|HAI LAMA AT MATALUNUS009801847B2 ALUN ALT PALMA HATI (12 ) United States Patent (10 ) Patent No. : US 9 ,801 , 847 B2 Dubé et al. (45 ) Date of Patent: * Oct. 31, 2017 (54 ) ISOMERS AND ISOMERIC (60 ) Provisional application No . 60 /898 ,376 , filed on Jan . MIXTURES AND METHODS OF USING THE 30 , 2007 , provisional application No. 60 /801 , 824 , SAME TO TREAT DISORDERS filed on May 19 , 2006 , provisional application No. 60 / 833 , 319 , filed on Jul. 25 , 2006 . ( 71) Applicants : Pernix Sleep , Inc ., Morristown , NJ (US ) ; ProCom One, Inc. , San Marcos , (51 ) Int. Cl. TX (US ) A61K 31 /335 (2006 . 01) (52 ) U . S . CI. @(72 ) Inventors : Susan E . Dubé, Carlsbad , CA (US ) ; CPC ...... A61K 31/ 335 (2013 .01 ) Neil B . Kavey , Chappaqua , NY (US ) (58 ) Field of Classification Search CPC ...... A61K 31/ 335 @( 73 ) Assignees: Pernix Sleep , Inc. , Morristown, NJ See application file for complete search history . (US ) ; ProCom One, Inc . , San Marcos , TX (US ) (56 ) References Cited ( * ) Notice : Subject to any disclaimer , the term of this U . S . PATENT DOCUMENTS patent is extended or adjusted under 35 6 ,211 ,229 B1 * 4 /2001 Kavey ...... A61K 31 /13 U . S .C . 154 (b ) by 0 days . 514 /217 This patent is subject to a terminal dis claimer . OTHER PUBLICATIONS Wyatt et. al. , Applied Spectroscopy , 1986 , Society for Applied (21 ) Appl . No. : 15 /289 , 288 Spectroscopy, vol. 40 ( 4 ), pp . 538 -542 . * ( 22 ) Filed : Oct . 10 , 2016 * cited by examiner (65 ) Prior Publication Data Primary Examiner — Sarah Pihonak US 2017 /0020839 A1 Jan . 26 , 2017 (74 ) Attorney, Agent, or Firm — Servilla Whitney LLC Related U .S . Application Data ( 57 ) ABSTRACT (63 ) Continuation of application No. 13 /692 ,415 , filed on The invention relates to use of the cis -( Z ) isomer or isomeric Dec. 3 , 2012 , now Pat. No . 9 ,463 , 181 , which is a mixtures containing specified ratios of the cis - ( Z ) and trans continuation of application No . 12 /535 ,640 , filed on ( E ) isomers of doxepin , metabolites of doxepin , pharmaceu Aug . 4 , 2009, now abandoned , which is a tically - acceptable salts of doxepin and prodrugs of the same; continuation -in -part of application No . 12 / 022, 628 , compositions containing the same, for the treatment of sleep filed on Jan . 30 , 2008 , now abandoned , and a disorders. continuation - in - part of application No. 11 /804 , 720 , filed on May 18 , 2007 , now Pat . No. 8 ,513 ,299 . 20 Claims, No Drawings US 9 , 801, 847 B2

DOXEPIN ISOMERS AND ISOMERIC result, many physicians are reluctant to prescribe, and MIXTURES AND METHODS OF USING THE patients are reluctant to take these drugs for chronic use in SAME TO TREAT SLEEP DISORDERS treating . The prescribing of a Schedule IV con trolled substance brings scrutiny from the Drug Enforcement RELATED APPLICATION Administration and other regulatory bodies, and requires registration and administrative controls in physicians' This application is a continuation of U . S . application Ser . offices . No. 13 /692 ,415 , filed Dec . 3 , 2012 , which is a continuation Also , the account for a large of U . S . application Ser . No . 12 / 535 ,640 , filed Aug . 4 , 2009 , percentage of the total prescriptions written for insomnia . which is a continuation - in -part of U . S . application Ser. No. 10 The National Disease and Therapeutic Index estimates that 12 /022 ,628 , filed Jan . 30 , 2008 , which claims the benefit of , more than 60 % of the 13 million annual prescrip and priority to , U . S . Provisional Application No. 60 / 898 , tions are written for the treatment of insomnia , even though 376 , filed Jan . 30 , 2007 ; and U . S . application Ser. No. trazodone is not indicated for that usage and has never been 12 /022 ,628 is a continuation - in -part of U . S . application Ser. promoted for that condition . Although there are very limited No. 11/ 804 , 720 , filed May 18 , 2007 , which claims priority 15 data to support the use of trazodone for insomnia and it is to U . S . Provisional Application Nos. 60 /801 ,824 , filed May associated with undesirable side effects , trazodone is often 19 , 2006 , and 60 /833 , 319 , filed Jul. 25 , 2006 . The entire prescribed because it is a non - scheduled agent, meaning content of all of these applications are incorporated herein non -addictive , unlike the and other GABA by reference . receptor agonists which are approved for the treatment of 20 insomnia . BACKGROUND OF THE INVENTION Recently a new with a mode of action different from other has been introduced . is a Field of the Invention receptor agonist with high affinity for melatonin The invention relates to use of the cis - ( Z ) isomer or MT1 and MT2 receptors . It is indicated for sleep onset isomeric mixtures containing specified ratios of the cis - ( Z ) 25 insomnia but it has not been shown to produce a sleep and the trans - ( E ) isomers of doxepin and metabolites of maintenance benefit . It does not affect the GABA - A receptor doxepin , as well as pharmaceutically -acceptable salts and complex , is not addicting and is not scheduled . prodrugs of the same; and compositions containing the Therefore , it is desirable to have a pharmacological agent same, for the treatment of sleep disorders . for the treatment of insomnia which is more effective and / or Description of the Related Art 30 has fewer side effects that those currently used . Sleep is essential for health and quality of life. Insomnia is a subjective complaint of dissatisfaction with the quantity , SUMMARY OF THE INVENTION quality or timing of sleep . Insomnia is estimated to occur in approximately 12 % to 25 % of the general population , In some embodiments , the present invention relates to a although this is probably an underestimate as there is 35 method for the treatment of a patient suffering from insom evidence that many adults do not report their sleep problems nia including administering to the patient doxepin , a phar to a health care professional. maceutically - acceptable salt or a prodrug thereof in a daily One study has found that fewer than 15 % of those who dosage ranging from about 0 .0001 to about 499 milligrams, suffer from insomnia are treated with prescription medica - wherein the doxepin , the salt or the prodrug is a geometric tions . Medications commonly used to treat sleep disorders 40 isomer mixture containing about 18 . 2 % to about 100 . 0 % of such as insomnia , include sedative antidepressants, antipsy - the cis - ( Z ) isomer or is 100 % cis - ( Z ) isomer. In some chotics, , agonists , benzo - embodiments , the present invention relates to a method for diazepines , and non - hypnotics . treating sleep maintenance insomnia characterized by frag Benzodiazepines work by binding to and activating sites mented sleep during the gth hour of sleep , the method on the GABA - A receptor complex . Short , intermediate and 45 comprising administering a dosage of doxepin or a pharma long - acting benzodiazepines such as , ceutically acceptable salt thereof to a patient having a sleep and were all commonly prescribed for this disorder in which , for a given 8 hour period of desired sleep , indication . While these agents have proven to be efficacious the patient experiences fragmented sleep during the final 60 and relatively safe, benzodiazepines are associated with a minutes of said period , wherein the dosage of doxepin or salt multitude of adverse effects, including residual daytime 50 thereof is between about 0 . 1 and about 6 mg , wherein the sedation (“ hangover ” ), amnesia , memory loss and respira - doxepin or salt thereof is a geometric isomer mixture tory depression . Rebound insomnia has also been associated containing about 18 . 2 % to about 100 . 0 % of the cis - ( Z ) with benzodiazepines. Tolerance to the hypnotic effects of isomer or is 100 % cis -( Z ) isomer, and wherein the dosage is the benzodiazepines is common and abrupt discontinuation administered prior to the start of the sleep period . In some can result in withdrawal symptoms such as agitation , 55 embodiments , the present invention relates to a method for rebound insomnia , perceptual changes , confusion , disorien - treating sleep maintenance insomnia characterized by early tation and even seizures . awakenings during the gth hour of sleep , the method com Non -benzodiazepine hypnotics have become the primary prising administering a dosage of doxepin or a pharmaceu class of medications for the treatment of insomnia . The tically acceptable salt thereof to a patient having a sleep leading approved non - benzodiazepine insomnia medica - 60 disorder in which , for a given 8 hour period of desired sleep , tions, , , and , also work by the patient experiences early awakenings during the final 60 binding to and activating the GABA - A receptors. All these minutes of said period ,wherein the dosage of doxepin or salt drugs approved for the treatment of insomnia that act via the thereof is between about 0 . 1 and about 6 mg, wherein the GABA - A receptor, including benzodiazepine and non - ben - doxepin or salt thereof is a geometric isomer mixture zodiazepine hypnotics , have a potential for addiction and 65 containing about 18 . 2 % to about 100 . 0 % of the cis - ( Z ) abuse and are classified as Schedule IV controlled sub - isomer or is 100 % cis - ( Z ) isomer, and wherein the dosage is stances by the U . S . Drug Enforcement Administration . As a administered prior to the start of the sleep period . The US 9 ,801 , 847 B2 geometric isomer mixture may contain more than 20 % , about 0 . 1 to about 20 milligrams, about 0 . 1 to about 10 50 % , 90 % , or 95 % of the cis - ( Z ) isomer. The geometric milligrams, or about 0 . 1 to about 5 milligrams. isomer mixture can , in some embodiments , contain at least In some embodiments , the composition may be formu 99 . 5 % or 99. 9 % of the cis -( Z ) isomer . Alternatively , the lated for oral or nasal administration . The unit dosage form geometric isomermixture may contain 100. 0 % of the cis -( Z ) 5 can be, for example , a pill, a tablet , a capsule , a gel cap, or isomer. The geometric isomer mixture may contain about a fast melt formulation . 20 % to about 99. 9 % of the cis -( Z ) isomer , about 30 % to In some embodiments , the present invention relates to a about 99. 5 % of the cis -( Z ) isomer , about 50 % to about 99 % method for treating insomnia including administering to a of the cis - ( Z ) isomer, about 75 % to about 97 % of the cis - ( Z ) patient a metabolite of doxepin , a pharmaceutically -accept isomer , or about 90 % to about 94 . 9 % of the cis - ( Z ) isomer . 10 able salt thereof, or a prodrug thereof in a daily dosage In some embodiments , the pharmaceutically - acceptable ranging from about 0 . 0001 to about 499 milligrams, wherein salt of doxepin can be the hydrochloride salt thereof. In the metabolite of doxepin , the salt or the prodrug is a some embodiments , the prodrug of doxepin can be a prodrug geometric isomer mixture containing about 18 . 2 % to about ester. 100 .0 % of the cis - ( Z ) isomer or is 100 % cis - ( Z ) isomer. The The daily dosage may be about 0 .001 to about 249 15 geometric isomer mixture may contain more than 20 % , milligrams, about 0 . 001 to about 99 milligrams, about 0 .001 50 % , 90 % , or 95 % of the cis - ( Z ) isomer. In some embodi to about 49 milligrams, 0 .001 to about 24 milligrams, about ments , the geometric isomer mixture can contain at least 20 to about 49 milligrams, about 0 .01 to about 24 milli 99 . 5 % or 99 . 9 % of the cis - ( Z ) isomer. In other embodi grams, about 0 .01 to about 20 milligrams, about 0 .01 to ments , the geometric isomer mixture can contain 100 % of about 10 milligrams, or about 0 . 1 to about 5 milligrams. 20 the cis - ( Z ) isomer. The geometric isomer mixture may In some embodiments , the insomnia is a chronic insom - contain about 20 % to about 99 . 9 % of the cis - ( Z ) isomer , nia . In other embodiments, the insomnia is a non -chronic about 30 % to about 99 . 5 % of the cis- ( Z ) isomer, about 50 % insomnia . The non - chronic insomnia may be a transient or a to about 99 % of the cis - ( Z ) isomer , about 75 % to about 97 % short - term insomnia . The insomnia may be, for example , of the cis - ( Z ) isomer, or about 90 % to about 94 . 9 % of the onset insomnia or maintenance insomnia . 25 cis - ( Z ) isomer . The patient in some embodiments can be suffering from The metabolite of doxepin , the pharmaceutically -accept depression . In other embodiments , the patient is not suffer - able salt , or the prodrug may be administered in a dosage ing from depression . ranging from about 0 . 001 to about 249 milligrams, about In some embodiments , a method disclosed herein can 0 . 001 to about 99 milligrams, about 0 . 001 to about 49 further include administering at least one of ramelteon , 30 milligrams, or about 0 .01 to about 24 milligrams. VEC - 162 , , APD125 , tiagabine , trazodone, indip - The insomnia may be a chronic or a non -chronic insom lon , AVE 8488 , MDL 100907, AVE 8488 , MDL 100907, nia . The non - chronic insomnia may be a transient or a , eszopiclone, zolpidem , or zaleplon . In some short - term insomnia . The insomnia can , in some embodi aspects, more than one of the foregoing can be administered . ments, be selected from the group consisting of onset In some embodiments, a method disclosed herein can further 35 insomnia and maintenance insomnia . The metabolite may be include administering at least one additional medication . desmethyldoxepin , hydroxydoxepin , hydroxyl- N - desmeth The at least one additionalmedication may be selected from yldoxepin , or doxepin N - oxide . a 5 -HT2 antagonist , a H3 agonist , an orexin antagonist , a method disclosed herein can , in some embodiments , noradrenergic antagonist , a galanin agonist , a CRH antago - further can include administering at least one of ramelteon , nist , a GABA - A direct agonists , a GABA reuptake inhibitor , 40 eszopiclone, zolpidem , or zaleplon . A method disclosed tiagabine, a growth hormone , a growth hormone agonist, herein , can , in some embodiments , further include admin estrogen , an estrogen agonist, or a melatonin agonist. istering at least one additional medication . The at least one In some embodiments , the present invention relates to a additional medication may be a sleep medication . The at composition including a pharmaceutically - acceptable car - least one additional sleep medication may be, for example , rier and doxepin , a pharmaceutically -acceptable salt of - 45 a 5 -HT2 antagonist , a H3 agonist, an orexin antagonist, a epin , or a prodrug of doxepin in a unit dosage form of about noradrenergic antagonist, a galanin agonist , a CRH antago 0 .0001 milligrams to about 499 milligrams, wherein the nist, a GABA - A direct agonist, a GABA reuptake inhibitor, doxepin , the salt or the prodrug is a geometric isomer a growth hormone , a growth hormone agonist, estrogen , an mixture containing about 18 . 2 % to about 100 . 0 % of the estrogen agonist , an ion channel blocker, and a melatonin cis - ( Z ) isomer or is 100 % cis - ( Z ) isomer . The geometric 50 agonist. The 5 -HT2 antagonist may be one selected from isomer mixture may contain more than 20 % , 50 % , 90 % , or ketanserin , , , pruvanserin , MDL 95 % of the cis - ( Z ) isomer . In some embodiments , the 100907, APD125 , and AVE 8488 . The at least one additional geometric isomer mixture can contain at least 99 . 5 % or medication may be selected from ketanserin , Gaboxadol, 99 . 9 % of the cis -( Z ) isomer. In other embodiments , the and tiagabine . The ion channel blocker may be one selected geometric isomer mixture can contain 100 % of the cis - ( Z ) 55 from lamotrigine , , and . The mela isomer. The geometric isomer mixture may contain about tonin agonist may be one selected from melatonin , remelt 20 % to about 99 . 9 % of the cis - ( Z ) isomer, about 30 % to eon , and . In some embodiments , the at least one about 99 . 5 % of the cis- ( Z ) isomer , about 50 % to about 99 % additional medication can be selected from clobazam , clon of the cis - ( Z ) isomer, about 75 % to about 97 % of the cis - ( Z ) azepam , clorazepate , diazepam , , flurazepam , isomer, or about 90 % to about 94 . 9 % of the cis - ( Z ) isomer . 60 , , , oxazepam , temazepam , In some embodiments , the pharmaceutically - acceptable triazolam , , , eszopiclone, zaleplon , zolpi salt ofdoxepin is the hydrochloride salt thereof. The prodrug dem , gaboxadol , vigabatrin , tiagabine, and the may be an ester. like. The unit dosage form can be, in some embodiments , about In some embodiments , the present invention relates to a 0 . 001 to about 249 milligrams, about 0 . 001 to about 99 65 composition including a pharmaceutically - acceptable car milligrams, about 0 . 001 to about 49 milligrams, about 0 .001 rier and a metabolite of doxepin , a pharmaceutically -accept to about 24 milligrams, about 0 . 1 to about 24 milligrams, able salt of the metabolite , or a prodrug of the metabolite in US 9 ,801 , 847 B2 a unit dosage form of about 0 . 0001 milligrams to about 499 pharmaceutically acceptable salts and prodrugs of the same, milligrams, wherein the doxepin , the salt or the prodrug is a as well as compositions of the same. In some aspects the geometric isomer mixture containing about 18 . 2 % to about isomers can be in a substantially pure form ( e . g . , at least 100 . 0 % of the cis - ( Z ) isomer of the metabolite . The geo - 80 % , 85 % , 90 % , 95 % , 97 % , 99 % , 99 . 5 % , 99 . 9 % or 100 % metric isomer mixture may contain more than 20 % , 50 % , 5 cis isomer ). In other aspects the isomers can be in an 90 % , or 95 % of the cis - ( Z ) isomer of the metabolite . In some isomeric mixture as described herein . Also , embodiments embodiments , the geometric isomer mixture can contain at relate to the use of the cis - ( Z ) isomer or geometric isomeric least 99 .5 % or 99 . 9 % of the cis - ( Z ) isomer of the metabolite . mixtures containing specified ratios of the cis - ( Z ) to trans In other embodiments , the geometric isomer mixture can ( E ) isomers of doxepin or doxepin metabolites, prodrugs, or contain 100 % of the cis - ( Z ) isomer of the metabolite . The 10 salts of the same to treat an individual suffering from a sleep geometric isomer mixture may contain about 20 % to about disorder, for example a disorder such as insomnia . Several 99 . 9 % of the cis - ( Z ) isomer of the metabolite , about 30 % to examples of insomnias that can be treated using the isomers about 99. 5 % of the cis -( Z ) isomer of the metabolite , about and isomeric mixtures are described below . In some embodi 50 % to about 99 % of the cis - ( Z ) isomer of the metabolite , ments , the sleep disorder, such as insomnia , can be treated about 75 % to about 97 % of the cis - ( Z ) isomer of the 15 by administering low dosages of doxepin or doxepin metabolite , or about 90 % to about 94 . 9 % of the cis - ( Z ) metabolite isomers and isomeric mixtures , while in others it isomer of the metabolite . can be administered in a higher dosage . Various dosages of The pharmaceutically -acceptable salt of the metabolite isomers are described below . Surprisingly , when used in may be the hydrochloride salt thereof. The metabolite may specific isomeric ratios described herein , low doses of be desmethyldoxepin , hydroxydoxepin , hydroxyl- N -desm - 20 doxepin isomers and isomers of doxepin metabolites are ethyldoxepin , or doxepin N -oxide . The prodrug may be an very effective in treating insomnia with very minimal side ester , for example . effects. The isomers and isomer mixtures, as well as their The unit dosage may be about 0 . 001 to about 249 milli uses, as described herein have not been described previ grams, about 0 .001 to about 99 milligrams, about 0 .001 to ously , particularly for use in the treatment of sleep disorders . about 49 milligrams, about 0 .001 to about 24 milligrams, 25 Doxepin is a tricyclic compound approved for the treat about 0 . 1 to about 24 milligrams, about 0 . 1 to about 20 ment of depression and anxiety . The recommended daily milligrams, about 0 . 1 to about 10 milligrams, or about 0 . 1 to dose for the treatment of depression and anxiety ranges from about 5 milligrams. 75 milligrams to 300 milligrams. Doxepin , unlike most FDA The composition may be formulated for oral or nasal approved products for the treatment of insomnia , is not a administration . The unit dosage form may be selected from 30 Schedule IV controlled substance . the group consisting of a pill, a tablet , a capsule , a gel cap , U . S . Pat. Nos. 5 , 502 ,047 and 6 ,211 , 229 , the entire con and a fast melt formulation . tents of which are incorporated herein by reference , describe In some embodiments , the present invention relates to a the use of doxepin for the treatment of chronic and non method for the treatment of a patient suffering from insom - chronic ( e . g . , transient /short term ) insomnias at dosages far nia including providing a composition enriched in cis isomer 35 below those used to treat depression . compared to the ratio of the cis - /trans - isomers in doxepin as No studies have investigated whether sleep disorders can typically prepared , a metabolite of doxepin , a salt of dox be effectively treated by isomers or geometric isomeric epin , a salt of a metabolite of doxepin , a prodrug of doxepin , mixtures of doxepin or doxepin metabolites, pharmaceuti or a prodrug of a metabolite of doxepin and administering cally -acceptable salts or prodrugs of the same, in particular prescribing to the patient the enriched composition of cis 40 mixtures containing higher proportions of the cis - ( Z ) isomer doxepin , a metabolite of doxepin , a salt of doxepin , a salt of than found in doxepin as typically prepared . According to a metabolite of doxepin , a prodrug of doxepin , or a prodrug USP 25 , 2002 . United States Pharmacopeial Convention , of a metabolite of doxepin . Inc ., Rockville , Md. P. 615 , doxepin hydrochloride U .S .P . is In some embodiments , the present invention relates to a a geometric isomer mixture " containing not less than 13 .6 % composition including doxepin , a metabolite of doxepin , a 45 and not more than 18 . 1 % ” of the cis isomer and “ not less salt of doxepin , a salt of a metabolite of doxepin , a prodrug than 81. 4 % and not more than 88 . 2 % " of the trans isomer . of doxepin , or a prodrug of a metabolite of doxepin , wherein Methods of Treating Sleep Disorders the ratio of the cis - / trans -isomers is greater than that found Some embodiments of the instant invention relate to in the doxepin as typically prepared . methods for the treatment of a patient suffering from a sleep In some embodiments , the present invention relates to a 50 disorder, such as insomnia . The methods can include the method for the treatment of a patient suffering from insom - administration to a patient of an isomer of doxepin , a nia including providing a composition enriched in cis isomer mixture of doxepin isomers , or an isomer of a metabolite of compared to the ratio of the cis - /trans - isomers in a metabo - doxepin , a mixture of metabolite isomers, or a pharmaceu lite of doxepin , a salt of doxepin , a salt of a metabolite of tically - acceptable salt or a prodrug thereof any of the afore doxepin , a prodrug of doxepin , or a prodrug of a metabolite 55 mentioned substances . The medication can be administered of doxepin , comparing the ratio of the cis - / trans - isomers to in any suitable dosage to treat the sleep disorder, including the ratio of cis - / trans - isomers in doxepin as typically pre- the dosages described herein . For example , the medication pared , and administering /prescribing to the patient the can be administered in a daily dosage ranging from about enriched composition of the cis isomer of the metabolite of 0 .001 , to about 9 milligrams, to about 24 milligrams, to doxepin , salt of doxepin , salt of the metabolite of doxepin , 60 about 49 milligrams, to about 99 milligrams, to about 249 prodrug of doxepin , or prodrug of the metabolite of doxepin . milligrams, or to about 499 milligrams. Also , as previously mentioned , the isomers can be administered alone ( e . g ., in a DETAILED DESCRIPTION OF THE substantially pure or pure form ) or in an isomeric mixture . PREFERRED EMBODIMENT Examples of isomeric ratios are described elsewhere herein . 65 As an example , the medication can contain about 18 .2 % to Generally , embodiments of the present invention relate to about 100 . 0 % , about 20 % to about 100 . 0 % , about 50 % to doxepin isomers , doxepin metabolite isomers , including about 100 . 0 % , about 80 % to about 100 . 0 % , about 95 % to US 9 ,801 , 847 B2 about 100 .0 % , about 99 % to about 100 .0 % , about 99 .5 % to another disorder such as a mental or neurological disorder, about 100 . 0 % , about 99. 9 % to about 100 . 0 % , or 100 . 0 % of a general medical condition , or a substance . In many cases , the cis- ( Z ) isomer. In some aspects a substantially pure such conditions may be associated with a chronic insomnia isomer can be administered , for example , at least 80 % , 85 % , and can include , but are not limited to , insomnia attributable 90 % , 95 % , 97 % , 98 % , 99 % , 99 . 5 % , or 99 . 9 % cis - ( Z ) 5 to a diagnosable DSM - IV disorder, a disorder such as isomer. In some aspects a pure or 100 % cis - ( Z ) isomer can anxiety or depression , or a disturbance of the physiological be used in the methods . The insomnia can be any insomnia , sleep -wake system . In some aspects the insomnia can be including those described herein . non - chronic , or of short duration ( e . g . , less than 3 - 4 weeks ) . Some embodiments relate to methods for the treatment of Examples of causes of such insomnia may be extrinsic or a patient suffering from insomnia , for example , by providing 10 intrinsic and include , but are not limited to environmental a composition enriched in cis isomer compared to the ratio sleep disorders as defined by the International Classification of the cis - / trans - isomers in doxepin as typically prepared , a of Sleep Disorders (ICSD ) such as inadequate sleep hygiene, metabolite of doxepin , a salt of doxepin , a salt of a metabo - altitude insomnia or adjustment sleep disorder ( e . g . , lite of doxepin , a prodrug of doxepin , or a prodrug of a bereavement) . Also , short -term insomnia may also be caused metabolite of doxepin , and administering/ prescribing to said 15 by disturbances such as shift -work sleep disorder . patient the enriched composition of cis isomer of doxepin , a Also , some embodiments can include the use of an isomer metabolite of doxepin , a salt of doxepin , a salt of a metabo - of doxepin , a mixture of doxepin isomers, an isomer of a lite of doxepin , a prodrug of doxepin , or a prodrug of a metabolite of doxepin , a mixture ofmetabolite isomers , or a metabolite of doxepin . “ Native” , “ native - occurring ” or “ as pharmaceutically -acceptable salt or a prodrug of any of the typically prepared” can refer , for example , to a common 20 aforementioned substances in combination with other form of the compound available in the pharmaceutical or insomnia or sleep medications. For example , the methods chemical industry or a form produced by standard chemical can include the use of one or more of ramelteon , VEC - 162 , synthesis . APD125 , trazodone , AVE 8488 , MDL 100907 , or the like . Some embodiments relate to methods for the treatment of Further, the methods can include the use of one or more of a patient suffering from insomnia , for example , by providing 25 5 -HT2 antagonists ( such as ketanserin ) , H3 agonists , orexin a composition enriched in cis isomer compared to the ratio antagonists , noradrenergic antagonists, galanin agonists and of the cis - / trans- isomers in one or more of the following: a CRH antagonists . Similarly , the methods can use GABA metabolite of doxepin , a salt of doxepin , a salt of a metabo - modulators ( e . g . , compounds that facilitate GABA neu lite of doxepin , a prodrug of doxepin , or a prodrug of a rotransmission ) such as benzodiazepines, nonbenzodiaz metabolite of doxepin ; comparing the ratio of the cis - / trans - 30 epine positive modulators such as eszopiclone, indiplon , isomers to the ratio of cis - / trans - isomers in doxepin as zolpidem and zaleplon , GABA - A direct agonists (such as typically prepared ; and administering /prescribing to the gaboxadol) , and GABA reuptake inhibitors ( such as patient the enriched composition of the cis isomer of the tiagabine ) . Finally , the methods can use growth hormone metabolite of doxepin , salt ofdoxepin , salt of themetabolite and growth hormone agonists , estrogen and estrogen ago of doxepin , prodrug of doxepin , or prodrug of the metabolite 35 nists , melatonin agonists or the like . The methods can also of doxepin . include the use of one or more antihistamines. Also , some embodiments relate to compositions that An isomer of doxepin , a mixture of doxepin isomers , an include doxepin , a metabolite of doxepin , a salt of doxepin , isomer of a metabolite of doxepin , a mixture of metabolite a salt of a metabolite of doxepin , a prodrug of doxepin , or isomers, or a pharmaceutically -acceptable salt or a prodrug a prodrug of a metabolite ofdoxepin , wherein the ratio of the 40 of any of the aforementioned substances may be used in cis - / trans- isomers in the composition is greater than that combination with ramelteon . Ramelteon ( ( S ) - N - [ 2 - ( 1 , 6 , 7 , found in the compound as typically synthesized . 8 - tetrahydro -2H - indeno - [5 , 4 - b ] furan - 8 -yl ) ethyl] propiona As mentioned above and elsewhere , the methods mide ) can be used in any dosage, but preferably can be used described herein can be used to treat individuals suffering in a dosage of about 0 . 5 milligrams to about 20 milligrams. from a sleep disorder, such as insomnia . The term “ insom - 45 More preferably , about 4 , 8 or 16 milligrams can be used , for nia ” generally refers to sleep problems characterized by example . difficulty falling asleep , wakings during the night, or waking An isomer of doxepin , a mixture of doxepin isomers , an up earlier than desired . Examples of insomnia include isomer of a metabolite of doxepin , a mixture of metabolite chronic and non - chronic insomnias. isomers, or a pharmaceutically -acceptable salt or a prodrug For chronic ( e . g ., greater than 3 - 4 weeks ) or non - chronic 50 of any of the aforementioned substances may be used in insomnias, a patient may suffer from difficulties in sleep combination with eszopiclone . Eszopiclone also can be used onset, sleep maintenance ( interruption of sleep during the in any suitable dosage . For example, the dosage can be about night by periods of wakefulness ) , sleep duration , sleep 0 . 1 to about 10 milligrams. Preferably , as an example , the efficiency, premature early -morning awakening , or a com dosage can be about 1 , 2 , or 3 milligrams. bination thereof . Also , the insomnia may be attributable to 55 An isomer of doxepin , a mixture of doxepin isomers , an the concurrent use of other medication . The non - chronic isomer of a metabolite of doxepin , a mixture of metabolite insomnia can be, for example, a short term insomnia or a isomers , or a pharmaceutically -acceptable salt or a prodrug transient insomnia . The chronic or non -chronic insomnia of any of the aforementioned substances may be used in can be a primary insomnia or an insomnia that is secondary combination with zolpidem . Zolpidem ( N , N , 6 -trimethyl - 2 or attributable to another condition , for example a disorder 60 p - tolylimidazo [ 1, 2 - a ] pyridine- 3 -acetamide L -( + ) - tartrate such as depression or chronic fatigue syndrome. In some ( 2 : 1 ) ) also can be used in any suitable dosage . For example , aspects, the patient can be one who is not suffering from an the dosage can be about 0 . 1 to about 20 milligrams. In some insomnia that is a component of a disease , the patient can be embodiments , as an example , the dosage can be about one whose insomnia is unrelated to a disease , or a patient can 6 . 25 -milligrams , 12 . 5 milligrams or a dosage that is a factor be treated who is otherwise healthy , for example . As previ - 65 thereof . In other embodiments , the dosage can be about ously mentioned , the chronic or non - chronic insomnia can 5 -milligrams , 10 -milligrams or a dosage that is a factor be a primary insomnia , that is , one that is not attributable to thereof. US 9 ,801 , 847 B2 10 Furthermore, an isomer of doxepin , a mixture of doxepin aspects the methods can specifically exclude treating a isomers, an isomer of a metabolite of doxepin , a mixture of chronic insomnia . As another example , without being lim metabolite isomers, or a pharmaceutically -acceptable salt or ited thereto , in some aspects the methods can specifically a prodrug of any of the aforementioned substances may be exclude treating an insomnia that is attributable to a condi used in combination with zaleplon . Zaleplon ( N - [ 3 - ( 3 -cy - 5 tion such as depression , anxiety or chronic fatigue. As a antopryazolo [ 1 , 5 - a ] pyrimidin - 7 - yl) phenyl] - N - ethylacet further example , in some aspects the methods and compo amide ) can be used in any suitable dosage . For example , the Sitions can specifically exclude one or more of the combin dosage can be about 0 . 1 to about 20 milligrams. Preferably , as an example, the dosage can be about 5 , 10 or 20 nation drugs . milligrams, for example . Compounds of Doxepin and Metabolites An isomer of doxepin , a mixture of doxepin isomers , an Doxepin : isomer of a metabolite of doxepin , a mixture of metabolite isomers , or a pharmaceutically -acceptable salt or a prodrug Doxepin has the following structure : of any of the aforementioned substances may be used in combination with gaboxadol. Gaboxadol ( 7 - tetra hydroisox - 15 azolo [ 5 , 4 - c ]pyridin - 3 - ol) can be used in any suitable dosage . For example , the dosage can be about 0 . 1 to about 20 40 milligrams. Preferably , as an example , the dosage can be about 0 . 5 to about 20 milligrams or 10 or 15 milligrams, for example . 20 An isomer of doxepin , a mixture of doxepin isomers , an isomer of a metabolite of doxepin , a mixture of metabolite isomers , or a pharmaceutically -acceptable salt or a prodrug of any of the aforementioned substances may be used in combination with VEC - 162. VEC - 162 can be used in any 25 suitable dosage . For example , the dosage can be about 0 . 1 to about 100 milligrams. Preferably , as an example , the dosage can be about 10 , 20 , 50 or 100 milligrams, for example . For all compounds disclosed herein , unless otherwise An isomer of doxepin , a mixture of doxepin isomers , an indicated , where a carbon -carbon double bond is depicted , isomer of a metabolite of doxepin , a mixture ofmetabolite 30 both the cis and trans stereoisomers, as well as mixtures isomers , or a pharmaceutically -acceptable salt or a prodrug thereof are encompassed . of any of the aforementioned substances may be used in It is contemplated that doxepin for use in the methods combination with indiplon . Indiplon (N -methyl - N - [ 3 - [ 3 - ( 2 thienylcarbonyl) -pyrazolo [ 1 , 5 - a ]pyrimidin - 7 -yl ] phenyl] ac described herein can be obtained from any suitable source or etamide ) can be used in any suitable dosage . For example , 35 made by any suitable method . As mentioned , doxepin is the dosage can be about 0 . 1 to about 10 milligrams . Pref approved and available in higher doses ( 75 - 300 milligrams) erably, as an example , the dosage can be about 5 or 10 for the treatment of depression and anxiety . Doxepin HCl is milligrams, for example . available commercially and may be obtained in capsule form An isomer of doxepin , a mixture of doxepin isomers , an from a number of sources . Doxepin is marketed under the isomer of a metabolite of doxepin , a mixture of metabolite 40 commercial name SINEQUAN® and in generic form , and isomers, or a pharmaceutically -acceptable salt or a prodrug can be obtained in the United States generally from phar of any of the aforementioned substances may be used in macies in capsule form in amounts of 10 , 25, 50 , 75 , 100 and combination with MDL 100907 . MDL 100907 (Sanofi 150 mg dosage , and in liquid concentrate form at 10 mg /mL . Aventis ) can be used in any suitable dosage . For example , Doxepin HCl can be obtained from Plantex Ltd . Chemical the dosage can be about 0 . 5 to about 100 milligrams, 45 Ind preferably from about 1 to about 50 milligrams. Industries (Hakadar Street , Industrial Zone, P . O . Box 160 , An isomer of doxepin , a mixture of doxepin isomers , an Netanya 42101 , Israel) , Sifavitor S . p . A . ( Via Livelli isomer of a metabolite of doxepin , a mixture of metabolite 1 — Frazione, Mairano , Italy ) , or from Dipharma S .p . A . isomers , or a pharmaceutically - acceptable salt or a prodrug (20021 Baranzate di Bollate , Milano , Italy ) . Also , doxepin is of any of the aforementioned substances may be used in 50 commercially available from PharmacyRx (NZ ) ( 2820 1 " combination with APD125 . APD125 (Arena Pharmaceuti Avenue , Castlegar, B . C . , Canada ) in capsule form in cals ) can be used in any suitable dosage. For example , the amounts of 10 , 25 , 50 , 75 , 100 and 150 mg. Furthermore , dosage can be about 1 to about 160 milligrams, preferably Doxepin HCl is available in capsule form in amounts of 10 , about 5 to about 80 milligrams, or more preferably about 10 25 , 50 , 75 , 100 and 150 mg and in a 10 mg/ml liquid to about 40 milligrams. An isomer of doxepin , a mixture of doxepin isomers , an concentrate from CVS Online Pharmacy Store (CVS . com ). isomer of a metabolite of doxepin , a mixture of metabolite Furthermore, doxepin ( 11 - ( 3 - dimethylaminopropy isomers , or a pharmaceutically -acceptable salt or a prodrug lidene ) - 6 , 11- dihydrodibenzo ( b , e )oxepin ) can be prepared of any of the aforementioned substances may be used in according to the method taught in U . S . Pat. No . 3 ,438 , 981 , combination with AVE8488 . AVE 8488 ( Sanofi - Aventis ) can 60 which is incorporated herein by reference in its entirety . An be used in any suitable dosage. For example, the dosage can example preparation is described below in Example 1 . be about 0 .5 to about 100 milligrams, preferably from about One available form of doxepin is a mixture of cis - ( Z ) and 1 to about 50 milligrams . trans - ( E ) isomers in a ratio of approximately 15 to 85 , It should be noted that in some aspects, the methods can respectively , as shown below . (Wyatt et al . , Applied Spec specifically exclude one or more of any of the sleep disor- 65 troscopy. ( 1986 ) 40 : 369- 373 ; which is incorporated herein ders described in the previous paragraph or elsewhere by reference in its entirety ) . ( E ) - doxepin and ( Z ) - doxepin herein . For example, without being limited thereto , in some have the following structures: US 9 , 801 , 847 B2 ? Desmethyldoxepin has the following structure : CH3 Hz ( E )

10 CH3 H - N CH3

15 Desmethyldoxepin is commercially available as a foren sic standard . For example , it can be obtained from Cam bridge Isotope Laboratories , Inc . (50 Frontage Road , Andover, Mass . Desmethyldoxepin for use in the methods 20 discussed herein can be prepared by any suitable procedure . The doxepin isomers can be prepared by any suitable for example , desmethyldoxepin can be prepared from method . For example , doxepin can be prepared in either of 3 -methylaminopropyl triphenylphosphonium hyd its ( Z ) or ( E ) isomers from 11 - [ 3 - (Dimethylamino )propyl ] - robromide and 6 , 11 - dihydrodibenz ( b , e Joxepin - 11 -one 6 , 11 - dihydrodibenzo [ b , eJoxepin - 11- ol as taught in U . S . Pat. according to the method taught in U . S . Pat . No. 3 , 509, 175 , No . 3 ,420 , 851 , which is incorporated herein by reference in 25 which is incorporated herein by reference in its entirety . As its entirety . Further, the (Z ) or ( E ) isomers can be isolated via another example , desmethyldoxepin can be prepared in its crystallization of doxepin hydrochloride from a mixture of ( E ) and ( Z ) isomers from desmethyldoxepin hydrochloride ethanol and diethyl ether as taught in the incorporated as taught in U . S . Pat. No. 5 ,332 ,661 , which is incorporated material of U . S . Pat. No . 3 , 420 , 851. For example , preferably herein by reference in its entirety . the ratio of Z / E isomers can be about 18 .2 /81 .8 , about 20 /80 , 30 Hydroxydoxepin has the following structure : about 30 / 70 , about 50 / 50 , about 75 /25 , about 80 /20 , about 90 / 10 , about 95 / 5 , or about 99 / 1 . In some aspects, the ratio of Z / E isomers can vary from about 18 . 2 /81 . 8 to about 100 / 0 , from about 20 /80 to about 99 . 9 / 0 . 1 , from about 30 /70 to about 99 . 5 / 0 . 5 , from about 50 /50 to about 99 / 1 , from about 75 / 25 to about 97 / 3 , from about 80 / 20 to about 94 . 9 / 5 . 1 , or the like . In some embodiments , a substantially pure or pure the cis isomer can be prepared . As used herein , the cis isomer can refer to a mixture containing at least 80 % , 40 at least 85 % , at least 90 % , at least 95 % , at least 98 % , at least 99 % , at least 99 . 5 % , at least 99 . 9 % , or 100 % of the cis isomer . Each of the references discussed above is incorporated by reference in its entirety . In some aspects , the teachings of * 2 -Hydroxydoxepin can be prepared in its ( Z ) and ( E ) one or more of the references can be included or combined isomers as taught by Shu et al. (Drug Metabolism and with instant methods or embodiments , while in other aspects Disposition ( 1990 ) 18 :735 -741 ) , which is incorporated the teachings of one or more of the references can be herein by reference in its entirety . specifically excluded from the methods and embodiments 50 Hydroxyl- N - desmethyldoxepin has the following struc described herein . As one example , the dosages used or the ture : patient population that is treated ( e . g ., age , health /disease profile , etc . ) in a reference can be excluded or included from the methods and embodiments described herein . Metabolites of Doxepin : 55 Also , isomers of doxepin metabolites can be prepared and used . By way of illustration , some examples of metabolites of doxepin can include, but are not limited to , desmethyl 0- D doxepin , hydroxydoxepin , hydroxyl - N -desmethyldoxepin , 60 doxepin N - oxide , N -acetyl - N -desmethyldoxepin , N - desm ethyl- N - formyldoxepin , quaternary ammonium - linked glu curonide , 2 - 0 -glucuronyldoxepin , didesmethyldoxepin , 3 - D - glucuronyldoxepin , or N -acetyldidesmethyldoxepin . Themetabolites of doxepin can be obtained or made by any 65 suitable method , including the methods described above for 2 -Hydroxy - N -desmethyldoxepin can be prepared in its doxepin . ( Z ) and ( E ) isomers as described in Examples 8 -9 . US 9 , 801, 847 B2 13 14 Doxepin N - oxide has the following structure: buN - acetyldidesmethyldoxepinmenim has the followingseis structure meses:

H 10 . The ( Z ) and ( E ) isomers of N -acetyldidesmethyldoxepin may be prepared by any suitable means. For example , Doxepin -N -oxide may be prepared by any suitable 15 (EN( E ) - N - acetyldidesmethyldoxepin has been produced in fila method . For example, doxepin - N -oxide can be prepared as mentous fungus incubated with doxepin as taught by Moody taught by Hobbs ( Biochem Pharmacol ( 1969 ) 18 : 1941 . et al. (Drug Metabolism and Disposition ( 1999 ) 27 : 1157 1954 ), which is hereby incorporated by reference in its 1164) , hereby incorporated by reference in its entirety . entirety . Didesmethyldoxepin has the following structure : The ( Z ) and ( E ) isomers of doxepin - N - oxide can be 20 prepared by any suitable method . For example, the N -oxide form of the ( Z ) isomer of doxepin can be prepared as described above for doxepin , by using purified ( Z ) - doxepin I as a starting material. Likewise , N -oxide form of the ( E ) isomer of doxepin can be prepared as described above for 25 doxepin , by using purified ( E ) - doxepin as a starting material. N -acetyl - N -desmethyldoxepin has the following struc ture :

30 CH3 The ( Z ) and ( E ) isomers of didesmethyldoxepin can be O N . prepared by any suitable means. For example, ( Z ) - and ( E ) -didesmethyldoxepin have been isolated from plasma HzC 5 and cerebrospinal fluid of depressed patients taking doxepin , as taught by Deuschle et al. (Psychopharmacology ( 1997 ) 131: 19 - 22 ) , hereby incorporated by reference in its entirety . 3 - 0 -glucuronyldoxepin has the following structure:

The ( Z ) and ( E ) isomers of N - acetyl- N -desmethyldoxepin 40* CH3 can be prepared by any suitable means . For example , ( E ) - N - acetyl- N -desmethyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by HON Moody et al. (Drug Metabolism and Disposition ( 1999 ) 27: 1157 - 1164 ) , hereby incorporated by reference in its OGluA entirety . N -desmethyl - N - formyldoxepin has the following struc ture : 50 The ( Z ) and ( E ) isomers of 3 -0 - glucuronyldoxepin can be prepared by any suitable means . For example , ( E )- 3 - 0 glucuronyldoxepin has been isolated from the bile of rats given doxepin , as described by Shu et al. (Drug Metabolism and Disposition ( 1990 ) 18 : 1096 - 1099 ) , hereby incorporated 55 by reference in its entirety . 2 - 0 - glucuronyldoxepin has the following structure : CH3 OGluA 60 Hz The ( Z ) and ( E ) isomers of N - desmethyl- N - formyldox epin may be prepared by any suitablemeans . For example , ( E ) - N -desmethyl - N - formyldoxepin has been produced in filamentous fungus incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition ( 1999 ) 65 27 : 1157 - 1164 ) , hereby incorporated by reference in its entirety . US 9 , 801 ,847 B2 15 16 The ( Z ) and ( E ) isomers of 2 - 0 - glucuronyldoxepin can be The term “ prodrug ” refers to a chemical entity that is prepared by any suitable means. For example , ( E ) -2 - 0 - rapidly transformed in vivo to yield an active drug, such as glucuronyldoxepin has been isolated from the bile of rats for example doxepin or a metabolite of doxepin , for given doxepin , and also in the urine of humans given example , by hydrolysis in blood or inside tissues . Examples doxepin , as described by Shu et al. (Drug Metabolism and 5 of pro - drug groups can be found in , for example , T . Higuchi Disposition ( 1990 ) 18 : 1096 - 1099 ) , hereby incorporated by and V . Stella , in “ Pro -drugs as Novel Delivery Systems, ” reference in its entirety. Vol. 14 , A . C . S . Symposium Series, American Chemical Quaternary ammonium - linked glucuronide of doxepin Society ( 1975 ); H . Bundgaard , “ Design of Prodrugs ,” Elsevier Science, 1985 ; and “ Bioreversible Carriers in Drug (doxepin N * - glucuronide ) has the following structure : 10 Design : Theory and Application ,” edited by E . B . Roche , Pergamon Press: New York , 14 - 21 ( 1987 ) , each of which is CH3 hereby incorporated by reference in its entirety . Preparation and Administration of Pharmaceutical Compo ON — Glua sitions As discussed above , the cis - (Z ) isomer or specified ratios CH3 of the cis - ( Z ) and trans - ( E ) isomers of doxepin , of doxepin 00 metabolites, of prodrugs of the same, of salts of the same, and compositions that include cis - ( Z ) isomer or specified ratios of the cis - ( Z ) and trans- ( E ) isomers of doxepin , of a 20 metabolite of doxepin , of a prodrug or of a doxepin salt can be used to treat a sleep disorder , for example , insomnia in a mammal, including a human . Also , doxepin isomer, metabo The ( Z ) and ( E ) isomers of doxepin N ' - glucuronide can lite isomer or isomer mix , pharmaceutically acceptable salts . be obtained by any suitable means. For example , doxepin and / or prodrugs of the same can be administered alone or in N * - glucuronide can be prepared , and the ( Z ) and ( E ) isomers 25 combination with other substances, such as for example , thereof can be isolated as taught by Luo et al . (Drug other insomnia or sleep medications, or with other medica Metabolism and Disposition , ( 1991) 19 : 722 -724 ), hereby tions that treat a primary illness. For example , doxepin , incorporated by reference in its entirety . doxepin metabolite , isomers , prodrugs or salts of the same Preferably the ratio of Z / E metabolite isomers can be can be used or administered with ramelteon , VEC - 162 , about 18 . 2 /81 . 8 , about 20 /80 , about 30 /70 , about 50 /50 , 30 gaboxadol, APD125 , trazodone , tiagabine, indiplon , AVE about 75 /25 , about 80 /20 , about 90 /10 , about 95/ 5 , about 8488 , MDL 100907 , AVE 8488 , MDL 100907 , eszopiclone , 98 / 2 , about 99 / 1 , about 99 . 5 / 0 . 5 , about 99 . 9 /0 . 1 , or about zolpidem tartrate , zaleplon or the like . Further, doxepin , 100 / 0 . In some aspects , the ratio of Z / E isomers can vary doxepin metabolite , isomers, prodrugs or salts of the same from about 18 . 2 /81 . 8 to about 100 / 0 , from about 20 /80 to can be administered with one or more of 5 -HT2 antagonists about 99 . 9 / 0 . 1 , from about 30 /70 to about 99 . 5 / 0 . 5 . from 35 (such as ketanserin ) , H3 agonists , orexin antagonists , nora about 50 /50 to about 99 / 1 , from about 75 /25 to about 97 / 3 , drenergic antagonists , galanin agonists , CRH antagonists , from about 80 / 20 to about 94 . 9 / 5 . 1 , or the like . Preferably , GABA - A direct agonists , GABA reuptake inhibitors , growth hormone and growth hormone agonists , estrogen and estro the cis isomer of the metabolite is prepared , wherein the Z / E gen agonists , melatonin agonists or the like . isomeric ratio is at least 80 / 20 , at least 85 / 15 , at least 90 / 10 , 40 The compositions as described herein can include dox at least 95/ 5 , at least 98 / 2 , at least 99 / 1 , at least 99. 5 / 0 .5 , at epin , a doxepin isomer or isomers, a metabolite of doxepin , least 99 . 9 /0 .1 , or is about 100 /0 . an isomer or isomers of a metabolite of doxepin , a pharma Pharmaceutically Acceptable Salts and Prodrugs : ceutically -acceptable salt of any of the aforementioned Asmentioned above, the methods and other embodiments (alone or in combination , including with other medications ) , described herein can utilize any suitable pharmaceutically . 45 or a prodrug of any of the aforementioned in a unit dosage acceptable salt or prodrug of doxepin or a metabolite of form . Unit dosage form can refer to a product form in which doxepin . Therefore, substitution of salts and prodrugs is premeasured dosages of the drug are packaged , in contrast specifically contemplated in the various embodiments , even to bulk preparations. Examples of unit dosage forms are though , only doxepin or doxepin metabolites may be spe - described herein , but several non limiting examples , include , cifically mentioned . The pharmaceutically - acceptable salts 50 a pill, a tablet , a capsule , a gel cap , a small liquid drug, an and prodrugs can be made by any suitable method . The acids ampoule , a fastmelt formulation , and the like . The isomers , that may be used to prepare pharmaceutically acceptable salts and prodrugs alone or in combination can be included acid addition salts are those that form non - toxic acid addi - and administered as a composition . Methods of use can tion salts, i . e . , salts containing pharmacologically acceptable include the step of administering a therapeutically - effective anions , such as the acetate , benzenesulfonate , benzoate , 55 amount of the compound or composition to a mammal in bicarbonate , bisulfate , bitartrate , borate , bromide , calcium need thereof by any suitable route or method of delivery , edetate , camsylate , carbonate , chloride , clavulanate , citrate , including those described herein . dihydrochloride , edetate , dislyate , estolate , esylate , ethyl Actual dosage levels of the compounds in the pharma succinate, fumarate , gluceptate , gluconate , glutamate , gly - ceutical compositions may be varied so as to administer an collylarsanilate , hexylresorcinate , hydrabamine , hydrobro - 60 amount of the compound that is effective to achieve the mide , hydrochloride, iodide, isothionate, lactate , desired therapeutic response for a particular patient. lactobionate , laurate , malate , maleate , mandelate , mesylate , Examples of dosages that can be used are described more methylsulfate , mucate, napsylate, nitrate , oleate , oxalate , fully elsewhere herein . pamoate (embonate ), palmitate , pantothenate , phospate / Suitable routes of administration include oral, buccal, diphosphate , polygalacturonate , salicylate , stearate , subac - 65 sublingual , transdermal, rectal, topical, transmucosal, or etate , succinate, tannate , tartrate , teoclate , tosylate , triethio intestinal administration ; parenteral delivery , including dode , and valerate salts . intramuscular, subcutaneous, intravenous, intramedullary US 9 ,801 , 847 B2 17 18 injections, as well as intrathecal, direct intraventricular, gelatin for use in an inhaler or insufflator may be formulated intraperitoneal, intranasal, or intraocular injections . containing a powder mix of the compound and a suitable For oral administration , the compounds can be formulated powder base such as lactose or starch . as pills , tablets , powders , granules , dragees , capsules, liq The compounds may be formulated for parenteral admin uids, sprays , gels , syrups , slurries, suspensions and the like , 5 istration by injection , e . g . , by bolus injection or continuous in bulk or unit dosage forms, for oral ingestion by a patient infusion . Formulations for injection may be presented in unit to be treated . the compounds can be formulated readily , for dosage form , e . g ., in ampoules or in multi - dose containers , example , by combining the active compound with any with an added preservative . The compositions may take such suitable pharmaceutically acceptable carrier or excipient. forms as suspensions , solutions or emulsions in oily or Pharmaceutical preparations for oral use can be obtained 10 aqueous vehicles , and may contain formulatory agents such by mixing one or more solid excipients with a pharmaceu - as suspending, stabilizing and /or dispersing agents . tical composition as described herein , optionally grinding Pharmaceutical formulations for parenteral administra the resulting mixture , and processing the mixture of gran - tion include aqueous solutions of the active compounds in ules, after adding suitable auxiliaries , if desired , to obtain water - soluble form . Additionally , suspensions of the active tablets or dragee cores . Suitable excipients are listed below . 15 compounds may be prepared as appropriate oily injection Some examples include fillers such as sugars , including suspensions . Suitable lipophilic solvents or vehicles include lactose , sucrose , mannitol, or sorbitol; cellulose preparations fatty oils such as sesame oil, or synthetic fatty acid esters , such as, for example , maize starch , wheat starch , rice starch , such as ethyl oleate or triglycerides, or liposomes . Aqueous potato starch , gelatin , gum tragacanth , methyl cellulose , injection suspensions may contain substances which hydroxypropylmethyl- cellulose , sodium carboxymethylcel - 20 increase the viscosity of the suspension , such as sodium lulose, and /or polyvinylpyrrolidone (PVP ) . If desired , dis - carboxymethyl cellulose , sorbitol, or dextran . Optionally, integrating agents may be added , such as the cross -linked the suspension may also contain suitable stabilizers or polyvinyl pyrrolidone, agar , or alginic acid or a salt thereof agents which increase the solubility of the compounds to such as sodium alginate . allow for the preparation of highly - concentrated solutions . The formulation can be in form suitable for bolus admin - 25 In addition , any of the compounds and compositions istration , for example . Oral administration can be accom - described herein can also be formulated as a depot prepa plished using fast- melt formulations , for example . As a ration . Such long acting formulations may be administered further example, the formulations can be included in pre - by implantation ( for example subcutaneously or intramus measured ampules or syringes , push - fit capsules made of cularly ) or by intramuscular injection . Thus, for example , gelatin , as well as soft, sealed capsules made of gelatin and 30 the compounds may be formulated with suitable polymeric a plasticizer , such as glycerol or sorbitol. The push - fit or hydrophobic materials ( for example as an emulsion in an capsules can contain the active ingredients in admixture with acceptable oil ) or ion exchange resins, or as sparingly filler such as lactose , binders such as starches , and /or soluble derivatives, for example , as a sparingly soluble salt . lubricants such as talc or magnesium stearate and , option . Furthermore , any of the compounds and compositions ally , stabilizers . In soft capsules , the active compounds may 35 described herein also can be formulated as a fast -melt be dissolved or suspended in suitable liquids , such as fatty preparation . The compounds and compositions can also be oils , liquid paraffin , or liquid polyethylene glycols . In addi formulated and administered as a drip , a suppository, a salve , tion , stabilizers may be added . All formulations for oral an ointment, an absorbable material such a transdermal administration should be in dosages suitable for such admin patch , or the like . istration . 40 One can also administer the compounds of the invention For buccal administration , the compositions may take any in sustained - release forms or from sustained - release drug suitable form , for example , tablets or lozenges . delivery systems. A description of representative sustained For topical administration , the compounds may be for release materials can be found in the incorporated materials mulated for administration to the epidermis as ointments , in Remington : The Science and Practice of Pharmacy ( 20th gels , creams, pastes , salves , gels , creams or lotions , or as a 45 ed , Lippincott Williams & Wilkens Publishers ( 2003 ) ) , transdermal patch . Ointments and creamsmay , for example , which is incorporated herein by reference in its entirety . be formulated with an aqueous or oily base with the addition A variety of techniques for formulation and administra of suitable thickening and / or gelling agents . Lotions may be tion can be found in Remington : The Science and Practice formulated with an aqueous or oily base and will in general of Pharmacy ( 20th ed , Lippincott Williams & Wilkens Pub also containing one or more emulsifying agents , stabilizing 50 lishers (2003 ) ) , which is incorporated herein by reference in agents , dispersing agents , suspending agents, thickening its entirety . agents , or coloring agents . As mentioned above , the compositions and formulations For injection , the agents of the invention may be formu - disclosed herein also can include one or more pharmaceu lated in aqueous solutions, preferably in physiologically tically -acceptable carrier materials or excipients . Such com compatible buffers such as Hanks ' s solution , Ringer' s solu - 55 positions can be prepared for storage and for subsequent tion , or physiological saline buffer. For transmucosal admin - administration . Any acceptable carriers or diluents for thera istration , penetrants appropriate to the barrier to be perme peutic use can be used , including those described , for ated can be used in the formulation . example , in the incorporated material of Remington : The For administration by inhalation , the compounds for use Science and Practice of Pharmacy (2003 ) . The term “ car according to the present invention are conveniently deliv - 60 rier ” material or " excipient” herein can mean any substance , ered in the form of an aerosol spray presentation from not itself a therapeutic agent, used as a carrier and / or diluent pressurized packs or a nebulizer, with the use of a suitable and /or adjuvant, or vehicle for delivery of a therapeutic propellant, e . g ., dichlorodifluoromethane , trichlorofluo agent to a subject or added to a pharmaceutical composition romethane, dichlorotetrafluoroethane , carbon dioxide , or to improve its handling or storage properties or to permit or other suitable gas. In the case of a pressurized aerosol the 65 facilitate formation of a dose unit of the composition into a dosage unit may be determined by providing a valve to discrete article such as a capsule or tablet suitable for oral deliver a metered amount. Capsules and cartridges of, e. g ., administration . Excipients can include , by way of illustra US 9 , 801 ,847 B2 20 tion and not limitation , diluents , disintegrants , binding the patientbeing treated . However, it is within the skill of the agents , adhesives , wetting agents , polymers , lubricants , gli art to start doses of the compound at levels lower than dants , substances added to mask or counteract a disagreeable required to achieve the desired therapeutic effect and to taste or odor , flavors , dyes, fragrances, and substances added gradually increase the dosage until the desired effect is to improve appearance of the composition . Acceptable 5 achieved . Also , a patient can be administered a higher low excipients include lactose , sucrose , starch powder, maize dose ( e .g ., 6 milligrams) of the isomer or isomeric mixture, starch or derivatives thereof, cellulose esters of alkanoic then the drug dosage can be tapered to a lower dosage. It will acids , cellulose alkyl esters, talc , stearic acid , magnesium stearate , magnesium oxide , sodium and calcium salts of be understood , however, that the specific dose level for any phosphoric and sulfuric acids , gelatin , acacia gum , sodium 10 particular patient can depend upon a variety of factors alginate , polyvinyl -pyrrolidone , and/ or polyvinyl , including the genetic makeup , body weight , general health , saline, dextrose , mannitol, lactose , lecithin , albumin , sodium diet , time and route of administration , combination with glutamate , cysteinehydrochloride , and the like. Examples of other drugs and the severity of the particular condition being suitable excipients for soft gelatin capsules include veg treated . etableetable oils , waxes, fats , , semisolid and liquidliquid polyolspolyols. SuitSuit - 1515 Any suitable dosage of the cis -( Z ) isomer or specified able excipients for the preparation of solutions and syrups ratios of the cis - ( Z ) and trans - ( E ) isomers of doxepin , a include . without limitation , water, polvols , sucrose . invert metabolite of doxepin , a pharmaceutical salt , or prodrug can sugar and glucose . Suitable excipients for injectable solu - be used to treat the sleep disorder such as insomnia . In some tions include , without limitation , water, , polyols , aspects , daily dosages of the cis -( Z ) isomer or specified glycerol, and vegetable oils . The pharmaceutical composi- 20 ratios of the cis -( Z ) and trans -( E ) isomers doxepin , of a tions can additionally include preservatives, solubilizers , doxepin metabolite , of a pharmaceutically -acceptable salt of stabilizers , wetting agents , emulsifiers, sweeteners , colo doxepin , or of a prodrug of doxepin may vary from about rants , flavorings, buffers , coating agents, or antioxidants. 0 .001 to about 9 milligrams, about 0 .001 to about 24 Sterile compositions for injection can be formulated accord milligrams, about 0 . 001 to about 49 milligrams, about 0 .001 ing to conventional pharmaceutical practice as described in 25 to about 99 milligrams, about 0 .001 to about 249 milligrams, the incorporated material in Remington : The Science and about 0 .0001 to about 499 milligrams, about 0 . 01 to about Practice of Pharmacy ( 2003 ). For example , dissolution or 49 milligrams, about 0 .01 to about 40 milligrams, from suspension of the active compound in a vehicle such as about 0 . 1 to about 40 milligrams, about 0 .01 to about 24 water or naturally occurring vegetable oil like sesame, milligrams, about 0 .01 to about 20 milligrams, from about peanut , or cottonseed oil or a synthetic fatty vehicle like 30 0 . 5 to about 30 milligrams, about 1 to about 20 milligrams, ethyl oleate or the like may be desired . Buffers , preserva - or from about 5 , 10 or 20 milligrams to about 49 milligrams. tives , antioxidants and the like can be incorporated accord Preferably , daily dosages of about 5 , about 9 , about 24 , about ing to accepted pharmaceutical practice . The compound can 49 milligrams, about 99 , about 249 , or about 499 or less can also be made in microencapsulated form . In addition , if utilized . In other aspects , a daily dosage of greater than desired , the injectable pharmaceutical compositions may 35 about 5 , about 10 , about 20 or about 30 milligrams can be contain minor amounts of nontoxic auxiliary substances , used . However, as it is recognized that each individual may such as wetting agents , pH buffering agents , and the like . If react differently to a given dose of the medication used , the desired , absorption enhancing preparations ( for example , dosages recited should be accorded flexibility. Further , any liposomes ), can be utilized . suitable unit dosage form can be formulated to contain the The compositions and formulations can include any other 40 cis - ( Z ) isomer or specified ratios of the cis - ( Z ) and trans - ( E ) agents that provide improved transfer, delivery, tolerance , isomers of doxepin , of a doxepin metabolite , of a prodrug of and the like . These compositions and formulations can doxepin or of pharmaceutically -acceptable salts of doxepin include, for example , powders , pastes , ointments , jellies , in the above - recited amounts ( e . g . , 0 .01 - 49 mg, or higher ) . waxes, oils , lipids, lipid ( cationic or anionic ) containing In general, lower doses of the cis - ( Z ) isomer or specified vesicles ( such as LipofectinTM ) , DNA conjugates , anhydrous 45 ratios of the cis - ( Z ) and trans- ( E ) isomers of doxepin , of the absorption pastes , oil - in -water and water - in - oil emulsions, metabolites , of the salts or of prodrugs of the same can be emulsions carbowax (polyethylene glycols of various preferred . These low doses are surprisingly effective and , in molecular weights ) , semi- solid gels , and semi- solid mix most patients, have almost no side effects . In some embodi tures containing carbowax . Any of the foregoing mixtures ments , daily dosages can be about 0 .01 , 0 . 02 , 0 .03 , 0 .04 , may be appropriate in treatments and therapies in accor - 50 0 .05 , 0 . 06 , 0 .07 , 0 . 08 or 0 .09 milligrams. In some embodi dance with the present invention , provided that at least one ments about 0 . 1 , 0 . 2 , 0 . 3 , 0 . 4 , 0 . 5 , 0 . 6 , 0 . 7 , 0 . 8 , 0 . 9 , or 1 . 0 active ingredient in the formulation is not inactivated by the milligrams can be used . In another embodiment, daily formulation and the formulation is physiologically compat- dosages of can be about 0 .01 , 0 . 5 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or ible and tolerable with the route of administration . See also 10 milligrams. In another embodiment, daily dosages can be Baldrick P . “ Pharmaceutical excipient development: the 55 about 11, 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , or 20 milligrams. need for preclinical guidance .” Regul . Toxicol. Pharmacol. Therapy at each of the doses described in this paragraph as 32 ( 2 ) : 210 - 8 ( 2000 ), Charman WN “ Lipids , lipophilic drugs, well as ranges between these doses , are particularly con and oral drug delivery -some emerging concepts ." J Pharm templated . These relatively low doses between 0 .01 milli Sci . 89 ( 8 ) : 967 - 78 ( 2000 ), Powell et al. “ Compendium of grams up to , for example , 2 , 3 , 4 , 5 , 10 , 15 or 20 milligrams, excipients for parenteral formulations” PDA J Pharm Sci 60 have reduced side effects and are surprisingly effective . Technol. 52 :238 - 311 (1998 ) and the citations therein for Further, in some embodiments , daily dosages of the additional information related to formulations, excipients cis - ( Z ) isomer or of specified ratios of the cis - ( Z ) and and carriers well known to pharmaceutical chemists . trans - ( E ) isomers of doxepin may be up to about 25 or 30 Dosages milligrams. In another embodiment, daily dosages of the The selected dosage level can depend upon , for example , 65 cis - ( Z ) isomer or of specified ratios of the cis -( Z ) and the route of administration , the severity of the condition trans- ( E ) isomers of doxepin may be up to about 35 or 40 being treated , and the condition and prior medical history of milligrams. In another embodiment, daily dosages of the US 9 ,801 , 847 B2 21 22 cis - ( Z ) isomer or of specified ratios of the cis - ( Z ) and is obtained . The crude product can however be used trans - ( E ) isomers of doxepin may be up to about 45 or 49 quite easily for further processing . milligrams. ( d ) 5 . 4 g ( 0 .02 mol) of the 11 -( 3 - chloropropylidene) - 6 , Doses of the cis - ( Z ) isomer or of the specified ratios of the 11 - dihydrodibenzo - [b , e ] - oxepine , prepared according cis - ( Z ) and trans- ( E ) isomers of doxepin , of doxepin 5 to ( c ) above , in 20 ml tetrahydrofuran and 5 . 5 g ( 0 .12 metabolites , of doxepin salts and of prodrugs of doxepin , for mol) dimethylamine in 20 ml ethanol is heated together example , greater than 50 milligrams per day can be used . For for 3 hours using a glass autoclave and a temperature of example a dosage of about 50 milligrams to about 500 95 - 100° C . (boiling water bath ) . Water and 6 N hydro chloric acid are added to the contents of the autoclave milligrams can be used . Also , a dosage of about 50 to about and the mixture is extracted with ether . The separated , 300 , about 50 to about 150 , or about 50 to about 75 10 aqueous- acid components are then made alkaline with milligrams can be used , for example . Such doses can treat dilute caustic soda solution , and the oil thereby sepa insomnia in patients not suffering from depression or in rated is taken up in ether . The ether residue , after otherwise healthy patients . distillation in a high vacuum , produces 4 . 1 g (73 . 5 % of theory ) of 11 - ( 3 -dimethylamino -propylidene ) - 6 , 11 - di EXAMPLES hydrodibenzo - [b , e ]- oxepine , having a B .P .0 . 1 147 - 150° C . The melting point of the hydrochloride is 182 - 184° Example 1 C . ( recrystallized from isopropanol) . Doxepin is prepared by the following method . Example 2 ( a ) A Grignard compound is prepared in the conventional 20 manner from 4 . 8 g ( 0 . 2 gram - atom ) magnesium in 100 Preparation of Doxepin Isomer ml ether and 30 g ( 34 ml) ( 3 - chloropropyl) -tertbutyl ether and 16 .40 grams ( 0 .078 mol) 6 , 11 - dihydrod Five grams of the cis / trans mixture of doxepin hydrochlo ibenzo - lb , e ] -oxepine - 11 - one dissolved in 100 ml ether ride is converted to the free base and then to the maleate salt , is added in dropwise fashion so that the contents of the 25 M . P . 168 - 169° C . Several recrystallizations from ethanol flask boil lightly . The mixture is heated for 1 hour with afford a pure isomeric maleate , M . P . 172 - 173° C . This is agitation in a reflux condenser to complete the reaction reconverted to the free base and then to the hydrochloric and then it is decomposed with ammonium chloride acid - addition salt . This is purified by recyrstallization from solution . The product which is obtained by separating , a mixture of ethanol and ether ; M . P . 192 - 193° C . The other drying and eliminating the solvent produced , when the 30 pure isomer is isolated by the concentration of the crystal ether residue (24 . 0 g ) is extracted with ligroin , amounts lization liquors to dryness, followed by converting the to 20 . 3 g ( 80 . 0 % of theory ) of 11 - ( 3 - tertbutoxypropyl) - residue to the free base and then converting the base to the 11 - hydroxy - 6 , 11 - dihydrodibenzo - [ b , e ] -oxepine , hav - hydrochloric -acid addition salt . After re - crystallization from ing a melting point of 124 - 126° C . The ( 3 -chloropro - a mixture of ethanol and ether, the salt has a M . P . of pyl) - tertbutyl ether is thereafter obtained in the 35 209 -210 . 5° C . following manner : 19 g ( 0 . 2 mol) 1 - chloropropanol (3 ) , 50 ml liquid isobutylene and 0 . 5 ml concentrated Example 3 sulfuric acid are permitted to stand for 24 hours in an autoclave , then are poured into excess sodium bicar Preparation of Desmethyldoxepin bonate solution and extracted with ether. The ether 40 solution is dried with calcium chloride and distilled . Desmethyldoxepin is prepared according to the following 23 .6 grams of ( 3 -chloropropyl ) - tertbutylether having a method . Anhydrous 3 -methylaminopropyltriphenylphos boiling point of 150 - 156° C . ( 78 % of theory ) are phonium bromide hydrobromide (1530 g ) prepared as in recovered U . S . Pat. No. 3 ,509 , 175 , is suspended in 4 . 5 1 dry tetrahy (b ) 30 . 8 grams of the 11 - ( 3 -tertbutoxypropyl ) - 11- hy - 45 drofuran and 6 .0 moles of butyl lithium in heptane is added droxy -6 , 11 - dihydrodibenzo -fb , el- oxepine obtained during 1 hour. After an additional 30 minutes, 483 g of according to ( a ) above and 150 ml absolute alcoholic 6 , 11 - dihydrodibenz( b , e )oxepin - 11 -one , is added to the deep hydrochloric acid are heated for 1 hour at ebullition . red solution and the reaction is maintained at reflux for 10 After removing the solvent by evaporation , the residue hours. Water, 500 ml, is added at room temperature and the is crystallized with ligroin , 21 . 0 grams (88 .5 % of 50 solvent is removed in vacuo . The crude residue is treated theory ) of 11- ( 3- hydroxypropylidene ) -6 ,11 - dihydrod - with 10 % hydrochloric acid until acidic (pH 2) and then 1. 5 ibenzo - [ b , e ) - oxepine having a melting point of 108 - 1 benzene is added . After stirring , the mixture separates into 111° C . were obtained . After recrystallization from three phases ( an insoluble hydrochloride salt product phase , acetic acid ester, the compound melts at 112 - 114° C . an aqueous phase and an organic phase ). The benzene layer ( c ) 5 . 0 ml thionyl chloride dissolved in 5 ml benzene is 55 is removed by decantation and the remaining mixture is added dropwise at room temperature to 12 . 6 g ( 0 .05 rendered basic with 10 % sodium hydroxide solution and is mol) of the 11 - ( 3 - hydroxypropylidene ) -6 , 11 - dihydrod - extracted with 3x1500 ml portions of benzene . The benzene ibenzo - [ b , e ] -oxepine obtained in part ( b ) above . After 1 extracts are washed , then dried with anhydrous sodium hour of standing, the contents of the flask are heated at sulfate and concentrated in a vacuum leaving a solid residue ebullition for 2 hours . The volatile components are 60 of desmethyldoxepin . thereafter removed and the remainder distilled using high vacuum . The yield amounts to 10 . 6 g ( 78 . 5 % of Example 4 theory ) of 11 - ( 3 - chloropropylidene ) - 6 ,11 -dihydrod ibenzo - [b , e ] - oxepine having a B . P . 0 . 1 169 - 172° C ., a Preparation of ( e ) -desmethyldoxepin melting point of 106 - 111° C . After recrystallization 65 from 20 ml of acetic acid ester , 9 . 1 g (67 . 5 % of theory ) ( E ) - Desmethyldoxepin is prepared from doxepin hydro of pure product having a melting point of 113 - 115° C . chloride as follows . Doxepin hydrochloride ( E / Z = 85 /15 ) US 9 ,801 , 847 B2 23 24 (55 . 0 g , 0 . 174 mol) is dissolved in 600 mL H20 , made basic (3x35 mL ) . The CHC1z extracts are combined , washed with with 6M NaOH , and extracted with CHC1z (3x600 mL ) . The 35 ml brine , dried over Na2SO4, and solvent removed in CHC1z extracts are combined , dried over Na2SO4, and vacuo . The resulting oil is re -dissolved in 4 mL CHC13 , 0 .65 solvent removed in vacuo . The resulting oil is dissolved in mL (4 .7 mmol) of triethylamine added , 0 .65 mL (4 .7 mmol) 250 mL EtOH , then 21. 15 g (0 . 182 mol ) of maleic acid 5 of 2 , 2 , 2 - trichloroethyl- chloroformate added , and reaction dissolved in 100 mL EtOH is added slowly , with stirring , stirred under N , for 3 .5 hours . The completed reaction is followed by an additional 350 mL EtOH . The resulting then diluted with 50 mL Et20 , washed successively with cloudy solution is refluxed until it becomes clear, then 0 .5M HC1 ( 2x50 mL ) , H , O (50 mL ) , and brine (50 mL ) , allowed to stand overnight at room temperature ; the result then dried over MgSO4 and solvent removed in vacuo . ing crystals are isolated by vacuum filtration . Additional 10 Resulting material is further purified by silica gel column recrystallization from EtOH yields a white crystalline prod chromatography, eluting with EtoAc/ Hex (20 /80 ), to afford uct ( ( E ) -Doxepin maleate) with an E / Z ratio of 98 / 2 . ( E ) 710 mg ( 1 .61 mmol ) of the desired product as a clear oil. The Doxepin maleate ( 2 .50 g , 6 . 32 mmol) is then partially N -protected ( Z ) -desmethyldoxepin (679 mg, 1 . 54 mmol) is dissolved in 60 mL H20 , made basic with 6M NaOH , and then dissolved in 5 . 7 mL THE , 1 . 36 g of zinc powder added , extracted with CHC13 ( 3x60 mL ). The CHC13 extracts are 15 1 . 1 mL of 1M sodium phosphate (pH = 5 .5 ) added , and combined , washed with 60 mL brine, dried over Na2SO4, reaction stirred for 17 hours . The reaction mixture is then and solvent removed in vacuo . The resulting oil is re vacuum filtered , filtrate solvent removed in vacuo , and dissolved in 10 mL CHC13 , 1. 8 mL ( 13 mmol) of triethyl resulting residue purified by silica gel column chromatog amine added , 1. 8 mL (13 mmol) of 2 , 2 , 2 -trichloroethyl raphy , eluting with THF /MeOH /NH OH ( 85 / 15 / 0 . 4 ) , then chloro - formate added , and reaction stirred under N2 for 3 . 5 20 THF /MeOHNHOH (82 / 18 / 0 . 4 ) , to afford 364 mg ( 1 . 37 hours . The completed reaction is then diluted with 140 mL mmol) of the desired product as a pale yellow solid . Et20 , washed successively with 0 .5M HC1 ( 2x140 mL ) , H20 ( 140 mL ) , and brine ( 140 mL ), then dried over MgSO4 Example 6 and solvent removed in vacuo . Resulting material is further purified by silica gel column chromatography, eluting with 25 Preparation of ( Z ) - 2 - Hydroxy -11 - ( 3 -dimethylamino EtOAc /Hex (20 / 80 ) , to afford 1 .48 g ( 3 . 36 mmol) of the propylidene) - 6 , 11- dihydrodibenzo [be ] oxepin desired product as a clear oil . The N - protected ( E ) - desm ethyldoxepin intermediate ( 1 . 44 g , 3 . 27 mmol) is then A mixture of 2 -methoxy -11 -( 3 -dimethylaminopropyl ) - 6 , dissolved in 12 mL THF, 2 .88 g of zinc powder added , 2 . 3 11 - dihydrodibenzo [ b , eJoxepin ( 165 mg, 0 . 005 mol ) with mL of 1M sodium phosphate (pH = 5 . 5 ) added , and reaction 30 glacial acetic acid ( 0 . 2 ml) and hydriodic acid ( 0 . 2 ml, 57 % ) stirred for 17 hours. The reaction mixture is then vacuum was stirred and heated for 5 hr at 90° C . The product was filtered , filtrate solvent removed in vacuo , and resulting then extracted and purified by pouring into ice water ( 25 ml) , residue purified by silica gel column chromatography , elut - made alkaline with sodium hydroxide (2N ) and extracted ing with THF /MeOH /NH , OH (85 / 15 / 0 . 4 ), then THF / with ether ( 2x10 ml) . The aqueous layer was then adjusted MeOH /NH ,OH (75 /25 / 0 . 4 ), to afford 744 mg ( 2 . 80 mmol) 35 to pH 6 . 8 with hydrochloric acid (6N ) . The mixture was then of the desired product as a pale yellow solid . brought to pH 7 by the addition of sodium bicarbonate solution ( 5 % ) and extracted with chloroform (2x10 ml) . The Example 5 extract was dried over anhydrous sodium sulfate and evapo rated in vacuo to give a yellowish solid . The crude reaction Preparation of ( z )- Desmethyl Doxepin 40 product was purified by preparative TLC ( chloroform / tolu (Z ) -Desmethyldoxepin is prepared from doxepin hydro ene /methanol / ammonia , 4 : 3 : 2 : 1 , v / v ) . chloride as follows. Doxepin hydrochloride (E /Z = 85 / 15 ) Example 7 ( 100 g , 0 .317 mol ) is dissolved in 800 mL H , O , made basic with 6M NaOH , and extracted with CHC12 (3x800 mL ) . The 45 Preparation of ( E ) - 2 -Hydroxy - 11 - ( 3 -dimethylamino CHC1z extracts are combined , dried over Na S04, and propylidene )- 6 , 11 -dihydrodibenzo [ b ,eJoxepin solvent removed in vacuo . The resulting oil is dissolved in 700 mL EtOH , then 36 . 7 g ( 0 .317 mol) of maleic acid A mixture of ( Z ) - 2 -Hydroxy - 11- ( 3 -dimethylaminopropy dissolved in 600 mL EtOH is added slowly , with stirring . lidene ) - 6 , 11 - dihydrodibenzo [ b ,eJoxepin ( 2 . 5 mg, 8 .5x10 - 6 The resulting cloudy solution is refluxed until clear, then 50 mol) was dissolved in a mixture of hydrochloric acid ( 1 ml) allowed to stand overnight at room temperature . Crystals are and methanol ( 9 ml) and heated at 140° C . (oil bath ) for 4 isolated by vacuum filtration and the mother liquor saved . hr. The product was isolated by means of HPLC and Crystals are recrystallized two additional times as above, evaporation of solvents . and the three mother liquors saved and combined and solvent removed in vacuo . Recrystallization of mother 55 Example 8 liquor material from refluxing EtOH eventually affords 24 g of a mother liquor product which is 65 % Z isomer in Preparation of ( Z ) - 2 -Hydroxy - 11 - ( 3 -methylamino composition . Recrystallization of this material from 450 mL propylidene ) - 6 , 11- dihydrodibenzo [ b , e ]oxepin EtOH gives crystals ( 9 . 1 g ) which are 80 % Z isomer. This material is recrystallized from 170 mL CHC12 / CC14 (50 /50 ) 60 A mixture of 2 - methoxy - 11 - ( 3 -methylaminopropyl ) - 6 , 11 at 4° C ., yielding 7 .65 g of crystalline material which is 87 % dihydrodibenzo [b ,eJoxepin ( 0 .005 mol) with glacial acetic Z isomer in composition . Three additional recrystallizations acid ( 0 . 2 ml) and hydriodic acid ( 0 . 2 ml, 57 % ) is stirred and from CHC12 /CC14 eventually affords 5 . 12 g ( 12 .9 mmol) of heated for 5 hr at 90° C . The product is then extracted and the desired product ( ( Z ) -Doxepin maleate ) with an E / Z ratio purified by pouring into ice water ( 25 ml) , made alkaline of 4 / 96 ; melting point: 1620 - 163° C . ( Z ) -Doxepin maleate 65 with sodium hydroxide ( 2N ) and extracted with ether (2x10 ( 1 .00 g , 2 . 53 mmol) is then partially dissolved in 35 ml ml) . The aqueous layer is then adjusted to pH 6 . 8 with H20 ,made basic with 6M NaOH , and extracted with CHC1Z hydrochloric acid (6N ) . The mixture is then brought to pH US 9 ,801 , 847 B2 25 26 7 by the addition of sodium bicarbonate solution ( 5 % ) and isolated from Cunninghamella elegans ( C . elegans ) as extracted with chloroform (2x10 ml) . The extract is dried described in the incorporated materials of Moody et al. over anhydrous sodium sulfate and evaporated in vacuo to (Drug Metabolism and Disposition ( 1999 ) 27 :1157 -1164 ) . give a yellowish solid . The crude reaction product is purified Briefly , cultures of C . elegans ATCC 9245 are incubated for by preparative TLC ( chloroform / / methanol / ammo - 5 48 h at 26° C . on a rotary shaker operating at 125 rpm and nia , 4 : 3 : 2 : 1 , v / v ) . then 10 mg of doxepin hydrochloride ( E . / Z ratio 83 : 16 % ) dissolved in 0 . 5 ml sterile physiological saline solution are Example 9 added . After 96 h of incubation , the contents of each flask , are filtered through glass wool into a separatory funnel and Preparation of (E )- 2 -Hydroxy -11 -( 3 -methylamino 10 extracted with three equal volumes of ethyl acetate. The propylidene ) -6 , 11- dihydrodibenzo [ b , eJoxepin organic extracts are dried over sodium sulfate and evapo rated to dryness in vacuo at 34° . The residue is dissolved in A mixture of ( Z )- 2 -Hydroxy - 11- (3 -methylaminopropy methanol and concentrated to approximately 100 uL by lidene )- 6 ,11 -dihydrodibenzo [b , eJoxepin (2 .5 mg) is dis 5 evaporation for analysis by HPLC . solved in a mixture ofhydrochloric acid ( 1 ml) and methanol The extract is injected repeatedly into a semipreparative ( 9 ml) and heated at 140° C . ( oil bath ) for 4 hr. The product scale HPLC system consisting of a Beckman model 100A is isolated by means of HPLC and evaporation of solvents . pump, a Waters 486 turntable UV absorbance detector, and a Shimadzu model CR601 Chromatopac integrator. The Example 10 20 compounds are eluted using a linear gradient of 30 to 75 % Preparation of Doxepin - N -Oxide methanol- buffer ( v / v ) over 30 min at 1 . 0 ml/min with a 10 . 0x250 mm column . The buffer used is 25 mM ammo An aqueous solution of doxepin hydrochloride was made nium acetate , pH 7 . 2 . Compounds with similar retention alkaline and extracted with methylene chloride. Solvent was times are pooled . NMR and mass spectral analysis confirms removed and the residue , dissolved in methanol, was treated 25 the isolation of ( E ) - N -acetyl - N - desmethyldoxepin , ( E ) - N for 5 days with an excess of 30 % hydrogen peroxidede . desmethyl- N - formyldoxepin , and ( E ) - N -acetyldidesmethyl Chromatographic examination indicated that the doxepin doxepin . had been completely replaced by a more polar substance determined from its mass spectrum to be the N -oxide . Example 14 Hobbs , D . C . , Distribution and Metabolism of Doxepin 30 ( 1969) Biochem Pharmacol 18 : 1941 - 1954 ; which is incor Isolation of ( Z ) - N -acetyl - N -desmethyldoxepin , porated herein by reference in its entirety . ( Z ) - N -desmethyl - N - formyldoxepin , and ( Z ) - N acetyldidesmethyldoxepin Example 11 35 (Z ) N -acetyl - N -desmethyldoxepin , (Z ) N -desmethyl Preparation of ( Z ) Doxepin - N - Oxide N - formyldoxepin , and ( Z ) - N -acetyldidesmethyldoxepin An aqueous solution of purified (Z )- doxepin hydrochlo are isolated from Cunninghamella elegans (C . elegans ) as ride is made alkaline and extracted with methylene chloride . described above in Example 12 for the ( E ) isomers. How Solvent is removed and the residue, dissolved in methanol, 40 ever , unlike Example 13 , the cultures are initially incubated is treated for 5 days with an excess of 30 % hydrogen with doxepin enriched for the cis ( Z ) - isomer of doxepin at peroxide . Chromatographic examination indicates that the a Z / E ratio of greater than 85 : 15 . NMR and mass spectral doxepin has been completely replaced by a more polar analysis confirms the isolation of ( Z ) - N -acetyl - N - desm substance determined from its mass spectrum to be the ethyldoxepin , ( Z ) - N -desmethyl - N - formyldoxepin , and N - oxide of the ( Z ) isomer of doxepin . 45 (2 ) — N -acetyldidesmethyldoxepin . Example 12 Example 15 Preparation of ( E ) Doxepin - N -Oxide Isolation of ( E ) - and ( Z ) — N - didesmethyldoxepin 50 An aqueous solution of purified ( E ) - doxepin hydrochlo - ( E ) - and ( Z ) - N - didesmethyldoxepin are isolated from ride is made alkaline and extracted with methylene chloride . blood serum and cerebrospinal fluid of patients treated with Solvent is removed and the residue, dissolved in methanol, doxepin according to the methods described in the incorpo is treated for 5 days with an excess of 30 % hydrogen rated materials of Deuschle et al. ( Psychopharmacology peroxide . Chromatographic examination indicates that the 55 ( 1997 ) 131 : 19 - 22 ) . Briefly , blood and cerebrospinal fluid are doxepin has been completely replaced by a more polar collected from patients being treated with doxepin . After substance determined from its mass spectrum to be the centrifugation , ( 15000 g for 5 min ) , 100 ul of the samples is N - oxide of the ( E ) isomer of doxepin . injected directly onto a clean -up column ( 10 .0x4 . 0 mm ) filled with Lichrospher RP - 8 DIOL . Interfering plasma or Example 13 60 CSF constituents are washed to waste using water contain ing 5 % acetonitrile at a flow rate of 1 . 5 ml/min . After 5 min Isolation of ( E )- N - acetyl - N - desmethyldoxepin , ( E ) the flow is switched onto an analytical column and the drugs N -desmethyl - N - formyldoxepin , and ( E ) - N -acetyl of interest are separated using methanol :acetonitrile : didesmethyldoxepin 0 .008M phosphate buffer, pH 6 .4 ( 188 : 578 : 235 ; V / V ) for 65 elution . NMR and mass spectral analysis confirms the iso ( E ) -N -acetyl - N -desmethyldoxepin , (E )- N -desmethyl - N - lation of ( E ) -N -didesmethyldoxepin and (Z ) N -didesmeth formyldoxepin , and ( E ) - N -acetyldidesmethyldoxepin are yldoxepin . US 9 ,801 ,847 B2 27 28 Example 16 0 . 0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milli ( Isolation of ( E )- 2- 0 - glucuronyldoxepin and (E )- 3 grams, taken prior to bedtime. Follow up reveals that the O - glucuronyldoxepin administration of the specified isomeric mixture of doxepin 5 relieves the insomnia and has him sleeping well . ( E ) -2 - 0 -glucuronyldoxepin and (E ) -3 - 0 -glucuronyldox epin are isolated from rat bile according to the methods Example 20 described in the incorporated materials of Shu et al. (Drug Metabolism and Disposition (1990 )18 :1096 -1099 ) . Briefly , The patient suffers from transient or short- term insomnia . samples of rat bile are collected from rats for 4 hours after 10 At the time of consultation , he is otherwise healthy with intraperitoneal injection with doxepin hydrochloride (28 normal affect with no depression , anxiety or substance mg/ kg ) . The samples are chromatographed on a gradient overuse. He is prescribed a mixture of cis -( Z ) and trans -( E ) HPLC system that consists of two solvent delivery pumps isomers of doxepin or a doxepin metabolite containing ( Waters M045 ) , a system controller (Waters Model 720 ) , a greater than 20 % cis - ( Z ) isomer in a daily dosage of 0 .0001 UV absorbance detector (Waters Model 441 ) , and an inte - 15 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 grator (Hewlett 3390A ) . Chromotography is carried out on milligrams, 10 milligrams, 20 milligrams or 40 milligrams, a column packed with Spherisorb nitrile ( 3 um , 0 . 46x15 cm ) taken prior to bedtime. Follow up reveals that the adminis and maintained at 50° C . The analysis begins with an initial tration of the specified isomeric mixture of doxepin relieves isocratic period ( 1 min ) with 95 % solvent A (water ) and 5 % the insomnia and has him sleeping well . solvent B ( acetonitrile /methanol , 75 : 25 , v / v ). Thereafter , a 20 linear gradient elution is established by increasing the pro Example 21 portion of solvent B from 5 % to 100 % from 1 to 16 min , followed by a final period ( 4 min ) of isocratic elution with The patient suffers from transient or short - term insomnia . 100 % solvent B . The flow rate is 1 .5 ml/min and UV At the time of consultation , he is otherwise healthy with absorbance is monitored at 254 nm with a sensitivity of 25 normal affect with no depression , anxiety or substance 0 .005 AUFS . NMR and mass spectral analysis confirms the overuse . He is prescribed a mixture of cis - ( Z ) and trans - ( E ) isolation of ( E ) - 2 - 0 - glucuronyldoxepin and ( E ) - 3 - 0 - glu isomers of doxepin or a doxepin metabolite containing curonyldoxepin . greater than 30 % and less than 99. 5 % cis- ( Z ) isomer in a daily dosage of 0 .0001 milligram , 0 . 1 milligram , 1 milli Example 17 30 gram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milli grams or 40 milligrams, taken prior to bedtime. Follow up Isolation of ( Z ) - 2 - 0 - glucuronyldoxepin and reveals that the administration of the specified isomeric ( Z ) - 3 - 0 - glucuronyldoxepin mixture of doxepin relieves the insomnia and has him sleeping well . ( Z ) - 2 - 0 - glucuronyldoxepin and ( Z ) - 3 - 0 - glucuronyldox - 35 epin are isolated from rat bile according to the methods Example 22 described above in Example 16 with the exception that the rats are injected with doxepin enriched for the cis ( Z ) - isomer The patient suffers from transient or short- term insomnia . of doxepin at a Z /E ratio of greater than 85: 15 . NMR and At the time of consultation , he is otherwise healthy with mass spectral analysis confirms the isolation of ( Z ) - 2 - 0 - 40 normal affect with no depression , anxiety or substance glucuronyldoxepin and ( Z ) - 3 - 0 - glucuronyldoxepin . overuse . He is prescribed the cis - ( Z ) isomer of doxepin or a doxepin metabolite in a daily dosage of 0 . 0001 milligram , Example 18 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken prior to Preparation of (E ) - and ( Z )- doxepin N +- glucuronide 45 bedtime. Follow up reveals that the administration of the doxepin isomer relieves the insomnia and has him sleeping The quaternary ammonium - linked glucuronide of dox - well. epin (doxepin N * - glucuronide ) is obtained by organic syn thesis as described in the incorporated materials of Luo et al. Example 23 ( Drug Metabolism and Disposition , ( 1991) 19: 722 -724 ) . 50 Briefly , the synthetic procedure involves quaternization of The patient suffers from transient or short- term insomnia . commercial samples of doxepin with methyl( 2 , 3 , 4 -tri - O - At the time of consultation , she also suffers from depression . acetyl- 1 -bromo - 1 - deoxy - a -D - glucopyranosid )urinate , and She is prescribed a mixture of cis - ( Z ) and trans -( E ) isomers subsequent removal of the protecting groups by treatment of doxepin or a doxepin metabolite containing greater than with sodium hydroxide. Thus, to prepare the ( Z ) -isomer of 55 18 . 1 % cis - ( Z ) isomer in a daily dosage of 0 . 0001 milligram , doxepin Nt- glucuronide , ( Z )- doxepin is used as the starting 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 material. To prepare the ( E ) - isomer of doxepin , ( E ) -doxepin milligrams, 20 milligrams or 40 milligrams, taken prior to is used as the starting material. bedtime. Follow up reveals that the administration of the specified isomeric mixture of doxepin relieves the insomnia Example 19 60 and has her sleeping well . The patient suffers from transient or short - term insomnia . Example 24 At the time of consultation , he is otherwise healthy with normal affect with no depression , anxiety or substance The patient suffers from transient or short- term insomnia . overuse. He is prescribed a mixture of cis -( Z ) and trans -( E ) 65 At the time of consultation , she also suffers from depression . isomers of doxepin or a doxepin metabolite containing She is prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers greater than 18 . 1 % cis - ( Z ) isomer in a daily dosage of of doxepin or a doxepin metabolite containing greater than US 9 , 801 ,847 B2 29 30 20 % cis - ( Z ) isomer in a daily dosage of 0 .0001 milligram , than 99. 5 % cis - ( Z ) isomer in a daily dosage of 0 .0001 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 20 milligrams or 40 milligrams, taken prior to milligrams, 10 milligrams, 20 milligrams or 40 milligrams, bedtime. Follow up reveals that the administration of the taken prior to bedtime. Follow up reveals that the adminis specified isomeric mixture of doxepin relieves the insomnia 5 tration of the specified isomeric mixture of doxepin relieves and has her sleeping well . the insomnia and has him sleeping well . Example 25 Example 30 The patient suffers from transient or short - term insomnia . 10 The patient suffers from chronic insomnia . At the time of At the time of consultation , she also suffers from depression . consultation , he is otherwise healthy with normal affect with She is prescribed a mixture of cis -( Z ) and trans -( E ) isomers no depression , anxiety or substance abuse . He is prescribed of doxepin or a doxepin metabolite containing greater than the cis - ( Z ) isomer of doxepin or a doxepin metabolite in a 30 % and less than 99. 5 % cis - ( Z ) isomer in a daily dosage of daily dosage of 0 .0001 milligram , 0 . 1 milligram , 1 milli 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, gram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milli 6 milligrams, 10 milligrams, 20 milligrams or 40 milli grams or 40 milligrams, taken prior to bedtime. Follow up grams, taken prior to bedtime. Follow up reveals that the reveals that the administration of the doxepin isomer administration of the specified isomeric mixture of doxepin relieves the insomnia and has him sleeping well . relieves the insomnia and has her sleeping well . 20 Example 26 Example 31 The patient suffers from transient or short - term insomnia . The patient suffers from chronic insomnia . At the time of At the time of consultation , she also suffers from depression . consultation , she also suffers from depression . She is pre She is prescribed the cis - ( Z ) isomer of doxepin or a doxepinin 25 scribed a mixture of cis - ( Z ) and trans- ( E ) isomers of doxepin metabolite in a daily dosage of 0 .0001 milligram , 0 . 1 or a doxepin metabolite containing greater than 18 . 1 % milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 cis - ( Z ) isomer in a daily dosage of 0 .0001 milligram , 0 . 1 milligrams, 20 milligrams or 40 milligrams, taken prior to milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 bedtime. Follow up reveals that the administration of the milligrams, 20 milligrams or 40 milligrams, taken prior to doxepin isomer relieves the insomnia and has her sleeping 30 bedtime. Follow up reveals that the administration of the well . specified isomeric mixture of doxepin relieves the insomnia and has her sleeping well . Example 27 Example 32 The patient suffers from chronic insomnia . At the time of 35 consultation , he is otherwise healthy with normal affect with The patient suffers from chronic insomnia . At the time of no depression , anxiety or substance abuse . He is prescribed consultation , she also suffers from depression . She is pre a mixture of cis - ( Z ) and trans- ( E ) isomers of doxepin or a scribed a mixture of cis - ( Z ) and trans- ( E ) isomers of doxepin doxepin metabolite containing greater than 18 . 1 % cis - ( Z ) or a doxepin metabolite containing greater than 20 % cis - ( Z ) isomer in a daily dosage of 0 .0001 milligram , 0 .1 milligram , 40 isomer in a daily dosage of 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams , 10 milligrams, 20 1 milligram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime. Follow milligrams or 40 milligrams, taken prior to bedtime. Follow up reveals that the administration of the specified isomeric up reveals that the administration of the specified isomeric mixture of doxepin relieves the insomnia and has him mixture of doxepin relieves the insomnia and has her sleeping well . 45 sleeping well. Example 28 Example 33 The patient suffers from chronic insomnia . At the time of The patient suffers from chronic insomnia . At the time of consultation , he is otherwise healthy with normal affectwith 50 consultation , she also suffers from depression . She is pre no depression , anxiety or substance abuse . He is prescribed scribed a mixture of cis - ( Z ) and trans - ( E ) isomers of doxepin a mixture of cis - ( Z ) and trans - ( E ) isomers of doxepin or a or a doxepin metabolite containing greater than 30 % and doxepin metabolite containing greater than 20 % cis - ( Z ) less than 99 . 5 % cis - ( Z ) isomer in a daily dosage of 0 . 0001 isomer in a daily dosage of 0 . 0001 milligram , 0 . 1 milligram , milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 1 milligram , 3 milligrams , 6 milligrams, 10 milligrams, 20 55 milligrams, 10 milligrams, 20 milligrams or 40 milligrams, milligrams or 40 milligrams, taken prior to bedtime. Follow taken prior to bedtime. Follow up reveals that the adminis up reveals that the administration of the specified isomeric tration of the specified isomeric mixture of doxepin relieves mixture of doxepin relieves the insomnia and has him the insomnia and has her sleeping well . sleeping well . 60 Example 34 Example 29 The patient suffers from chronic insomnia . At the time of The patient suffers from chronic insomnia . At the time of consultation , she also suffers from depression . She is pre consultation , he is otherwise healthy with normal affect with scribed the cis - ( Z ) isomer of doxepin or a doxepin metabo no depression , anxiety or substance abuse . He is prescribed 65 lite in a daily dosage of 0 .0001 milligram , 0 .1 milligram , 1 a mixture of cis - ( Z ) and trans - ( E ) isomers of doxepin or a milligram , 3 milligrams, 6 milligrams, 10 milligrams, 20 doxepin metabolite containing greater than 30 % and less milligrams or 40 milligrams, taken prior to bedtime. Follow US 9 ,801 , 847 B2 31 32 up reveals that the administration of the doxepin isomer 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, relieves the insomnia and has her sleeping well . 6 milligrams, 10 milligrams, 20 milligrams or 40 milli grams, taken prior to bedtime. Follow up reveals that the Example 35 administration of the specified isomeric mixture of doxepin 5 relieves the insomnia and has him sleeping well . The patient suffers from maintenance (non -chronic ) insomnia . At the time of consultation , he is otherwise Example 40 healthy with normal affect with no depression , anxiety or substance overuse . He is prescribed a mixture of cis -( Z ) and The patient suffers from maintenance ( chronic ) insomnia . trans- ( E ) isomers of doxepin or a doxepin metabolite con - 10 At the time of consultation , he is otherwise healthy with taining greater than 18 . 1 % cis -( Z ) isomer in a daily dosage normal affect with no depression , anxiety or substance of 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milli abuse . He is prescribed a mixture of cis -( Z ) and trans -( E ) grams, 6 milligrams, 10 milligrams , 20 milligrams or 40 isomers of doxepin or a doxepin metabolite containing milligrams, taken prior to bedtime. Follow up reveals that greater than 90 % trans- ( E ) isomer in a daily dosage of the administration of the specified isomeric mixture of 13 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, doxepin relieves the insomnia and has him sleeping well . 6 milligrams, 10 milligrams, 20 milligrams or 40 milli grams, taken prior to bedtime . Follow up reveals that the Example 36 administration of the specified isomeric mixture of doxepin relieves the insomnia and has him sleeping well . The patient suffers from maintenance (non - chronic ) 20 insomnia . At the time of consultation , he is otherwise Example 41 healthy with normal affect with no depression , anxiety or substance overuse . He is prescribed a mixture of cis - ( Z ) and The patient suffers from maintenance ( chronic ) insomnia . trans - ( E ) isomers of doxepin or a doxepin metabolite con - At the time of consultation , he is otherwise healthy with taining greater than 20 % cis -( Z ) isomer in a daily dosage of 25 normal affect with no depression , anxiety or substance 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, abuse . He is prescribed a mixture of cis - ( Z ) and trans - ( E ) 6 milligrams, 10 milligrams, 20 milligrams or 40 milli isomers of doxepin or a doxepin metabolite containing grams, taken prior to bedtime. Follow up reveals that the greater than 90 % and less than 99. 5 % trans- ( E ) isomer in a administration of the specified isomeric mixture of doxepin daily dosage of 0 .0001 milligram , 0 . 1 milligram , 1 milli relieves the insomnia and has him sleeping well. gram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milli grams or 40 milligrams, taken prior to bedtime. Follow up Example 37 reveals that the administration of the specified isomeric mixture of doxepin relieves the insomnia and has him The patient suffers from maintenance (non -chronic ) sleeping well . insomnia . At the time of consultation , he is otherwise 35 healthy with normal affect with no depression , anxiety or Example 42 substance overuse . He is prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of doxepin or a doxepin metabolite con The patient suffers from maintenance ( chronic ) insomnia . taining greater than 30 % and less than 99. 5 % cis -( Z ) isomer At the time of consultation , he is otherwise healthy with in a daily dosage of 0 . 0001 milligram , 0 . 1 milligram , 1 40 normal affect with no depression , anxiety or substance milligram , 3 milligrams, 6 milligrams, 10 milligrams, 20 abuse . He is prescribed the trans -( E ) isomer of doxepin or a milligrams or 40 milligrams, taken prior to bedtime. Follow doxepin metabolite in a daily dosage of 0 . 0001 milligram , up reveals that the administration of the specified isomeric 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 mixture of doxepin relieves the insomnia and has him milligrams, 20 milligrams or 40 milligrams, taken prior to sleeping well . 45 bedtime . Follow up reveals that the administration of the doxepin isomer relieves the insomnia and has him sleeping Example 38 well. The patient suffers from maintenance (non -chronic ) Example 43 insomnia . At the time of consultation , he is otherwise 50 healthy with normal affect with no depression , anxiety or The patient suffers from onset ( non - chronic ) insomnia . At substance overuse. He is prescribed the cis - (Z ) isomer of the time of consultation , she is otherwise healthy with doxepin or a doxepin metabolite in a daily dosage of 0 . 0001 normal affect with no depression , anxiety or substance milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 abuse . She is prescribed a mixture of cis - ( Z ) and trans - ( E ) milligrams, 10 milligrams, 20 milligrams or 40 milligrams, 55 isomers of doxepin or a doxepin metabolite containing taken prior to bedtime. Follow up reveals that the adminis greater than 18 . 1 % cis - ( Z ) isomer in a daily dosage of tration of the doxepin isomer relieves the insomnia and has 0 .0001 milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, him sleeping well . 6 milligrams, 10 milligrams, 20 milligrams or 40 milli grams, taken prior to bedtime. Follow up reveals that the Example 39 60 administration of the specified isomeric mixture of doxepin relieves the insomnia and has her sleeping well . The patient suffers from maintenance ( chronic ) insomnia . At the time of consultation , he is otherwise healthy with Example 44 normal affect with no depression , anxiety or substance abuse. He is prescribed a mixture of cis - ( Z ) and trans- ( E ) 65 The patient suffers from onset (non - chronic ) insomnia . At isomers of doxepin or a doxepin metabolite containing the time of consultation , she is otherwise healthy with greater than 88 .2 % trans- ( E ) isomer in a daily dosage of normal affect with no depression , anxiety or substance US 9 ,801 , 847 B2 33 34 abuse . She is prescribed a mixture of cis -( Z ) and trans- ( E ) affect with no depression , anxiety or substance abuse . She is isomers of doxepin or a doxepin metabolite containing prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of greater than 20 % cis - ( Z ) isomer in a daily dosage of 0 .0001 doxepin or a doxepin metabolite containing greater than milligram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 90 % and less than 99. 5 % trans - ( E ) isomer in a daily dosage milligrams, 10 milligrams, 20 milligrams or 40 milligrams, 5 of 0 . 0001 milligram . 0 . 1 milligram . 1 milligram . 3 milli taken prior to bedtime. Follow up reveals that the adminis tration of the specified isomeric mixture of doxepin relieves grams, 6 milligrams, 10 milligrams, 20 milligrams or 40 the insomnia and has her sleeping well . milligrams, taken prior to bedtime. Follow up reveals that the administration of the specified isomeric mixture of doxepin relieves the insomnia and has her sleeping well. Example 45 10 The patient suffers from onset (non - chronic ) insomnia . At Example 50 the time of consultation , she is otherwise healthy with normal affect with no depression , anxiety or substance The patient suffers from onset (chronic ) insomnia . At the abuse . She is prescribed a mixture of cis - ( Z ) and trans - ( E ) time of consultation , she is otherwise healthy with normal isomers of doxepin or a doxepin metabolite containing 15 affect with no depression , anxiety or substance abuse . She is greater than 30 % and less than 99 . 5 % cis - ( Z ) isomer in a prescribed the trans- ( E ) isomer of doxepin or a doxepin daily dosage of 0 .0001 milligram , 0 .1 milligram , 1 milli metabolite in a daily dosage of 0 .0001 milligram , 0 . 1 gram , 3 milligrams, 6 milligrams, 10 milligrams, 20 milli milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 grams or 40 milligrams, taken prior to bedtime. Follow up milligrams, 20 milligrams or 40 milligrams, taken prior to reveals that the administration of the specified isomeric 20 bedtimeh . Follow up reveals that the administration of the mixture of doxepin relieves the insomnia and has her doxepin isomer relieves the insomnia and has her sleeping sleeping well . well . Example 46 Example 51 The patient suffers from onset ( non - chronic ) insomnia . At 25 the time of consultation , she is otherwise healthy with The patient suffers from a sleep disorder. The patient is normal affect with no depression , anxiety or substance prescribed a mixture of cis - ( Z ) and trans -( E ) isomers of a abuse . She is prescribed the cis - ( Z ) isomer of doxepin or a pharmaceutically -acceptable salt of doxepin or a doxepin doxepin metabolite in a daily dosage of 0 .0001 milligram , metabolite containing greater than 18 . 1 % cis - ( Z ) isomer in 0 .1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 30 a daily dosage of 1 milligram , 2 milligrams, 3 milligrams, 6 milligrams, 20 milligrams or 40 milligrams, taken prior to milligrams, 10 milligrams, 20 milligrams or 40 milligrams, bedtime. Follow up reveals that the administration of the taken prior to bedtime. Follow up reveals that the adminis doxepin isomer relieves the insomnia and has her sleeping tration of the specified isomeric mixture of the doxepin salt well . relieves the insomnia and has him sleeping well . 35 Example 47 Example 52 The patient suffers from onset (chronic ) insomnia . At the The patient suffers from a sleep disorder . The patient is time of consultation , she is otherwise healthy with normal prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of a affect with no depression , anxiety or substance abuse . She is 40 pharmaceutically -acceptable salt of doxepin or a doxepin prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of metabolite containing greater than 20 % cis - ( Z ) isomer in a doxepin or a doxepin metabolite containing greater than daily dosage of 1 milligram , 2 milligrams, 3 milligrams, 6 88 . 2 % trans -( E ) isomer in a daily dosage of 0 .0001 milli - milligrams, 10 milligrams, 20 milligrams or 40 milligrams, gram , 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milli - taken prior to bedtime. Follow up reveals that the adminis grams, 10 milligrams, 20 milligrams or 40 milligrams, taken 45 tration of the specified isomeric mixture of the doxepin salt prior to bedtime. Follow up reveals that the administration relieves the insomnia and has him sleeping well . of the specified isomeric mixture of doxepin relieves the insomnia and has her sleeping well . Example 53 Example 48 50 The patient suffers from a sleep disorder. The patient is prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of a The patient suffers from onset ( chronic ) insomnia . At the pharmaceutically -acceptable salt of doxepin or a doxepin time of consultation , she is otherwise healthy with normal metabolite containing greater than 30 % and less than 99 . 5 % affect with no depression , anxiety or substance abuse . She is cis - (Z ) isomer in a daily dosage of 1 milligram , 2 milli prescribed a mixture of cis -( Z ) and trans- ( E ) isomers of 55 grams, 3 milligrams, 5 milligrams, 6 milligrams , 10 milli doxepin or a doxepin metabolite containing greater than grams, 20 milligrams or 40 milligrams, taken prior to 90 % trans - ( E ) isomer in a daily dosage of 0 . 0001 milligram , bedtime. Follow up reveals that the administration of the 0 . 1 milligram , 1 milligram , 3 milligrams, 6 milligrams, 10 specified isomeric mixture of the doxepin salt relieves the milligrams, 20 milligrams or 40 milligrams, taken prior to insomnia and has him sleeping well . bedtime. Follow up reveals that the administration of the 60 specified isomeric mixture of doxepin relieves the insomnia Example 54 and has her sleeping well. The patient suffers from a sleep disorder . The patient is Example 49 prescribed the cis -( Z ) isomer of a pharmaceutically -accept 65 able salt of doxepin or a doxepin metabolite in a daily The patient suffers from onset (chronic ) insomnia . At the dosage of 1 milligram , 2 milligrams, 3 milligrams, 5 milli time of consultation , she is otherwise healthy with normal grams, 6 milligrams, 10 milligrams, 20 milligrams or 40 US 9 , 801, 847 B2 35 36 milligrams, taken prior to bedtime. Follow up reveals that the final 60 minutes of said period , wherein the dosage the administration of the isomer of the doxepin salt relieves of doxepin or salt thereof is between about 0 . 1 and the insomnia and has him sleeping well . about 6 mg, wherein the doxepin or salt thereof is a geometric isomer mixture containing about 18 . 2 % to Example 55 about 100 . 0 % of the cis - ( Z ) isomer or is 100 % cis - ( Z ) isomer , and wherein the dosage is administered prior to The patient suffers from a sleep disorder . The patient is the start of the sleep period . prescribed a mixture of cis - ( Z ) and trans- ( E ) isomers of a 2 . The method of claim 1, wherein said geometric isomer prodrug of doxepin or a doxepin metabolite containing mixture contains more than 20 % of the cis - ( Z ) isomer. greater than 18 . 1 % cis - ( Z ) isomer in a daily dosage of 1 10 3 . The method of claim 1, wherein said geometric isomer milligram , 2 milligrams, 3 milligrams, 5 milligramsmilligrams, 6 mixture contains more than 50 % of the cis - ( Z ) isomer. milligrams, 10 milligrams, 20 milligrams or 40 milligrams, 4 . The method of claim 1 , wherein said geometric isomer taken prior to bedtime. Follow up reveals that the adminis mixture contains more than 90 % of the cis - ( Z ) isomer. tration of the specified isomeric mixture of the doxepin 5 . The method of claim 1 , wherein said geometric isomer he insomnia and has him sleeping well. 15 mixture contains more than 95 % of the cis - ( Z ) isomer . prodrug relieves the insomnia and has him sleeping well. 15 mix6 . The method of claim 1 , wherein said geometric isomer Example 56 mixture contains about 20 % to about 99 . 9 % of the cis - ( Z ) isomer . The patient suffers from a sleep disorder . The patient is 7 . The method of claim 1, wherein the dosage is about 1 prescribed a mixture of cis - ( Z ) and trans - ( E ) isomers of a to about 6 milligrams. prodrug salt of doxepin or a doxepin metabolite containing 8 . The method of claim 1 , wherein the dosage is about 1 greater than 20 % cis - ( Z ) isomer in a daily dosage of 1 milligram . milligram , 2 milligrams, 3 milligrams, 5 milligrams, 6 9 . The method of claim 1 , wherein the dosage is about 3 milligrams, 10 milligrams, 20 milligrams or 40 milligrams, milligrams. taken prior to bedtime. Follow up reveals that the adminis - 35 10 . The method of claim 1 , wherein the dosage is about tration of the specified isomeric mixture of the doxepin 6 milligrams. prodrug relieves the insomnia and has him sleeping well . 11 . A method for treating sleep maintenance insomnia characterized by early awakenings during the gth hour of Example 57 sleep , the method comprising : administering a dosage of doxepin or a pharmaceutically 30 The patient suffers from a sleep disorder. The patientllent ieis acceptable salt thereof to a patient having a sleep prescribed a mixture of cis -( Z ) and trans- (E ) isomers of a disorder in which , for a given 8 hour period of desired prodrug of doxepin or a doxepin metabolite containing sleep , the patient experiences early awakenings during greater than 30 % and less than 99. 5 % cis - ( Z ) isomer in a the final 60 minutes of said period , wherein the dosage daily dosage of 1 milligram , 2 milligrams, 3 milligrams, 5 35 of doxepin or salt thereof is between about 0 . 1 and milligrams, 6 milligrams, 10 milligrams , 20 milligrams or about 6 mg, wherein the doxepin or salt thereof is a 40 milligrams, taken prior to bedtime. Follow up reveals that geometric isomer mixture containing about 18 . 2 % to the administration of the specified isomeric mixture of the about 100 . 0 % of the cis - ( Z ) isomer or is 100 % cis - ( Z ) doxepin prodrug relieves the insomnia and has him sleeping isomer, and wherein the dosage is administered prior to well . the start of the sleep period . 4040 12 . The method of claim 11 , wherein said geometric Example 58 isomer mixture contains more than 20 % of the cis - ( Z ) isomer . The patient suffers from a sleep disorder . The patient is 13 . The method of claim 11, wherein said geometric prescribed the cis -( Z ) isomer of a prodrug of doxepin or a 10 isomer mixture contains more than 50 % of the cis - ( Z ) doxepin metabolite in a daily dosage of 1 milligram , 2 isomer . milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10 1 4 . The method of claim 11 , wherein said geometric milligrams, 20 milligrams or 40 milligrams, taken prior to isomer mixture contains more than 90 % of the cis - ( Z ) bedtime. Follow up reveals that the administration of the isomer. isomer of the doxepin prodrug relieves the insomnia and has s 15 . The method of claim 11, wherein said geometric him sleeping well . isomer mixture contains more than 95 % of the cis -( Z ) Many modifications and variations of the embodiments isomer. described herein may be made without departing from the 16 . The method of claim 11, wherein said geometric scope , as is apparent to those skilled in the art . The specific isomer mixture contains about 20 % to about 99 . 9 % of the embodiments described herein are offered by way of se cis - ( Z ) isomer. example only . 17 . The method of claim 11 , wherein the dosage is about What is claimed is : 1 to about 6 milligrams. 1 . A method for treating sleep maintenance insomnia 18 . The method of claim 11 , wherein the dosage is about characterized by fragmented sleep during the gth hour of 1 milligram . sleep , the method comprising : 19 . The method of claim 11 , wherein the dosage is about administering a dosage of doxepin or a pharmaceutically 3 milligrams. acceptable salt thereof to a patient having a sleep 20 . The method of claim 11 , wherein the dosage is about disorder in which , for a given 8 hour period of desired 6 milligrams. sleep , the patient experiences fragmented sleep during * * * * *