmaceutically valite® ), colestipol (Colestid® ), colesevelam ( Welchol® ) , acceptable salts thereof as described in the pharmaceutical anticholinergic and antispasmodic medications, (Levsin ) composition section above and in paragraphs [ 0127 ] through and dicyclomine (Bentyl® ) . [0139 ] . US 2017 /0348263 A1 Dec . 7 , 2017
[ 0144 ] In one embodiment, the present application failure , irritable bowel syndrome and similar gastrointestinal describes a method for treating LUTS , obesity , type 2 disorders , pre - term labor, depression and anxiety , wherein diabetes , heart failure , irritable bowel syndrome and similar the one more additional therapeutic agents or treatments are gastrointestinal disorders , pre - term labor, depression and selected from the groups consisting of: antimuscarinic anxiety, comprising administering a pharmaceutical compo agents ; alpha adrenoceptor blockers ; botulinum toxin ; puri sition for the delivery of solabegron , comprising an imme nergics ; cannabinoids ; transient receptor potential ( TRP ) diate release composition , comprising solabegron and at protein inhibitors; prostaglandins ; percutaneous tibial nerve least one pharmaceutically acceptable carrier or diluent; and stimulation ; 5 - alpha reductase inhibitors ; and phosphodies a modified release composition , comprising solabegron and terase- 5 inhibitors . Further embodiments describe methods, at least one pharmaceutically acceptable carrier or diluent to wherein the one or more additional therapeutic agents may a subject in need thereof. Further embodiments describe be administered prior to , simultaneously with , or following methods, wherein the subject achieves a blood plasma Cmax the administration of the pharmaceutical composition com of about 0 . 5 ug /mL to about 3 . 5 ug /mL in about 0 . 75 to about prising solabegron . Further embodiments describe methods, 4 hours after administration . Further embodiments describe wherein the pharmaceutical composition is administered methods, wherein the subject achieves a blood plasma Cmin once a day to a subject in need thereof. from about 0 .25 ug /mL to about 1 . 5 ug /mL in about 4 to [0146 ] In one embodiment the present application about 8 hours after administration . Further embodiments describes a method for treating LUTS , obesity , type 2 describe methods, wherein the subject achieves a blood diabetes , heart failure , irritable bowel syndrome and similar plasma Cmax of about 1 . 5 ug /mL to about 4 ug /mL in about gastrointestinal disorders , pre - term labor, depression and 2 to about 8 hours after the first Cmin . Further embodiments anxiety , comprising administering a pharmaceutical compo describe methods , wherein the subject achieves a blood sition for the delivery of solabegron , comprising an imme plasma Cmin from about 0 .01 ug /mL to about 1 .0 ug /mL diate release composition , comprising solabegron and at before about 24 hours after administration . Further embodi least one pharmaceutically acceptable carrier or diluent ; and ments describe methods, further comprising administering a modified release composition , comprising solabegron and one or more additional therapeutic agents or treatments at least one pharmaceutically acceptable carrier or diluent to useful for the treatment of LUTS , obesity , type 2 diabetes, a subject in need thereof . Additional embodiments describe heart failure , irritable bowel syndrome and similar gastro methods, wherein the subject achieves a blood plasma Cmax intestinal disorders , pre - term labor, depression and anxiety , of about 1 . 5 ug/ mL to about 4 ug/ mL in about 1 to about??? 3 wherein the one more additional therapeutic agents or treat hours after administration . Further embodiments describe ments are selected from the groups consisting of : antimus methods , wherein the subject achieves a blood plasma Cminmin carinic agents; alpha adrenoceptor blockers ; botulinum from about 0 . 5 ug /mL to about 1 . 5 ug /mL in about 3 to about toxin ; purinergics ; cannabinoids ; transient receptor potential 5 hours after administration . Still further embodiments ( TRP ) protein inhibitors ; prostaglandins; percutaneous tibial describe methods, wherein the subject achieves a blood nerve stimulation ; 5 - alpha reductase inhibitors ; and phos plasma Cmar of about 1 . 5 ug/ mL to about 4 ug/ mL in about phodiesterase - 5 inhibitors. Further embodiments describe 5 to about 11 hours after administration . Additional embodi method , wherein the one or more additional therapeutic ments describe methods, wherein the subject achieves a agents may be administered prior to , simultaneously with , or blood plasma Cmin less than about 0 . 5 ug/ mL after about 12 following the administration of the pharmaceutical compo hours after administration . Still additional embodiments sition comprising solabegron . Further embodiments describe methods, wherein the pharmaceutical composition describe methods, wherein the pharmaceutical composition is administered every other day ( COD ), once a day ( QD ), is administered once a day to a subject in need thereof. twice a day (BID ) or three times a day (TID ) to a subject in [0145 ] In one embodiment, the present application need thereof. Still other embodiments of the present appli describes a method for treating LUTS , obesity , type 2 cation describe pharmaceutical compositions , further com diabetes, heart failure, irritable bowel syndrome and similar prising one or more additional therapeutic agents or treat gastrointestinal disorders , pre - term labor, depression and ments useful for the treatment of LUTS , obesity , type 2 anxiety, comprising administering a pharmaceutical compo diabetes , heart failure , irritable bowel syndrome and similar sition , comprising a therapeutically effective amount of gastrointestinal disorders , pre - term labor, depression and solabegron , wherein the pharmaceutical composition anxiety , wherein the one more additional therapeutic agents releases at least two releases of solabegron , wherein a first or treatments are antimuscarinic agents , alpha adrenoceptor release of solabegron achieves a first target Cmor, a second blockers , botulinum toxin , purinergics , cannabinoids, tran release of solabegron achieves a second target C more a first sient receptor potential (TRP ) protein inhibitors , prostaglan dins, 5 - alpha reductase inhibitors , phosphodiesterase - 5 target Cmin is achieved between the first release and the inhibitors or percutaneous tibial nerve stimulation and the second release and a second Cminm77 is achieved after the second release . Further embodiments describe methods, one or more additional therapeutic agents may be adminis wherein said first target Cmor is about 0 . 5 ug /mL to about 3 . 5 tered prior to , simultaneously with , or following the admin ug /mL . Further embodiments describe methods, wherein istration of the pharmaceutical composition comprising sol said second target Cmor is about 1 . 5 ug /mL to about 4 ug /mL . abegron . Further embodiments describe methods , wherein said first [0147 ] In one embodiment the present application Cmin is about 0 .25 ug /mL to about 1. 5 ug/ mL . Further describes a method for treating LUTS , obesity, type 2 embodiments describe methods , wherein said second m 2772 is diabetes, heart failure , irritable bowel syndrome and similar about 0 .01 ug /mL to about 1 .0 ug /mL . Further embodiments gastrointestinal disorders , pre -term labor, depression and describe methods, further comprising administering one or anxiety , comprising administering a pharmaceutical compo more additional therapeutic agents or treatments useful for sition , comprising a therapeutically effective amount of the treatment of LUTS , obesity , type 2 diabetes, heart solabegron , wherein the pharmaceutical composition US 2017 /0348263 A1 Dec . 7 , 2017 21 releases at least two releases of solabegron , wherein a first second Cmin is from about 0 .01 ug /mL to about 1 .0 ug/ mL . release of solabegron achieves a first target Cmax a second Further embodiments describe once - daily treatments , fur release of solabegron achieves a second target Cmor, a first ther comprising administering one or more additional thera target Cmin is achieved between the first release and the peutic agents or treatments useful for the treatment of LUTS , second release and a second Cmin is achieved after the obesity , type 2 diabetes , heart failure , irritable bowel syn second release . Additional embodiments describe methods, drome and similar gastrointestinal disorders , pre - term labor , wherein said first target Cmax is about 1 . 5 ug /mL to about 4 depression and anxiety , wherein the one more additional ug /mL , said second target Cmar is about 1 . 5 ug. mL to about therapeutic agents or treatments are selected from the groups 4 ug /mL , said first Cmin is about 0 . 5 ug /mL to about 1 . 5 consisting of: antimuscarinic agents ; alpha adrenoceptor ug/ mL and said second Cmin is about 0 .01 ug /mL to about 0 .5 blockers ; botulinum toxin ; purinergics ; cannabinoids; tran ug /mL . Still other embodiments of the present application sient receptor potential ( TRP ) protein inhibitors ; prostaglan describe pharmaceutical compositions , further comprising dins; percutaneous tibial nerve stimulation ; 5 -alpha reduc one or more additional therapeutic agents or treatments tase inhibitors ; and phosphodiesterase -5 inhibitors . Further useful for the treatment of LUTS , obesity , type 2 diabetes , embodiments describe once - daily treatments , wherein the heart failure , irritable bowel syndrome and similar gastro one or more additional therapeutic agents may be adminis intestinal disorders , pre - term labor, depression and anxiety , tered prior to , simultaneously with , or following the admin wherein the one more additional therapeutic agents or treat istration of the pharmaceutical composition comprising sol ments are antimuscarinic agents , alpha adrenoceptor block abegron . ers , botulinum toxin , purinergics , cannabinoids, transient [0150 ] In one embodiment, the present application receptor potential ( TRP ) protein inhibitors , prostaglandins , describes a once -daily treatment for LUTS , obesity, type 2 5 - alpha reductase inhibitors , phosphodiesterase - 5 inhibitors diabetes , heart failure , irritable bowel syndrome and similar or percutaneous tibial nerve stimulation and the one or more gastrointestinal disorders , pre - term labor, depression and additional therapeutic agents may be administered prior to , anxiety that achieves a desired blood plasma Cmax while also simultaneously with , or following the administration of the not desensitizing the beta - 3 adrenoceptor, comprising at pharmaceutical composition comprising solabegron . Still least one immediate release composition , comprising sol further embodiments describe methods, wherein the phar abegron and at least one pharmaceutically acceptable carrier maceutical composition is administered every other day or diluent; and at least one modified release composition , ( COD ), once a day (CD ) , twice a day (BID ) or three times comprising solabegron and at least one pharmaceutically a day ( TID ) to a subject in need thereof. acceptable carrier or diluent. In some embodiments the [ 0148 ] In one embodiment the present application pharmaceutical composition may have any of the Cmore describes a method of treating one or more symptoms of Cmin , Tmax , or Tmin described herein . Further embodiments OAB , comprising administering a pharmaceutical composi describe once - daily treatments , wherein the at least one tion , comprising a therapeutically effective amount of sol immediate release composition comprises about 75 mg to abegron and at least onepharmaceutically acceptable diluent about 250 mg solabegron . Further embodiments describe or carrier, wherein the one or more symptoms of OAB are once - daily treatments , wherein the at least one modified selected from the group consisting of: frequency of urinary release composition comprises about 100 mg to about 400 urgency ; nocturia ; increase in urinary micturition frequency ; mg solabegron . Further embodiments describe once - daily and urinary incontinence . Further embodiments describe treatments , wherein the at least one immediate release methods, wherein the pharmaceutical composition may be composition achieves a blood plasma Cmax in about 0 .75 to administered in the morning or the pharmaceutical compo about 4 hours after administration to a subject in need of sition may be administered with a meal . Additional embodi treatment. Further embodiments describe once - daily treat ments describe methods , wherein the improvement in the ments , wherein the at least one modified release composition one or more symptoms of over active bladder is increased achieves a blood plasma Cmax in about 2 to about 8 hours bladder volume as measured by void volume. after the first min . Further embodiments describe once -daily [0149 ] In one embodiment, the present application treatments , further comprising administering one or more describes a once -daily treatment for LUTS , obesity, type 2 additional therapeutic agents or treatments useful for the diabetes , heart failure , irritable bowel syndrome and similar treatment of LUTS , obesity , type 2 diabetes, heart failure , gastrointestinal disorders, pre - term labor, depression and irritable bowel syndrome and similar gastrointestinal disor anxiety that achieves a desired blood plasma Cmax while also ders , pre - term labor, depression and anxiety , wherein the one not desensitizing the beta - 3 adrenoceptor, comprising a more additional therapeutic agents or treatments are selected pharmaceutical composition , comprising a therapeutically from the groups consisting of: antimuscarinic agents ; alpha effective amount of solabegron , wherein the pharmaceutical adrenoceptor blockers ; botulinum toxin ; purinergics ; can composition releases at least two releases of solabegron , nabinoids ; transient receptor potential ( TRP ) protein inhibi wherein a first release of solabegron achieves a first target tors; prostaglandins; percutaneous tibial nerve stimulation ; Cmar, a second release of solabegron achieves a second 5 -alpha reductase inhibitors ; and phosphodiesterase - 5 target Cmax , a first target Cmin is achieved between the first inhibitors . Further embodiments describe once - daily treat release and the second release and a second Cmin is achieved ments , wherein the one or more additional therapeutic after the second release. Further embodiments describe agents may be administered prior to , simultaneously with , or once -daily treatments, wherein said first target Cmax is about following the administration of the pharmaceutical compo 0 . 5 ug /mL to about 3 . 5 ug /mL . Further embodiments sition comprising solabegron . describe once - daily treatments , wherein said second target [0151 ] In one embodiment the present application Cmax is about 1 . 5 ug. mL to about 4 ug /mL ., wherein said first describes a once - daily treatment for LUTS , obesity , type 2 Cmin is about 0 .25 ug /mL to about 1 . 5 ug/ mL . Further diabetes , heart failure , irritable bowel syndrome and similar embodiments describe once -daily treatments , wherein said gastrointestinal disorders , pre -term labor, depression and US 2017 /0348263 A1 Dec . 7 , 2017 anxiety that achieves a desired blood plasma Cmax while also EXAMPLES not desensitizing the beta - 3 adrenoceptor or the biochemical 10153 ] HEK cells transfected with the human beta - 3 adre pathways leading to the functional response, comprising a noceptor according to the method of Vrygag et al ( 2009 ) will pharmaceutical composition , comprising a therapeutically be employed . Additional cell lines, such as CHO , SK - N -MC effective amount of solabegron , wherein the pharmaceutical neuroblastoma cells or cultured human adipocytes may be composition releases at least two releases of solabegron , considered . wherein a first release of solabegron achieves a first target [0154 ] For the desensitization experiments , the cells will Cmax , a second release of solabegron achieves a second be cultured for 0 . 5 hr to 24 hr in a serum - free medium in the target Cmor , a first target Cmin is achieved between the first presence of vehicle or a concentration of 0 .01 to 10 -uM release and the second release and a second Cmin is achieved beta - 3 adrenoceptor agonists . Beta - 3 agonists that may be after the second release . Additional embodiments describe studied include solabegron , CL 316 , 243 or isoproterenol. treatments , wherein said first target Cmax is about 1. 5 ug /mL Cells will be washed with serum - free medium for a period to about 4 ug /mL , said second target mar is about 1 . 5 ug .mL of 1 to 4 hr. to about 4 ug /mL , said first Cm is about 0 . 5 ug /mL to about 1 .5 ug /mL and said second Cmin is about 0 .01 ug/ mL to about Example 1 0 . 5 ug /mL . Further embodiments describe treatments further comprising administering one or more additional therapeutic Cyclic AMP Accumulation or ERK Activation agents useful for the treatment of LUTS , obesity , type 2 Endpoint Assessment of Beta - 3 Adrenoceptor diabetes , heart failure , irritable bowel syndrome and similar Desensitization gastrointestinal disorders, pre - term labor, depression and [ 0155 ] Cells will be detached from the surface using anxiety, wherein the one more additional therapeutic agents enzyme - free cell dissociation buffer and washed once with are selected from the groups consisting of: antimuscarinic Hank ' s balanced salt solution (HBSS ). Cells will be re agents ; alpha adrenoceptor blockers ; 5 -alpha reductase suspended in HBSS supplemented with 5 mM HEPES and inhibitors ; and phosphodiesterase - 5 inhibitors , wherein the 0 .05 % bovine serum albumin . The cells will be stimulated one or more additional therapeutic agents may be adminis with the appropriate concentration -response to a beta - 3 tered prior to , simultaneously with , or following the admin adrenoceptor agonist or vehicle . The stimulation mixture istration of the pharmaceutical composition comprising sol will contain the cAMP phosphodiesterase inhibitors IBMX abegron . and RO 20 - 1724 ( 100 UM each ) . Cells will be added to the stimulation mixture 1 : 1 in a 384 well optiplate and stimu [ 0152 ] In one embodiment the present application lated for 30 min at room temperature . CAMP detection will describes a once -daily treatment for LUTS , obesity , type 2 be using a LANCER CAMP Kit ( PerkinElmer ) . ERK acti diabetes , heart failure, irritable bowel syndrome and similar vation will be measured by ELISA . Desensitization at the gastrointestinal disorders , pre - term labor, depression and level of adenylyl cyclase will be confirmed by measuring the anxiety that achieves a desired blood plasma Cmax while also not desensitizing the beta - 3 adrenoceptor, comprising at response to forkolin . least one immediate release composition , comprising sol Example 2 abegron and at least one pharmaceutically acceptable carrier Radioligand - Binding Studies Endpoint Assessment or diluent; and at least one modified release composition , comprising solabegron and at least one pharmaceutically of Beta - 3 Adrenoceptor Desensitization acceptable carrier or diluent. In some embodiments the [0156 ] [ H ] - L 748 , 337 saturation radioligand binding will pharmaceutical composition may have any of the Cmore be performed as previously described ( van Wieringen et al. Cmin , Tmax , or Tmin described herein . Additional embodimax 2011) . Briefly , cells at approximately 80 % confluence will ments describe treatments, wherein the at least one imme be washed with PBS , harvested by scraping the culture diate release composition comprises about 100 mg to about flasks with a cell scraper , washed twice by centrifugation , 300 mg solabegron and the at least one modified release and then homogenized in ice -cold buffer (50 mM Tris , 0 .5 composition comprises about 100 mg to about 300 mg mM EDTA , PH 7 . 5 ) . The homogenates will be centrifuged solabegron . Further embodiments describe treatments , for 20 min at 50 , 000xg at 4° C . The pellets will be wherein the at least one immediate release composition resuspended in buffer and stored at - 80° C . Aliquots of the achieves a blood plasma Cmax in about 1 to about 3 hours respective membrane preparation (approximately 50 - 100 ug after administration to a subject in need of treatment and the protein / assay ) will be incubated in a total volume of 250 ul at least one modified release composition achieves a blood of binding buffer ( 10 mM Tris , 0 . 9 mN NaCl at pH 7 . 4 ) at plasma Cmor in about 5 to about 11 hours after administra 25° C . for 60 min . Non - specific binding will be defined tion to a subject in need of treatment . Still further embodi using 100 uM isoproterenol. In saturation experiments , eight ments describe treatments, further comprising administering radioligand concentrations will be used . All experiments one or more additional therapeutic agents useful for the will be performed in duplicates in 96 well plates, and treatment of LUTS , obesity , type 2 diabetes , heart failure , incubations will be terminated by rapid vacuum filtration . irritable bowel syndrome and similar gastrointestinal disor Each filter will be washed with approximately 2 - 3 mL of ders , pre - term labor , depression and anxiety , wherein the one ice - cold buffer. Radioactivity adherent to the filters will be more additional therapeutic agents are selected from the quantified in Perkin Elmer scintillator counter. groups consisting of : antimuscarinic agents ; alpha adreno Example 3 ceptor blockers ; 5 - alpha reductase inhibitors ; and phos phodiesterase - 5 inhibitors , wherein the one or more addi Alteration in G -Protein Expression Endpoint tional therapeutic agents may be administered prior to , Assessment of Beta - 3 Receptor Desensitization simultaneously with , or following the administration of the [0157 ] Cells treated with beta - 3 agonists at various time pharmaceutical composition comprising solabegron . points will be washed with PBS, harvested , homogenized US 2017 /0348263 A1 Dec . 7 , 2017 and centrifuged . The pellets will be re -homogenized , boiled drug . At the end of the final wash period the tissues were loaded on to SDS gels and electrophoresed for approxi- stimulated with EFS , and left to equilibrate for at least 30 mately 1 hr at 40 mA . Primary antibodies ( rabbit polyclonal) min . A CCRC was then performed in each tissue . Tissue for detection of G protein subunits ( G . Gil ,Gi2 , Gi3 ,Gq / 11 ) responses were calculated as the mean (SEM ) and expressed will be used . Immunoblotting will be performed for approxi as percentage of EFS induced tone . mately 12 hr at 4° C . Following washing, a secondary 10163 ] Determination of EC , concentration for beta - 3 antibody ( i. e . donkey anti - rabbit coupled to horseradish adrenoceptor agonists to inhibit EFS - induced contraction in peroxidase ) will be used . Luminescence signals will be rat isolated bladder detected and quantified . [0164 ] In the initial pilot experiments , concentration response curves were performed to the test compounds to Example 4 determine an EC , , value for use in later experiments . The calculated values for CL - 316 , 243 and solabegron were Prevention of Receptor Desensitization 0 .042 and 1 . 0 uM , respectively. Effect of the Washout Period Following a One Hr Incubation [ 0158 ] Macroscopically normal bladders obtained from with Test Compound Male CD rats (220 - 250 g ) were used . Tissues were rejected [0165 ] Tissues were incubated with the EC90 concentra if they did not respond adequately to viability checks. Each tion of the test compounds for one hr followed by one hr , bladder was cleaned free of surrounding connective tissue three hr or six hr of washing with PSS . After only one hr of and halved longitudinally . The bladder longitudinal smooth washing , the response to solabegron was significantly muscle , with the urothelium still attached were mounted in attenuated ( FIG . 2 ) . Responses to higher concentrations of 25 mL organ baths containing physiological saline solution solabegron were also significantly attenuated after three hr ( PSS ) ( composition : 119 . 0 mM NaC1, 4 . 7 mM KC1, 1 . 2 mm of washing . After six hr of washing the response to solabe MgSO4, 24 . 9 mM NaHCO2 , 1 . 2 mM KH , POA, 2 . 5 mM gron was similar to that seen in tissues that had not been CaCl, and 11. 1 mM glucose ) supplemented with 1 uM pre -exposed to the test compound ( FIG . 2 ) . This EFS prazosin ( Q , - adrenoceptor antagonist ) and 30 nM induced potentiation of bladder contraction from baseline ICI118551 (B2 - adrenoceptor antagonist) , aerated with 95 % was not observed with solabegron . These data suggest that 0 ,75 % CO , gas mix , warmed and maintained at approxi incubation of the rat bladder with beta - 3 adrenoceptor mately 37° C . throughout the experiment. Changes in force agonists produced marked receptor desensitization , and that production were recorded using transducers . After mount the receptor is re - sensitized in a time -dependent manner ing , the bladder halves were allowed to equilibrate for at following removal of the agonist by removing the ligand by least 30 min before they were set to a stable tension of washing out. Effect of the washout period following a three approximately 1. 0 g . The tissue was then allowed to equili hr incubation with test compound . brate over at least a 60 min period with washes every 15 min . 10166 ]. In the next series of experiments , tissues were [ 0159 ] EFS parameters and viability check incubated with the EC2, concentration of the test compounds [0160 ] In initial experiments the parameters for the EFS for three hr followed by either one hr, three hr or six hr of were assessed by performing a frequency curve to determine washing with PSS . a frequency that would give a response that was approxi [0167 ] After only one hr of washing , the responses to mately 80 % of the response seen to 80 mM KCl. Optimal solabegron and CL -316 , 243 were significantly attenuated EFS parameters were determined to be : 30 Volts , square (FIGS . 3 AND 4 ). Responses to the highest concentrations pulse of 0 . 1 ms, train of 4 seconds every 120 seconds, 15 Hz . of solabegron were also significantly attenuated after three This frequency was then used to stimulate the tissue for all hr of washing . After six hr of washing the responses to subsequent experiments . The viability of bladder strips was solabegron or the tool compound CL - 316 , 243 were similar tested by stimulating the tissue with EFS for minimum of ten to that seen in tissues which had not been pre -exposed to the minutes . Tissues that failed to produce a response of at least test compound (FIGS . 3 AND 4 ) . 1 . 0 g were rejected . Experimental Protocol Conclusions: [0168 ] The data in the present experiments demonstrate [0161 ] Pilot studies to determine EC90 concentrations of that prolonged administration of beta - 3 adrenoceptor ago the test compounds were performed . Upon stabilization of nists produce time- dependent desensitization of the beta - 3 the baseline tension , the bladder muscle strips were stimu adrenoceptor in the rat bladder. Recovery of receptor desen lated with EFS parameters described above. The resulting sitization was achieved by removal or washing -out the contractile responses were allowed to stabilize before adding agonist from the tissue , such that the receptor -mediated cumulative concentrations of test compound ( half - log incre functional response in the bladder returns to vehicle - treated ments ) in a cumulative concentration response curve or baseline conditions . (CCRC ) . A vehicle and a positive control (CL - 316 , 243 ) [0169 ] Following either a one hr or three hr incubation were run in the same manner in order to compare with the with the EC90 concentration of solabegron , the ability of test compounds. From the data obtained in these experi solabegron to reduce the magnitude of EFS -mediated ments , EC70 concentrations of the test compounds were responses in rat bladder muscle was still attenuated mark determined for use in subsequent experiments . edly when the tissue was washed for only one or three hr. [0162 ] The bladder muscle strips were incubated with the After 6 hr ofwashing post - incubation , the ability of solabe EC , determined for each test compound in the pilot studies , gron to reduce EFS was not significantly different than that for a period of 1 or 3 hr. Following compound incubation , seen in muscle strips that had only been exposed to an the tissues were washed with PSS for a period of 1 , 3 or 6 equivalent volume of vehicle and not to solabegron . These hr, with washes approximately every 15 min , to remove the data indicate that the effects of the exposure of the tissue to US 2017 /0348263 A1 Dec . 7 , 2017 24 an EC90 concentration of solabegron produced desensitiza - (0174 ] Similar to the data obtained in the rat bladder, the tion of the responses mediated by the beta - 3 adrenoceptor. data in these experiments demonstrate that prolonged and The EC90 concentration of the beta - 3 adrenoceptor agonists sustained administration of a beta -3 adrenoceptor agonist used in this study was selected because it reflects a clinically produce time- dependent desensitization of the beta - 3 adre relevant concentration comparable to the Cmax observed in noceptor in the human bladder . Recovery of receptor desen subjects . Beta - 3 receptor desensitization appeared to occur sitization was achieved by removal or washing - out the rapidly , as only 1 hr incubation was necessary to produce agonist from the tissue , such that the receptor- mediated marked inhibition of the beta - 3 receptor mediated response . functional response in the bladder returns to vehicle -treated 10170 ] The re - sensitization response occurred in a time or baseline conditions. The re - sensitization response dependent manner , indicating the functional defect in the occurred in a time- dependent manner, indicating the func tissue was reversible , and recovery was completed within 6 tional defect in the tissue was reversible , and recovery was hr. Such a time course of desensitization and re - sensitization time- dependent. Such a time course of desensitization and is consistent with the time course that will be used for a re - sensitization is consistent with the time course that will be pulsatile formulation administration of solabegron in sub used for a pulsatile formulation administration of solabegron jects . in subjects . [ 0171 ] CL -316 , 243 was used as a reference standard as a rodent selective beta - 3 adrenoceptor agonist . Attenuation in Example 6 the ability of CL - 316 , 243 to reduce the magnitude of EFS responses in rat bladder muscle tissue was also seen after a Multiparticulate Formulation for the Release of three hr pre - incubation to the EC90 concentration of CL -316 , Solabegron 243 . Following washout of CL - 316 , 243 the recovery of the [0175 ] A formulation utilizing solabegron is proposed , beta - 3 adrenoceptor mediated response occurred in a time wherein pellets or mini- tablets containing solabegron will dependent manner, as was seen with solabegron . form the basis for multiple releases of solabegron to a [0172 ] The data in the present experiments demonstrate subject in need . The formulation will contain at least two that prolonged administration of beta - 3 adrenoceptor ago populations of pellets , wherein at least one population nists can produce time - dependent desensitization of the comprises an immediate or early release population and at beta - 3 adrenoceptor -mediated responses in the rat bladder. least one population comprises a modified ( i .e . sustained Recovery of receptor desensitization and prevention of and /or delayed ) release population . The immediate release prolonged receptor desensitization can be achieved by pellets will release solabegron immediately or soon there removal of the agonist from the tissue , such that the recep after in the GI tract, whereas the modified release pellets will tor -mediated functional response returns to baseline condi release solabegron at a later time or distance inside the GI tions . Beta - 3 receptor desensitization can be prevented by tract. The modified release pellets may be coated with either giving sufficient time between drug exposures for the tissue a pH dependent ( enteric ) coating or a time dependent to recover . Therefore , prevention of prolonged administra coating so as to delay the second release of solabegron to the tion of a beta - 3 adrenoceptor agonist in subjects with OAB desired position in the GI tract. Both types of pellets may may be desirable in order to preserve and increase thera contain any physical form of solabegron such as , for peutic efficacy . Thus, the daily administration of a beta -3 example , amorphous or crystalline solid . The pellets may be adrenoceptor agonist that is formulated to occur in a pulsa drug - layered pellets , matrix - type pellets , or mini- tablets tile manner may be the viable approach for chronic treat containing active drug in its matrix . ment. Such an approach will reduce beta - 3 adrenoceptor desensitization and promote recovery of desensitized recep Example 7 tors to become active . Drug Coated Spheres /Pellet with an Inert Core for Example 5 the Release of Solabegron Prevention of Receptor Desensitization in Human [0176 ] A formulation utilizing solabegron is proposed , Bladder wherein spheres /pellets with an inert core layered with solabegron will form the basis for multiple releases of [ 0173] Beta - 3 adrenoceptor desensitization and resensiti solabegron to a subject in need . The formulation will contain zation were examined in the human bladder . Similar to the at least two populations of spheres / pellets with an inert core , protocol used in the rat bladder, isolated human bladder wherein at least one population comprises an immediate or tissue strips were studied for EFS responses. Optimal EFS early release population and at least one population com parameters were determined to be : 30 volts, square pulse of prises a modified ( i . e . sustained and / or delayed ) release 0 . 1 ms, train of 5 seconds every 60 seconds , 8 - 10 Hz . population . The immediate , early spheres/ pellets with an Solabegron ( 10 - 10000 UM ) produced concentration -depen inert core will release solabegron immediately or soon dent inhibition of EFS - induced bladder smooth muscle thereafter in the GI tract , wherein the modified release contraction . Human bladder muscle strips were incubated spheres /pellets with an inert core will release solabegron at with the EC70 for solabegron for a period of 1 or 3 hr. a later time inside the GI tract. The modified release spheres / Following compound incubation , the tissues were washed pellets with an inert core may be coated with either a pH with PSS for a period of 1 or 3 hr, with washes approxi dependent ( enteric ) coating or a time dependent coating so mately every 15 min , to remove the drug . At the end of the as to delay the second release of solabegron to the desired final wash period the tissues were stimulated with EFS , and position in the GItract . Both types of spheres/ pellets with an left to equilibrate for at least 30 min . A concentration inert core may contain any physical form of solabegron such response curve was then performed in each tissue . as, for example , amorphous or crystalline solid . US 2017 /0348263 A1 Dec . 7 , 2017 25
Example 8 abegron will form the basis for the multiple releases of solabegron to a subject in need . The formulation will contain Multi -Layer Tablet for the Release of Solabegron a tablet or capsule having both an immediate release and [0177 ] A formulation utilizing solabegron is proposed , modified release component . The immediate layer will wherein a multi -layer tablet containing solabegron will form release solabegron immediately in the GI tract, wherein the the basis for the multiple releases of solabegron to a subject modified release layer will release solabegron at a later time in need . The formulation will contain a tablet having both an inside the GI tract. The gastroretentive oral dosage form may immediate / early release layer and a modified release layer. The immediate layer will release solabegron immediately or utilize mucoadhesive , swellable , high density or floating soon thereafter in the GI tract, whereas the modified release technologies to prolong residence time in the stomach layer will release solabegron at a later time inside the GI thereby allowing a prolonged period for release of both first tract . The modified release layer may be coated with either and second releases in the stomach or upper GI. Both a pH dependent ( enteric ) coating or a time dependent releases may contain any physical form of solabegron such coating so as to delay the second release of solabegron to the as, for example , amorphous or crystalline solid . desired position in the GI tract. The layers may contain any physical form of solabegron such as , for example , amor Example 12 phous or crystalline solid . An example of a multi- layer tablet is shown in FIG . 8 . Proposed Formulations for Pellets in Solabegron Example 9 Formulations Matrix Tablet for the Release of Solabegron [0181 ] TABLE 1 illustrates the dosage formulations com [0178 ] A formulation utilizing solabegron is proposed , prising amorphous solabegron and a polymer with or with wherein a matrix tablet containing solabegron will form the out excipients formed into small 2 mm diameter tablets by basis for the multiple releases of solabegron to a subject in either hot- melt extrusion (HME ) or spray drying techniques . need thereof. The formulation will contain a well -mixed The drug loading of solabegron to polymer may be in any composite of drug ( s ) with rate - controlling excipients . ratio from 1 : 99 to 99: 1 by weight. The final dosage form Numerous sustained and / or delayed release tablets such as membrane controlled system , matrices with water soluble / includes a proportion of tablets that are immediate release insoluble polymers , and osmotic systems may be utilized . formulation and a proportion of tablets that are modified The tablet may contain either the amorphous form of sol release formulation that may receive additional coating abegron or the crystalline form . The delayed / sustained enclosed in a capsule as illustrated in FIG . 5 . The tablets that release can be achieved by applying a permeable or semi are additionally coated , receive a coating that prevents permeable membrane to the tablet core or by mixing the dissolution in the GI until they reach the appropriate location drug with excipient that is either a hydrophilic polymer with in the GI. At which point, the coating dissolves and breaks high viscosity and gel forming capability or a hydrophobic away from the tablet . There may optionally be a third excipient that slows down the diffusion of drug molecule . An population of tablets having an immediate release core but immediate release drug layer can be coated or press coated coated with a non - pH dependent polymer. The non -pH to the tablet that will be available for an early release in the dependent coating may then be further coated so as to allow GI tract, while the delayed / sustained release core will be dissolution at a chosen point in the GI. designed to delay the drug release after a time period in a designed region of the GI tract . TABLE 1 Plasticizer Example 10 Processing Drug of other Multicore Tablet or Capsule for the Release of Method Polymer Load excipients Solabegron ??? HPMC . 1 to . 5 Yes or No ??? Polyethylene Glycol MW = 20000 . 1 to . 5 Yes or No [0179 ] A formulation utilizing solabegron is proposed , ??? Hydroxypropylmethyl cellulose acetate . 1 to .5 Yes or No wherein a multicore tablet or capsule containing solabegron succinate will form the basis for the multiple releases of solabegron to ??? Hydroxypropylmethyl cellulose - to .5 Yes or No phthalate (HPMCP ) a subject in need thereof. The formulation will contain a ??? Hydroxypropyl ß Cyclodextrin . 1 to . 5 Yes or No multicore tablet or capsule that comprises multiple discrete HME PVP K30 . 1 to . 5 Yes or No cores consisting of at least one immediate release core and HME Hydroxypropyl cellulose . 1 to . 5 Yes or No at least one delayed / sustained release core contained within HME Poloxamer 188 - to . 5 Yes or No the same tablet or capsule . The at least one immediate HME Poloxamer 407 . 1 to . 5 Yes or No Spray Dry HPMC to . 5 Yes or No release core will be available for an early release in the GI Spray Dry Polyethylene Glycol MW = 20000 to . 5 Yes or No tract , while the at least one delayed / sustained release core Spray Dry Hydroxypropylmethyl cellulose acetate . 1 to . 5 Yes or No will be designed to delay the drug release after a time period succinate in a designed region of the GI tract. Spray Dry Hydroxypropylmethyl cellulose . 1 to . 5 Yes or No phthalate (HPMCP ) Example 11 Spray Dry Hydroxypropyl B Cyclodextrin . 1 to . 5 Yes or No Spray Dry PVP K30 . 1 to . 5 Yes or No Gastroretentive Delivery System for the Release of Spray Dry Hydroxypropyl cellulose . 1 to . 5 Yes or No Solabegron Spray Dry Poloxamer 188 . 1 to . 5 Yes or No [ 0180 ] A formulation utilizing solabegron is proposed , Spray Dry Poloxamer 407 . 1 to . 5 Yes or No wherein a gastroretentive oral dosage form containing sol US 2017 /0348263 A1 Dec . 7 , 2017 26 .
Example 13 Example 14 Proposed Formulations for the Release of Dissolution of Solabegron Formulations of Solabegron Example 12 [0182 ] It is proposed that solabegron be formulated as a [0183 ] Certain solabegron formulation described in once - daily formulation having two distinct release compo Example 12 were subjected a dissolution study, wherein the nents . It is envisioned that such formulations may exist solabegron -polymer formulation was placed in a phosphate wherein both the two release components contain the same buffered saline ( PBS ) solution at pH 6 . 8 . The amount of or different amounts of solabegron and when different either the first or second release may contain the greater amount of solabegron in solution is illustrated as a function of time in solabegron . Provided below in TABLE 2 are formulations FIG . 6 . A formulation of 20 % weight solabegron spray -dried that should provide a therapeutic amount of solabegron to a in polyvinyl pyrrolidine (PVPK30 ) demonstrated good dis solution properties and was found to form a uniform amor subject in need without desensitizing the beta - 3 adrenocep phous phase by Fourier - transform infrared spectroscopy tor . (FTIR ) FIG . 7 . TABLE 2 Example 15 Low Dose High Dose Mixed Dose Cmax 1 (hours after 0 .75 - 4 . 0 0 . 75 - 4 .0 0 . 75 - 4 . 0 Stability of Solabegron -Polymer Pellets administration ) Cmin 1 (hours after 4 . 0 - 8 . 0 4 . 0 - 8 . 0 4 .0 - 8 . 0 administration ) [0184 ] A series of formulations comprising amorphous Cmax 2 (hours after 2 . 0 - 8 . 0 2 . 0 - 8 . 0 2 . 0 - 8 . 0 solabegron and a polymer formed into small 2 mm diameter Cmin 1 ) tablets by either hot- melt extrusion (HME ) or spray drying OOOCmin 2 (hours after 24 24 24 administration ) techniques were prepared according to TABLE 3 . The actual Time Between Cmax 1 2 , 0 - 8 , 0 2 . 0 - 8 . 0 2 . 0 - 8 . 0 loading weight percentage of solabegron was determined at and Cmax 2 (hours ) formation and the purity of the product was measured after one week to determine the amount of product degradation . TABLE 3 Solabegron ( Salt) Purity Formulation Stability ( Temp/ Days ) Loading ( % ) ( % Area ) HME _ Kollidon 12PF :Solabegron (80 : 20 ) 40 C ./ 75RH Closed , 8 days 16 .6 98 .95 HME _ Kollidon 12PF : Solabegron ( 80 : 20 ) 40 C ./ 75RH Open , 8 days 15 . 2 98 . 56 HME _ Kollidon 12PF :Solabegron ( 80 : 20 ) RT, 8 days 16 . 7 98 . 99 SD _ PVP K30 : Solabegron ( 80 : 20 ) 40 C ./ 75RH Closed , 8 days 17 . 8 99 . 82 SD _ PVP K30 :Solabegron ( 80 : 20 ) 40 C . /75RH Open , 8 days 16 . 9 99 . 90 SD _ PVP K30 :Solabegron ( 80 : 20 ) RT, 8 days 17 . 9 100 SD _ CD :Solabegron (80 :20 ) 40 C ./ 75RH Closed , 7 days 19 . 5 100 SD _ CD : Solabegron (80 : 20 ) 40 C . /75RH Open , 7 days 18 . 0 98 . 32 SD _ CD :Solabegron (80 :20 ) RT, 7 days 19 . 3 100 SD _ HPMC: Solabegron (80 : 20 ) 40 C . /75RH Closed , 7 days 22 . 0 100 SD _ HPMC: Solabegron (80 :20 ) 40 C . /75RH Open , 7 days 21. 4 98 . 82 SD _ HPMC: Solabegron ( 80 : 20 ) RT, 7 days 21 . 8 99 . 83 PVP K30 : Solabegron ( 50 : 50 ) Initial ( TO ) 49 . 1 100
TABLE 2 - continued Example 16 Spheronized Compositions of Solabegron High Dose Low Dose Mixed Dose [0185 ] formulation utilizing solabegron is proposed , wherein solabegron is made into small spheres or spheroids. Cmax 1 (ug /mL ) 0 . 5 - 2 1 . 5 - 3 . 5 0 . 5 - 2 The formulation will contain at least two populations of Cmax 2 (ug / mL ) 1 . 5 - 3 2 . 5 - 4 2 . 5 - 4 spheres , wherein at least one population comprises an imme Cmin 1 ( ug/ mL ) 0 . 25 - 1 . 0 0 . 5 - 1 . 5 0 . 25 - 1 . 0 diate or early release population and at least one population Cmin 2 (ug / mL ) 0 .01 - 1 0 . 25 - 1 0 .01 - 1 comprises a modified (i . e . sustained and / or delayed ) release First Release 75 - 250 75 - 250 75 - 250 population . The immediate , early spheres release solabegron Second Release 100 -400 100 - 400 100 - 400 immediately or soon thereafter in the GI tract , wherein the modified release spheres will release solabegron at a later Time at or below about 6 to about 6 to about 6 to time inside the GI tract. The modified release spheres may 1 . 0 ug/ mL over a about 9 about 9 about 9 be coated with either a pH dependent (enteric ) coating or a 24 hour period time dependent coating so as to delay the second release of (hours ) solabegron to the desired position in the GI tract. Both types of spheres may contain any physical form of solabegron such as, for example , amorphous or crystalline solid . US 2017 /0348263 A1 Dec . 7 , 2017 27
Example 17 The core is sub -coated with Opadry Clear 03019001 fol lowed by a final coating of PlasACRYL HTP20 /Eudragit Composition A : 200 mg Solabegron Modified L30 D - 55 . The final Eudragit coating ensures release at Release Tablet with Sodium Lauryl Sulfate (SLS ) approximately pH 5 . 5 and greater . The composition is more [0186 ] A pressed tablet core containing solabegron HC1 specifically defined as follows: freebase equivalent and additional excipients was prepared . The core is sub - coated with Opadry Clear 03019001 fol lowed by a final coating of PlasACRYL HTP20 /Eudragit Chemical Name % w / w L30 D - 55 . The final Eudragit coating ensures release at Tablet Micronized Solabegron HCI (D90 = ~ 4 um ) 27 . 5 approximately pH 5 .5 and greater . The composition is more Core Mannitol 28 . 8 Microcrystalline Cellulose specifically defined as follows: Kolliphor P188 (aka Poloxamer 188 ) Croscarmellose Sodium Citric Acid Chemical Name % w / w Sodium Lauryl Sulfate 2 . 7 Colloidal SiO2 0 . 5 Tablet Micronized Solabegron HCl (D90 = - 4 um ) 27 . 5 Sodium Stearyl Fumarate 1 . 8 Core Mannitol ? Microcrystalline Cellulose Sub - total 91. 6 Croscarmellose Sodium DR Opadry Clear 2 . 7 Citric Acid ??? Layer Eudragit L30 D55 4 . 5 Sodium Lauryl Sulfate ? Plasacryl HTP20 1 . 1 Colloidal SiO2 ? Sodium Stearyl Fumarate ? Sub - total 100 Sub - total 91 . 6 DR Opadry Clear 2 .7 Layer Eudragit L30 D55 4 . 5 Example 20 Plasacryl HTP20 1 . 1 Composition D : 275 mg Solabegron Combined Immediate / Early Release and Modified Release Total 100 Tablet with Sodium Lauryl Sulfate (SLS ) [0189 ] A pressed tablet core containing solabegron HCI Example 18 freebase equivalent and additional excipients was prepared . The core is sub - coated with Opadry Clear 03019001 fol Composition B : 200 mg Solabegron Modified lowed by a final coating of PlasACRYL HTP20 /Eudragit L30 D -55 . The final Eudragit coating ensures release at Release Tablet with Poloxamer 188 (P188 ) approximately pH 5 . 5 and greater. The Eudragit coated core [0187 ] A pressed tablet core containing solabegron HCI is then coated with a 50 /50 suspension of micronized freebase equivalent and additional excipients was prepared . solabegron HC1/ Opadry Clear 03019001 until 75 mg of The core is sub -coated with Opadry Clear 03019001 fol lowed by a final coating of PlasACRYL HTP20 /Eudragit solabegron HCl freebase is applied . The composition is L30 D -55 . The final Eudragit coating ensures release at more specifically defined as follows : approximately pH 5 . 5 and greater. The composition is more specifically defined as follows: Chemical Name % w / w Tablet Micronized Solabegron HCl (D90 = ~ 4 um ) 22 . 8 Core Mannitol 31 . 4 Chemical Name % w / w Microcrystalline Cellulose 7 . 6 Tablet Micronized Solabegron HCI (D90 = - 4 um ) 27 .5 Croscarmellose Sodium 7 . 5 Core Mannitol 31 .6 Citric Acid 2 .3 Microcrystalline Cellulose 9 . 2 Sodium Lauryl Sulfate 2 .3 Kolliphor P188 (aka Poloxamer 188 ) Colloidal SiO2 0 .4 Croscarmellose Sodium Sodium Stearyl Fumarate 1 . 6 Citric Acid Colloidal SiO2 Sub - total 76 aano DR Opadry Clear 2 . 3 Sodium Stearyl Fumarate büroo Layer Eudragit L30 D55 3. 8 Sub - total 91. 6 Plasacryl HTP20 0 . 9 DR Opadry Clear 2 .7 Layer Eudragit L30 D55 4 . 5 Sub - total 82 . 9 Plasacryl HTP20 1 . 1 IR Solabegron HCl 8 . 5 Layer Opadry Clear 8 . 5 Total 100 Total 100 Example 19 Example 21 Composition C : 200 mg Solabegron Modified Modified Release Dosage Form Containing 30 % Release Tablet with Sodium Lauryl Sulfate ( SLS ) Solabegron as a Suspension in an Enteric Capsule and Poloxamer 188 (P188 ) ( 100 mg Solabegron ) [ 0188 ] A pressed tablet core containing solabegron HC1 [0190 ] Micronized solabegron HCl suspension blended freebase equivalent and additional excipients was prepared . into a suspension with Tween 80 and Propylene Glycol. The US 2017 /0348263 A1 Dec . 7 , 2017 suspension is weighed and dispensed into an enteric capsule designed to dissolve at approximately pH 5 . 5 and greater. -continued The composition is more specifically defined as follows: Condition Setting Acid Stage Bath Media Volume: 1000 mL 0 .01N HCl Sample Times: 60 , 120 minutes Chemical Name % w / w Sample Dilution : N / A Buffer Stage Bath Media Volume: 1000 mL Propylene Glycol 33 .65 % 0 .05M Phosphate Sample Times : 30 , 60 , 120 minutes Tween 80 33 .65 % Buffer , pH 6 . 8 (after media change ) Micronized Solabegron HCl (D90 = ~ 4 um ) 32 . 70 % with 2 % SLS Sample Dilution : 2 . 5 mL sample into 2 . 5 mL diluent Total 100 .00 % [0207 ] FIG . 14 shows the dissolution curve of composi Example 22 tion A ( Example 17 ) . [ 0208 ] FIG . 15 shows the dissolution curve of composi Fasted State Simulated Gastric Fluid (FaSSGF ) tion B ( Example 18 ) . Dissolution Studies of Solabegron Formulations [0209 ] FIG . 16 shows the dissolution curve of composi tion C (Example 19 ) . [0191 ] Dissolution studies were conducted under the fol [ 0210 ] FIG . 17 shows the dissolution curve of composi lowing conditions: FaSSGF media , pH 1 . 6 , 75rpm for the tion D ( Example 20 ) . first 60 minutes , then 200 rpm until the infinity pull ( 120 10211 ] The dissolution studies in Examples 22 and 23 minutes) underscore the role surfactants can have in the compositions. [0192 ] USP II paddles , 37 . 0 C . Surfactants improve solabegron in vivo dissolution through [0193 ] 500 mL media / vessel enhanced dispersion , wetting and solubilization . [0194 ] 45 um filters then 5 . 0 um filters , both collected [0212 ] The particle size used in these solabegron formu and analyzed . lations is ~ 4 microns ( 490 ) . The surface area to mass ration [0195 ] Sample pull at 10 , 30 , 60 minutes , then increase at that d90 is improved over the same at a d90 of ~ 100 rpm and pull infinity at 120 minutes . microns . In order to take advantage of the improved disso 0196 ] FIG . 9 shows the dissolution curve of composition lution of the smaller particle size the solabegron particles A (Example 17 ) . must be separated and kept from agglomerating until they [0197 ] FIG . 10 shows the dissolution curve of composi have had a chance to go into solution . By intermingling tion B (Example 18 ). surfactant with solabegron particles these particles are pro [0198 ] FIG . 11 shows the dissolution curve of composition tected at the time of wetting allowing them to disperse C (Example 19 ) . avoiding their natural tendency to agglomerate . [0199 ] FIG . 12 shows the dissolution curve of composi [0213 ] Solabegron is hydrophobic . Surfactants in this for tion E ( Example 21 ) . mulation act to allow an otherwise hydrophobic molecule to 102001 Another dissolution study was conducted under the closely interface with water. following conditions : FaSSGF media , pH 1 . 6 , 75 rpm for the [0214 ) Surfactants have been demonstrated to dramati first 60 minutes, then 200 rpm until the infinity pull ( 120 cally improve the equilibrium solubility of solabegron . minutes ) [0201 ] USP II paddles , 37. 0 C . Example 24 10202 ] 500 mL media / vessel [0203 ] 45 um filters then 5 . 0 um filters, both collected Pharmacokinetic Concentrations Over 24 Hours of and analyzed . Solabegron Formulations [0204 ] Sample pull at 10 , 30 , 60 minutes , then increase rpm and pull infinity at 120 minutes . [0215 ) Pharmacokinetic concentration data from phase I [ 0205 ) FIG . 13 shows the dissolution curve of a 75 mg clinical trials was used to evaluate the PK concentration of immediate release coated delayed release placebo core in immediate release solabegron formulations at a single dose 500 mL of FaSSGF . of 50 mg, 100 mg or 150 mg respectively and the PK concentration of a single dose 200 mg modified release Example 23 solabegron formulation (Surfactant Loaded ) .
Dissolution Studies of Solabegron Formulations Time (Hrs ) IR - A 50 mg IR - B 100 mg IR - C 150 mg DR 200 mg * [ 0206 ] Dissolution studies were conducted under the fol 0 . 6 0 . 0 0 . 0 0 . 2 lowing conditions: 0 . 5 137 . 5 2 . 8 528 . 0 8 . 2 600 . 1 192. 0 2370 . 0 27 .4 1 . 5 686 . 2 246 . 0 2600 . 0 50 . 0 Condition Setting 704 . 7 308 . 0 2405 . 0 60 . 6 ????? Apparatus USP II , Paddies 590 . 3 299. 0 2085 . 0 115 . 6
Tablets in Sinkers ? Agitation Rate 75 RPM ? 446 . 4 236 . 0 1470 . 0 280 . 9 Vessel Temperature 37° C . + 0 .5° C . ? Sample Volume 5 ml (manual ) 326 . 9 164 . 0 1380 . 0 Filters 10 um in - line 5 . 5 US 2017 /0348263 A1 Dec . 7 , 2017
- continued [0220 ] immediate release/ modified release profile for 100 mg immediate release solabegron combined with Time (Hrs ) IR - A 50 mg IR - B 100 mg IR - C 150 mg DR 200 mg * 200 mg modified release solabegron ( FIG . 20 ) 180 . 0 89 . 1 748 . 5 1052 . 7 [ 0221 ] immediate release /modified release profile for 6 . 5 interpolated 125 mg immediate release solabegron 122 . 5 74 . 2 545 . 0 combined with 200 mg modified release solabegron u 92 . 1 69 . 9 410 . 0 763 . 3 (FIG . 21 ) 8 .5 [0222 ] immediate release /modified release profile for 70 . 8 58 .9 346 .5 150 mg immediate release solabegron combined with 9 . 5 200 mg modified release solabegron ( FIG . 22 ) 10 55 . 6 53 . 5 268 . 0 10 . 5 11 Example 25 11 . 5 12 38 . 3 33. 4 191. 5 281. 6 12 . 5 281. 6 Phase 1 Study to Evaluate the Safety , Tolerability 13 and Pharmacokinetics of Candidate Formulations of 13 . 5 Orally Administered Solabegron under Fed and 14 23 . 3 21. 5 105 . 2 Fasted Conditions to Healthy Male 14 . 5 23 .3 21. 5 105. 2 15 15 . 5 [0223 ] A parallel , single - blind , cross- over study; up to 9 16 118 . 6 groups of 10 subjects will receive single doses of candidate 16 . 5 formulations of solabegron drug products under fasting and 17 fed conditions. The candidate formulations of solabegron 17 . 5 drug products differ based in their composition . 18 14 . 5 1111. 2 53. . 00 121 . 6 18 . 5 [0224 ] Solabegron immediate release and modified release 19 investigational product formulations will be provided as 19 . 5 tablets or capsules . Up to 9 formulations of solabegron will 20 107 . 2 20 .5 be assessed . 21 [0225 ] All formulations listed are single dosing units 21. 5 except where designated below . IR is immediate /early 22 22 . 5 release and DR is modified or delayed release : 23 [0226 ] solabegron 200 mg DR , Composition C (Ex 23 . 5 ample 19 ) ; 24 0 1010 . 0 7 7 .. 6 9 2727 . 9 6363. 22 [0227 ] solabegron 200 mg DR , Composition A , (Ex * DR 200 mg PK data truncated at 24 hour point. ample 17 ) ; [ 0228 ] solabegron 200 mg DR Composition B (Ex [ 0216 ] Using the clinical data (above ), linear interpolation ample 18 ) ; was performed between the 50 mg and 100 mg immediate [0229 ] solabegron 200 mg DR total dose , solabegron release study results to estimate PK concentration profile for 2x100 mg DR , Composition E ( Example 21 ) ; an analogous 75 mg immediate release formulation . Simi [0230 ] solabegron 275 mg (75 mg IR /200 mg DR , larly linear interpolation was performed between the 100 mg Composition D , Example 20 ) ; and 150 mg immediate release study results to estimate PK [0231 ] solabegron 75 mg IR (solabegron as a suspen concentration profile for an analogous 125 mg immediate sion in a geletin capsule imicronized solabegron HC1 release formulation . (about 32 .70 % w / w /) suspension blended into a sus [0217 ] Within all four of the datasets (50 mg, 100 mg and pension with tween 80 (about 33 .65 % ) and propylene 150 mg immediate release formulations and 200 mg modi glycol (about 33 .65 % w / w ) ) ; fied release formulation ) , linear interpolations were per [0232 ] solabegron 275 mg total dose ( solabegron 75 mg formed between actual measurement points ( sample times ) IR (above ) and solabegron 200 mg DR (Composition as necessary to align the different sample times between the A ), given in two separate pharmaceutical composi two Phase 1 studies to allow different individual PK profiles tions ) . to be combined . Once all the data points were aligned , the [0233 ] The objective of this study is to investigate the individual immediate release PK concentration profiles were pharmacokinetics of candidate formulations of solabegron each combined through linear summation with the modified and to investigate the safety and tolerability of candidate release PK concentration profile to yield estimated imme formulations of solabegron administered under fasting and diate release /modified release PK profile data and graphs, as fed conditions. indicated below : [ 0218 ] immediate release/ modified release PK profile Pharmacokinetics: for 50 mg immediate release solabegron combined with [0234 ] Maximum observed plasma drug concentration 200 mg modified release solabegron (FIG . 18 ) (Cmax ) ; terminal phase half - life (t1 / 2 ) ; area under the plasma [ 0219 ] immediate release /modified release profile for drug concentration versus time curve (AUC0 - 4, AUCO) ; interpolated 75 mg immediate release solabegron com clearance (CL / F ) ; volume of distribution (Vd / F ) ; terminal bined with 200 mg modified release solabegron (FIG . elimination rate constant ( a ) ; Tmax ; other PK parameters 19 ) may be calculated , as appropriate . US 2017 /0348263 A1 Dec . 7 , 2017 30
[ 0235 ] Blood samples ( ~ 4 mL ) for the determination of Analyses plasma concentrations of solabegron will be collected at the [0245 ] Demographics and baseline characteristics will be nominal times ( u5 min ) indicated in the Time and Events listed and summarized descriptively by cohort, treatment Table (FIGS . 23 and 24 ) . and overall . [0246 ] Safety analyses will be performed on data from all Treatment Period subjects in the Safety Population . AEs, clinical laboratory [0236 ] Up to 9 groups of 10 subjects each will participate evaluations, and other safety measures ( e . g . , vital signs , in the study (maximum of 90 subjects ) . Eligible subjects will ECGs) will be listed and summarized . No formal statistical be admitted to the research unit on Day - 1 to perform analysis of safety data is planned . All available data will be pre - dose (baseline ) assessments . Some baseline assessments reviewed throughout the study , as the data become available . may occur on Day 1 prior to dosing . All assessments and the [0247 ] Concentration time data for solabegron will be relative timings for these are listed in the Time and Events evaluated using standard non - compartmental analysis meth Table (FIGS . 23 and 24 ) . ods. If feasible , PK parameters at all doses will include more 102371 On Day 1 , subjects will receive one of the candi t12, AUCO AUCO . , Tmax+ 771 , CL / F , Vd/ F , and Nz. Other PK date formulations under fed conditions and 96 hours later parameters will be calculated , as appropriate . Trends in the will receive a second dose of the same study medication PK parameters will be evaluated across dose groups . Model under fasted conditions . Subjects will remain confined until based analyses may be performed following examination of approximately 48 hours after their second and final dose . the data . 10238 ] Subjects who have completed dosing with one of [ 0248 ] Pharmacokinetic data will be presented in graphi the formulations will be eligible to be dosed with one cal and/ or tabular form and will be summarized descrip additional formulation . At least five days should elapse tively . between completion of dosing with the first formulation and [0249 ] Derived PK parameters and plasma concentrations the start of dosing with the additional formulation . Subjects will be listed and summarized descriptively by dose . will be required to undergo rescreening if more than 30 days Descriptive statistics ( n , arithmetic mean , standard devia have elapsed since the time of their previous discharge . tion , 90 % confidence interval (CI ) , minimum , median and maximum ) will be calculated for all pharmacokinetic param eters . In addition , for loge- transformed PK parameters , geo Inclusion / Exclusion Criteria metric mean , 90 % CI, and CV % will be provided . [0239 ] A subject must meet all Inclusion Criteria (not 10250 ) The derived PK parameters will be compared to the described ) , and none of the Exclusion Criteria ( not derived parameters obtained from healthy volunteers . described ) , to participate in this study. [ 0251 ] Further analysis will be predicated upon review of the data . Fed /Non Fed [ 0240 ] For the first dosing period (under fed conditions) Adverse Events ( AE) and Serious Adverse Events ( SAE ) and the second dosing period (under fasting conditions ) , [0252 ] An AE is any untoward medical occurrence in a subjects must not have anything to eat a minimum of 8 hours study subject that is temporally associated with the use of a before dosing. For the fed dosing period , following the medicinal product, regardless of its potential relationship to overnight fast, subjects will have their pre- dose blood the medicinal product . An AE , therefore, can be any unfa sample drawn followed by a standard FDA high fat (50 % ) vorable or unintended sign , including an abnormal labora breakfast 30 minutes prior to dosing and will be asked to eat tory finding , symptom , or disease (new or exacerbated ) , the meal in s30 minutes. Dosing will begin approximately whether or not related to the study drug . 30 minutes after the start of the meal on Day 1 . [0253 ] The definition of an SAE is any untoward medical occurrence that, at any dose : results in death ; is life - threat Dosage and Administration ening , requires hospitalization or prolongation of existing hospitalization , results in disability /incapacity , or is a con [ 0241 ] Subjects will be administered study drug with 240 genital anomaly /birth defect. mL of water under fed and fasting conditions . [0254 ] All AES and SAEs will be reported . Data Analysis and Statistical Considerations Results [0255 ] The mean PK data for the Solabegron 200 mg total Sample Size dose DR , Composition E (Example 21 ) for the fed arm of 10 [0242 ] Sample size is based on feasibility , and the study is patients is shown in FIGS . 25 and 26 . This delayed release observational in nature . Planned sample size is up to 9 formulation exhibits the characteristics necessary for the groups of 10 subjects for a maximum of 90 subjects . modified release portion of the compositions of the inven tion . The mean PK parameters for this arm are as follows : Populations for Analysis AUC 24 hours is about 12 ,246 ng. hr / mL ; AUC 48 hours is about 12, 660 ng .hr /mL ; Cmax is about 3 . 14 ug /mL ; Tmax [0243 ] Safety Population : includes all subjects who ( time to Cmax ) is about 4 . 10 hours and Ty is about 5 . 37 receive one dose of study medication . hours. [0244 ] PK Population : includes all subjects who receive a [0256 ] Although the present disclosure has been described dose of solabegron and have at least one plasma sample in considerable detail with reference to certain preferred obtained and analyzed for solabegron concentration . versions thereof, other versions are possible . Therefore, the US 2017 /0348263 A1 Dec . 7 , 2017 31 spirit and scope of the application should not be limited to 12 . The pharmaceutical composition according to claim 1 ,
the description of the preferred versions described herein . wherein the first target Cmax22 is achieved at about 0 . 75 to 102571. All features disclosed in the specification , includ - about 4 hours after the first administration . ing the abstract and drawings , and all the steps in any 13 . The pharmaceutical composition according to claim 1 , method or process disclosed , may be combined in any wherein the second target Cmax is achieved at about 2 to combination , except combinations where at least some of about 8 hours after the first Cmin . such features and / or steps are mutually exclusive . Each 14 . The pharmaceutical composition according to claim 4 , feature disclosed in the specification , including abstract and wherein the first release comprises about 75 mg to about 400 drawings, can be replaced by alternative features serving the mg of solabegron same, equivalent or similar purpose , unless expressly stated 15 . The pharmaceutical composition according to claim 4 , otherwise . Thus, unless expressly stated otherwise , each wherein the second release comprises about 100 mg to about feature disclosed is one example only of a generic series of 400 mg of solabegron . equivalent or similar features . Various modifications of the 16 . The pharmaceutical composition according to claim 1, application , in addition to those described herein , will be further comprising one or more additional therapeutic agents apparent to those skilled in the art from the foregoing selected from the group consisting of: antimuscarinic agents ; description . Such modifications are also intended to fall alpha adrenoceptor blockers; botulinum toxin ; purinergics ; within the scope of the appended claims. cannabinoids ; transient receptor potential ( TRP ) protein [ 0258 ] Throughout the above specification a number of inhibitors ; prostaglandins ; percutaneous tibial nerve stimu references have been cited and or referred to it is to be lation ; 5 - alpha reductase inhibitors ; and phosphodies understood that unless specifically noted , all references cited terase - 5 inhibitors . in the above specification and or referred to in the above 17. A pharmaceutical composition for the delivery of specification are hereby incorporated by reference in their solabegron , comprising entirety . a . at least one immediate release composition , comprising What is claimed is : solabegron and at least one pharmaceutically accept 1. A pharmaceutical composition comprising a therapeu able carrier or diluent; and tically effective amount of solabegron , wherein the pharma b . at least one modified release composition , comprising ceutical composition achieves a first target Cmar, a second solabegron and at least one pharmaceutically accept target Cmax , a first target Cmin between the first target Cmax able carrier or diluent . and the second target Cmax , and a second target Cmin after the 18 . The pharmaceutical composition according to claim second target Cmax 17 , wherein the at least one immediate release composition 2. The pharmaceutical composition of claim 1, wherein comprises about 75 mg to about 400 mg solabegron . said pharmaceutical composition achieves a plasma concen 19 . The pharmaceutical composition according to claim tration of about 1 ug /mL or less for about 6 hours to about 17, wherein the at least one modified release composition 9 hours during a twenty - four hour period . comprises about 100 mg to about 400 mg solabegron . 3. The pharmaceutical composition of claim 1, wherein 20 . The pharmaceutical composition according to claim said pharmaceutical composition achieves a target AUC of 17, wherein the at least one immediate release composition about 5 , 000 ng hr/mL to about 30 ,000 ng hr/ mL . achieves a blood plasma Cmor in about 0 . 75 to about 4 hours 4 . The pharmaceutical composition of claim 1 , wherein after administration to a subject in need of treatment. the first target Cmax is achieved after the start of a first release 21. The pharmaceutical composition according to claim of solabegron and the second target Cmax is achieved after 17 , wherein the at least one modified release composition the start of a second release of solabegron . achieves a blood plasma Cmor in about 2 to about 8 hours 5 . The pharmaceutical composition according to claim 1, after the first Cmin . wherein said first target Cmar is about 0 . 5 ug /mL to about 3 .5 22 . The pharmaceutical composition according to claim ug /mL . 17 , further comprising one or more additional therapeutic 6 . The pharmaceutical composition according to claim 1 , agents or treatments useful for the treatment of LUTS , obesity , type 2 diabetes , heart failure , irritable bowel syn wherein said second target Cmax is about 1 .5 ug /mL to about drome and similar gastrointestinal disorders , pre - term labor, 4 ug /mL . depression and anxiety , wherein the one more additional 7 . The pharmaceutical composition according to claim 1 , therapeutic agents or treatments are selected from the groups wherein said first Cmin is about 0 . 25 ug /mL to about 1 . 5 consisting of: antimuscarinic agents ; alpha adrenoceptor ug /mL . blockers ; botulinum toxin ; purinergics ; cannabinoids; tran 8 . The pharmaceutical composition according to claim 1 , sient receptor potential ( TRP ) protein inhibitors ; prostaglan wherein said second Cmin is about 0 .01 ug /mL to about 1 .0 dins; percutaneous tibial nerve stimulation ; 5 - alpha reduc ug /mL . tase inhibitors ; and phosphodiesterase - 5 inhibitors . 9 . The pharmaceutical composition according to claim 1 , 23 . The pharmaceutical composition according to claim wherein the time between the first target Cmax and the second 22 , wherein the one or more additional therapeutic agents target Cmax is about 2 to about 8 hours . may be administered prior to , simultaneously with , or fol 10 . The pharmaceutical composition according to claim 1 , lowing the administration of the pharmaceutical composi wherein the first Cmin is achieved at about 4 to about 8 hours tion comprising solabegron . after the first administration . 24 . The pharmaceutical composition according to claim 11 . The pharmaceutical composition according to claim 1, 17 , wherein the at least one immediate release composition wherein the second Cminm22 is achieved before about 24 hours achieves a blood plasma Cmor from about 0 . 5 ug /mL to about after administration of the pharmaceutical composition . 3 . 5 ug /mL . US 2017 /0348263 A1 Dec . 7 , 2017 32
25 . The pharmaceutical composition according to claim in a subject in need thereof, comprising administering to the 17 , wherein the at least one modified release composition subject, a pharmaceutical composition , comprising a thera achieves a blood plasma Cmax from about 1 . 5 ug/ mL to about peutically effective amount of solabegron , wherein the phar 4 ug /mL . maceutical composition releases at least two releases of 26 . The pharmaceutical composition according to claim solabegron , wherein a first release of solabegron achieves a 17 , wherein a Cmin from about 0 . 25 ug /mL to about 1 . 5 first target Cmore a second release of solabegron achieves a ug /mL is achieved in about 4 to about 8 hours after admin second target Cmax , a first target Cmin is achieved between istration to a subject in need of treatment . the first release and the second release and a second Cmin is 27 . The pharmaceutical composition according to claim achieved after the second release . 17 , wherein a Cmin from about 0 .01 ug /mL to about 1 . 0 38 . The method according to claim 37 , wherein said first ug /mL is achieved before about 24 hours after administra target Cmor is about 0 . 5 ug /mL to about 3 . 5 ug /mL . tion to a subject in need of treatment. 39 . The method according to claim 37 , wherein said 28 . A method of treating LUTS , obesity , type 2 diabetes , second target Cmor is about 1 . 5 ug /mL to about 4 ug /mL . heart failure , irritable bowel syndrome, gastrointestinal dis 40 . The method according to claim 37 , wherein said first orders , pre - term labor, depression and anxiety in a subject in Cmin is about 0 .25 ug /mL to about 1 . 5 ug /mL . need thereof, comprising administering to the subject, a 41 . The method according to claim 37 , wherein said pharmaceutical composition for the delivery of solabegron , second Cmin is about 0 .01 ug/ mL to about 1 . 0 ug/ mL . comprising an immediate release composition , comprising 42 . The method according to claim 37 , further comprising solabegron and at least one pharmaceutically acceptable administering one or more additional therapeutic agents or carrier or diluent; and a modified release composition , treatments useful for the treatment of LUTS , obesity, type 2 comprising solabegron and at least one pharmaceutically diabetes , heart failure , irritable bowel syndrome and similar acceptable carrier or diluent . gastrointestinal disorders , pre - term labor, depression and 29 . The method according to claim 28, wherein the anxiety , wherein the one more additional therapeutic agents subject achieves a blood plasma Cmor of about 0 . 5 ug /mL to or treatments are selected from the groups consisting of: about 3 . 5 ug/ mL in about 0 .75 to about 4 hours after antimuscarinic agents ; alpha adrenoceptor blockers ; botuli administration . num toxin ; purinergics ; cannabinoids ; transient receptor 30 . The method according to claim 28 , wherein the potential ( TRP ) protein inhibitors; prostaglandins; percuta subject achieves a blood plasma Cmin from about 0 . 25 ug /mL neous tibial nerve stimulation ; 5 -alpha reductase inhibitors ; to about 1 . 5 ug/ mL in about 4 to about 8 hours after and phosphodiesterase- 5 inhibitors . administration . 43. The method according to claim 42 , wherein the one or 31 . The method according to claim 28 , wherein the more additional therapeutic agents may be administered subject achieves a blood plasma Cmax of about 1. 5 ug /mL to prior to , simultaneously with , or following the administra about 4 ug /mL in about 2 to about 8 hours after the first mine22 . tion of the pharmaceutical composition comprising solabe 32 . The method according to claim 28 , wherein the gron . subject achieves a blood plasma Cminmy from about 0 .01 ug /mL 44 . The method according to claim 37 , wherein the to about 1 . 0 ug/ mL before about 24 hours after administra pharmaceutical composition is administered once a day to a tion . 33 . The method according to claim 28 , further comprising subject in need thereof. administering one or more additional therapeutic agents or 45 . The method of claim 37 , wherein said LUTS is treatments useful for the treatment of LUTS , obesity , type 2 selected from overactive bladder and a prostate disorder. diabetes , heart failure , irritable bowel syndrome and similar 46 . The method of claim 36 , wherein treating overactive gastrointestinal disorders, pre - term labor, depression and bladder comprises treating one or more symptoms of OAB anxiety, obesity , type 2 diabetes, heart failure, irritable selected from the group consisting of: frequency of urinary bowel syndrome, gastrointestinal disorders , pre - term labor, urgency ; nocturia ; increase in urinary micturition frequency ; depression and anxiety , wherein the one more additional and urinary incontinence , voided volume, post -void residual therapeutic agents or treatments are selected from the groups volume and subject reported outcomes. consisting of: antimuscarinic agents ; alpha adrenoceptor 47 . The pharmaceutical composition of claim 1 , wherein blockers ; botulinum toxin ; purinergics ; cannabinoids ; tran the solabegron is the amorphous solid form of solabegron . sient receptor potential ( TRP ) protein inhibitors ; prostaglan 48 . The pharmaceutical composition of claim 47 , further dins; percutaneous tibial nerve stimulation ; 5 - alpha reduc comprising two separate and distinct releases of solabegron . tase inhibitors ; and phosphodiesterase - 5 inhibitors . 49 . The pharmaceutical composition of claim 48 , wherein 34 . The method according to claim 33 , wherein the one or the two release are contained within two separate and more additional therapeutic agents may be administered distinct drug delivery systems. prior to , simultaneously with , or following the administra 50. The pharmaceutical composition of claim 48 , wherein tion of the pharmaceutical composition comprising solabe the two releases are contained within a single drug delivery gron . system . 35 . The method according to claim 28 , wherein the 51. The pharmaceutical composition of claim 49, wherein pharmaceutical composition is administered once a day to a the drug delivery system is selected from the group consist subject in need thereof. ing of: tablets ; bi- layer tablets ; capsules ; 36 . The method of claim 28 , wherein said LUTS is multiparticulates; drug coated spheres/ pellets ; matrix tab selected from overactive bladder and a prostate disorder. lets ; and multicore tablets . 37 . A method of treating LUTS , obesity , type 2 diabetes, 52 . The pharmaceutical composition of claim 50 , wherein heart failure , irritable bowel syndrome and similar gastro - the drug delivery system is selected from the group consist intestinal disorders , pre- term labor, depression and anxiety , ing of: tablets ; bi- layer tablets ; capsules ; US 2017 /0348263 A1 Dec . 7 , 2017 33
multiparticulates ; drug coated spheres /pellets ;matrix tab 66 . The pharmaceutical composition of claim 65 , wherein lets ; and multicore tablets . the pharmaceutically acceptable polymer is selected from 53 . A pharmaceutical composition comprising a multipar the group consisting of hydroxypropylmethyl cellulose ; ticulate formulation ofmini - tablets each comprising a thera polyethylene glycol; hydroxypropyl B -cyclodextrin ; polyvi peutically effective amount of solabegron , wherein the phar nyl pyrrolidine ; poloxamer, and hydroxypropyl cellulose . 67 . The method of claim 45 , wherein treating overactive maceutical composition achieves a first target Cmar , a bladder comprises treating one or more symptoms of OAB second target Cmor , a first target Cmin777 between the first target selected from the group consisting of: frequency of urinary Cmax and the second target Cmax , and a second target Cmin urgency ; nocturia ; increase in urinary micturition frequency ; after the second target Cmax . and urinary incontinence , voided volume, post - void residual 54 . The pharmaceutical composition of claim 53 , further volume and subject reported outcomes. comprising at least two separate populations of mini- tablets 68 . The method of claim 28 , wherein said pharmaceutical selected from the group consisting of: immediate release composition provides a therapeutically effective amount of mini- tablets ; sustained - release mini- tablets ; delayed - release solabegron , wherein the pharmaceutical composition mini- tablets ; and modified - release mini- tablets . achieves a first target Cmax , a second target Cmar, a first 55 . The pharmaceutical composition of claim 54 , wherein target Cmin between the first target Cmax and the second the mini- tablets are optionally coated . target Cmax, and a second target Cmin after the second target 56 . The pharmaceutical composition of claim 55 , wherein Cmarmax the mini- tablets comprise solabegron and at least one phar 69. The method of claim 28 , wherein the immediate maceutically acceptable polymer . release comprises about 75 mg to about 250 mg of solabe 57. The pharmaceutical composition of claim 56 , wherein gron . the pharmaceutically acceptable polymer is selected from 70 . The method of claim 28 , wherein the modified release the group consisting of hydroxypropylmethyl cellulose ; comprises about 100 mg to about 400 mg of solabegron . polyethylene glycol; hydroxypropyl B - cyclodextrin ; polyvi 71. The method of claim 28 , wherein the immediate nyl pyrrolidine ; poloxamer ; and hydroxypropyl cellulose . release comprises 50 , 55 , 60 , 65 , 75, 80 , 85 , 90 , 95 , 100 , 105 , 58 . The pharmaceutical composition of claim 57 , wherein 110 , 115 , 120 , 125 , 130 , 135 , 140 , 145 or 150 mg of at least one population of mini- tablets further comprises a solabegron . controlled -release excipient . 72 . The method of claim 28 , wherein the modified release 59 . The pharmaceutical composition of claim 57 , wherein comprises 100 , 105 , 110 , 115 , 120 , 125 , 130 , 135 , 140 , 145 , at least one population ofmini - tablets further comprises an 150 , 155 , 160 , 165 , 170 , 175 , 180 , 185 , 190 , 195 , 200 , 205 . enteric release coating . 210 , 215 , 220 , 225 , 230 , 235 , 240 , 245 , 250 , 255 , 260 , 265 . 60 . The pharmaceutical composition of claim 53 , wherein 270 , 275 , 280 , 285, 290 , 295 , 300 , 305 , 310 , 315 , 320 , 325 , the multiparticulate formulation is contained within a cap 330 , 335 , 340 , 345 or 350 mg of solabegron . sule . 73 . The method of claim 28 , wherein the immediate 61 . A pharmaceutical composition comprising a therapeu release composition is an immediate release drug layer and tically effective amount of the amorphous form of solabe the modified release composition is a delayed release core , gron and at least one pharmaceutically acceptable carrier or wherein the immediate release drug layer is coated on the diluent. delayed release core. 62 . The pharmaceutical composition of claim 61 , wherein 74 . The method of claim 28 , wherein the pharmaceutical the therapeutically effective amount of amorphous solabe composition is a single unit dose administered once daily . gron is about 150 mg to about 850 mg. 75 . The method of claim 28 , wherein the pharmaceutical 63 . The pharmaceutical composition of claim 62 , wherein composition reduces desensitization of the beta - 3 adreno the pharmaceutical composition is prepared by spray - drying ceptor, when compared to an immediate release pharmaceu the therapeutically effective amount of amorphous solabe tical composition of solabegron administered twice daily . gron with at least one pharmaceutically acceptable polymer. 76 . A method for treating overactive bladder in a patient 64 . The pharmaceutical composition of claim 63, wherein in need thereof comprising orally administering once a day the pharmaceutically acceptable polymer is selected from to the patient a pharmaceutical composition comprising : an the group consisting of hydroxypropylmethyl cellulose ; immediate release drug layer comprising about 75 mg to polyethylene glycol; hydroxypropyl B - cyclodextrin ; polyvi about 250 mg solabegron and at least one pharmaceutically nyl pyrrolidine ; poloxamer ; and hydroxypropyl cellulose . acceptable carrier or diluent ; and a delayed release core 65 . The pharmaceutical composition of claim 62 , wherein comprising about 100 mg to about 400 mg solabegron and the pharmaceutical composition is prepared by hot- melt at least one pharmaceutically acceptable carrier or diluent, extruding the therapeutically effective amount of amorphous wherein the immediate release drug layer is coated on the solabegron with at least one pharmaceutically acceptable delayed release core . polymer . * * * * *