Method of using low-dose doxepin for improvement of sleep

Field of invention The present invention relates to the use of low dose doxepin (eg, 1-6 milligrams) to improve sleep, including sleep efficiency and early awakening in individuals.

Background of the invention Sleep is essential for good health and quality of life. Insomnia is an increasing health problem in the United States. It is estimated that more than 10 to 15 million people suffer from chronic insomnia, and 70 million more each year suffer from some form of insomnia. Insomnia is characterized by difficulty falling asleep (sleeping), often waking up at night (divided sleep), waking up too early (early final awakening), and / or feeling unhealthy when waking up. It is in a state. At the National Sleep Foundation (NSF) Sleep in America Poll 2005, 42% of survey respondents reported that they often woke up at night, and 22% of adults reported that they woke up too early to fall asleep again.38 % Reported that they woke up and felt they were not recovering.

Difficulty in maintaining sleep is the most commonly reported symptom in primary care patients with chronic insomnia and is the most common complaint in depressed patients, medically ill populations, especially those with pain symptoms, and the elderly.

Drugs commonly used to treat sleep disorders such as insomnia include sedative antidepressants, antihistamines, benzodiazepines, and non-benzodiazepine hypnotics.

Although some advances have been made in drug treatment for insomnia, it is often difficult to find the ideal drug to treat a particular type of insomnia. One common problem is early arrest of sleep or early final awakening. For example, many individuals may wake up early and fall asleep again, thereby failing to achieve overnight sleep. Many drugs that are effective in inducing or promoting sleep are less effective, especially in maintaining sleep from the 8th hour to the last hour of sleep. Drugs that are strong enough to induce a full eight hours of sleep often cause serious aftereffects: the patient has difficulty awakening and / or feels sedated, lethargic, or disorientated and mental. It may also indicate impaired motor function.

In addition to patients who have difficulty with premature sleep arrest during the last 60, 90, or 120 minutes of the 8-hour sleep period, some patients have problems with fragmented or interrupted sleep. That is, during that period the patient awakens once or multiple times and then falls asleep again. Such fragmented sleep patterns impair the sense of rest and prevent the patient from enjoying a good night's sleep.

Both patient groups will benefit significantly from drugs that address that particular sleep deprivation.

Doxepin is a tricyclic antidepressant known to have beneficial effects in the treatment of insomnia. See, for example, US Pat. Nos. 5,502,047 (Patent Document 1) and 6,211,229 (Patent Document 2). However, prior to the present invention, doxepin was not known to have specific efficacy in treating premature sleep arrest at the end of the 8-hour sleep period, and at the end of the 8-hour sleep period. It was also not known to be effective in treating patients with sleep-disturbing patterns between 60, 90, or 120 minutes. The average half-life of doxepin is 17 hours, and its major active metabolite, desmethyldoxepin, has a half-life of 51 hours. Therefore, when taken at the beginning of the sleep cycle, most of the drug or active metabolite will still remain in the body at the end of the sleep cycle. As a result, a dose of doxepin sufficient to address the early final arousal or sleep efficiency of the last hour in the elderly will also cause post-sleep sedation or other unwanted side effects.

The present invention describes the amazing ability of doxepin to treat sleep efficiency and early final arousal in a patient for the last hour without adverse side effects.

<p><patcit num="1"><text>U.S. Pat. No. 5,502,047</text></patcit><patcit num="2"><text>U.S. Pat. No. 6,211,229</text></patcit></p>

Some aspects provide a method of reducing or preventing premature arousal in patients in need of it. In some embodiments, the method identifies a patient with a sleep disorder who experiences a sleep period that ends during the last 60 minutes of that period during a given 8-hour period of desired sleep. Stages; and to the patient, doxepin, its pharmaceutically acceptable salt, or a prodrug thereof, may be effective in prolonging the sleep period, from 1 mg (mg) to 6 mg. Includes the step of administering at a dose between. In some aspects of the embodiment, the patient can be identified as experiencing a sleep period ending during the last 45 minutes of that period. In some aspects of the embodiment, the patient can be identified as experiencing a sleep period ending during the last 30 minutes of that period. In some embodiments, the sleep period can be extended to end during or after the 7th hour of that period. In some embodiments, the sleep period can be extended to end during or after the 7.5th hour of that period. In some aspects, the patient can be further identified as needing to reduce post-sleep awakening time. In another embodiment, the patient suffers from chronic or non-chronic insomnia. In yet another embodiment, the patient suffers from transient insomnia.

Some embodiments provide a method of reducing fragmented sleep at the 8th hour of the patient's sleep period. In some embodiments, the method identifies a patient suffering from fragmented sleep during the 8th hour of sleep; and gives the patient doxepin, its pharmaceutically acceptable salt, or a prodrug. Includes the step of administering at a dose between about 1 mg and 6 mg. In some embodiments, the dose of doxepin is, for example, about 1 mg, 3 mg or 6 mg. Therefore, in one aspect, the dose of doxepin can be about 1 mg. In one aspect, the dose of doxepin can be about 3 mg. In one aspect, the dose of doxepin can be about 6 mg. In another embodiment, the patient suffers from chronic or non-chronic insomnia. In yet another embodiment, the patient suffers from transient insomnia.

Some embodiments are treatments for sleep disorders, including sleep deprivation associated with one or more of LPS, WASO, TST, TWT, SE, latency to second stage sleep, WTDS, or WTAS. Including the step of identifying a patient suffering from transient insomnia; and the step of administering to that patient doxepin, its pharmaceutically acceptable salt, or prodrug at a dose between about 0.5 mg and 6 mg. Provide a method to include. In one embodiment, the dose of doxepin is about 1 mg, 3 mg or 6 mg. In other embodiments, the dose of doxepin is about 0.5 mg, 1 mg, 3 mg or 6 mg.

Some embodiments reduce premature arousal in patients with sleep disorders who experience a sleep period that ends during the last 60 minutes of that period during a given 8 hours of desired sleep. Or to provide the use of doxepin, a pharmaceutically acceptable salt thereof, or a prodrug thereof in a dose between 0.5 mg and 6 mg in the preparation or manufacture of a drug for use in preventing. In certain embodiments, the patient experiences a sleep period that ends during the last 45 minutes or the last 30 minutes of that period, and the sleep period ends during or after the 7th or 7.5th hour of that period. Is extended as

In some embodiments, doxepin, a pharmaceutically acceptable salt thereof, in the preparation or manufacture of a drug for use in treating a patient suffering from disrupted sleep during the 8th hour of the sleep period. Alternatively, use of the prodrug at a dose between about 0.5 mg and 6 mg is provided. In one embodiment, the dose of doxepin is about 1 mg, 3 mg or 6 mg. In certain embodiments, the dose of doxepin is approximately 0.5 mg, 1 mg, 3 mg or 6 mg. [Claim 1001] A method of reducing or preventing premature arousal in patients in need, including the following steps: The stage of identifying a patient with a sleep disorder, in which during a given 8-hour period of desired sleep, the patient experiences a sleep period that ends during the last 60 minutes of that period; and Prior to the sleep period, the patient is administered doxepin, a pharmaceutically acceptable salt thereof, or a prodrug thereof at a dose between 0.5 mg and 6 mg effective for prolonging the sleep period. [Claim 1002] The method of claim 1001, wherein the patient is identified as experiencing a sleep period ending during the last 45 minutes of the period. [Claim 1003] The method of claim 1001, wherein the patient is identified as experiencing a sleep period ending during the last 30 minutes of the period. [Claim 1004] The method of claim 1001, wherein the sleep period is extended to end during or after the 7th hour of the period. [Claim 1005] The method of claim 1001, wherein the sleep period is extended to end during or after the 7.5th hour of the period. [Claim 1006] The method of claim 1001, wherein the patient is further identified as needing to reduce post-sleep awakening time. [Claim 1007] The method of claim 1001, wherein the patient suffers from chronic or non-chronic insomnia. [Claim 1008] The method of claim 1007, wherein the patient suffers from transient insomnia. [Claim 1009] A method of reducing fragmented sleep at the 8th hour of a patient's sleep period, including the following steps: The stage of identifying patients with fragmented sleep during the 8th hour of sleep; and The step of administering to said patient doxepin, a pharmaceutically acceptable salt thereof, or a prodrug at a dose between about 0.5 mg and 6 mg. [Claim 1010] The method of claim 1009, wherein the dose of doxepin is about 1 mg, 3 mg or 6 mg. [Claim 1011] The method of claim 1010, wherein the dose of doxepin is about 0.5 mg. [Claim 1012] The method of claim 1010, wherein the dose of doxepin is about 1 mg. [Claim 1013] The method of claim 1010, wherein the dose of doxepin is about 3 mg. [Claim 1014] The method of claim 1010, wherein the dose of doxepin is about 6 mg. [Claim 1015] The method of claim 1009, wherein the patient suffers from chronic or non-chronic insomnia. [Claim 1016] The method of claim 1015, wherein the patient suffers from transient insomnia. [Claim 1017] A treatment for sleep disorders that includes the following steps: Patients with transient insomnia, including sleep deprivation associated with one or more of LPS, WASO, TST, TWT, SE, second-stage sleep latency, WTDS, or WTAS Stage to identify; and The step of administering to said patient doxepin, a pharmaceutically acceptable salt thereof, or a prodrug at a dose between about 0.5 mg and 6 mg, or at a dose that achieves the target plasma concentration characteristics by any suitable route of administration. .. [Claim 1018] The method of claim 1017, wherein the dose of doxepin is about 1 mg, 3 mg or 6 mg. [Claim 1019] The method of claim 1017, wherein the dose of doxepin is about 0.5 mg. [Claim 1020] The method of claim 1017, wherein the dose of doxepin is about 1 mg. [Claim 1021] The method of claim 1017, wherein the dose of doxepin is about 3 mg. [Claim 1022] The method of claim 1017, wherein the dose of doxepin is about 6 mg. [Claim 1023] In reducing or preventing premature arousal in patients with sleep disorders who experience a sleep period ending during the last 60 minutes of the period during a given 8 hour period of desired sleep. Use in doses between 0.5 mg and 6 mg of doxepin, its pharmaceutically acceptable salt, or its prodrug in the preparation of drugs for use in. [Claim 1024] The use according to claim 1023, wherein the patient experiences a sleep period ending during the last 45 minutes of the period. [Claim 1025] The use according to claim 1023, wherein the patient experiences a sleep period ending during the last 30 minutes of the period. [Claim 1026] The use of claim 1023, wherein the sleep period is extended to end during or after the 7th hour of the period. [Claim 1027] The use of claim 1023, wherein the sleep period is extended to end during or after the 7.5th hour of the period. [Claim 1028] Between about 0.5 mg and 6 mg of doxepin, its pharmaceutically acceptable salt, or its prodrug in the preparation of drugs for use in treating fragmented sleep during the 8th hour of the sleep period. Use at dose. [Claim 1029] The use according to claim 1028, wherein the dose of doxepin is about 1 mg, 3 mg or 6 mg. [Claim 1030] The use according to claim 1028, wherein the dose of doxepin is about 0.5 mg. [Claim 1031] The use according to claim 1029, wherein the dose of doxepin is about 1 mg. [Claim 1032] The use according to claim 1029, wherein the dose of doxepin is about 3 mg. [Claim 1033] The use according to claim 1029, wherein the dose of doxepin is about 6 mg.

<figref num="1">It is a figure which illustrates the different parameters which can be analyzed using a polysomnography.</figref><figref num="2">It is a graph which shows the plasma profile concentration of doxepin at various time points for 1mg, 3mg and 6mg doxepin.</figref><figref num="3">Graphs showing hourly sleep efficiency (SE) at night in the elderly after treatment with 1 mg, 3 mg and 6 mg doxepin (protocol-compliant population data).</figref><figref num="4">It is a graph which shows the SE every hour at night in the adult (18-64 years old) treated with 1 mg, 3 mg or 6 mg doxepin.</figref><figref num="5">FIG. 5 is a graph showing hourly SE at night in adults treated with placebo, 3 mg doxepin or 6 mg doxepin.</figref><figref num="6">It is a graph which shows the SE by the hour of the night of the 1st night, the 15th night and the 29th night in an adult treated with 3 mg doxepin or 6 mg doxepin.</figref><figref num="7">A graph showing the hourly SE of the first night: ITT analysis population.</figref><figref num="8">It is a graph which shows the SE every hour at night in the adult of transient insomnia treated with 6 mg doxepin.</figref>

Detailed description of the invention Currently, many individuals suffer from sleep disorders such as insomnia. Some of these individuals with insomnia have a short total sleep period due to early final awakening. Similarly, some of these individuals suffer from temporary arousal, especially during the last 1-2 hours of their sleep period. Early final awakenings and temporary awakenings in the last hours of sleep can cause an individual to become tired, unable to rejuvenate, and reduce their overall health and productivity. Therefore, there is a need for methods of treating such individuals in order to improve sleep efficiency and total sleep time.

The present invention relates to the use of doxepin, eg, low dose doxepin, to improve sleep in such individuals. Some aspects relate to the use of doxepin to prevent or reduce an individual's early final arousal. Similarly, some embodiments relate to reducing the temporary arousal of an individual's last hour of sleep, preferably the last hour of sleep.

As mentioned above, various drugs are currently approved for the treatment of sleep disorders such as insomnia. Many of the licensed drugs have unfavorable side effects. In addition, previously approved drugs do not effectively control the sleep experience of individuals taking the drug. For example, licensed drugs do not improve a patient's fragmented sleep during the last hours of sleep, especially during the last hour of the sleep period. Moreover, as an example, many already approved drugs do not reduce or prevent the early final arousal of an individual taking the drug. Simply put, currently approved drugs do not completely improve a patient's sleep experience during the last hours of sleep.

Doxepin HCl is a currently approved tricyclic compound for the treatment of depression. The recommended daily dose for the treatment of depression ranges from 75 mg to 300 mg. Doxepin, unlike most FDA-approved formulations for the treatment of insomnia, is not a Grade IV regulated substance. U.S. Pat. Nos. 5,502,047 and 6,211,229 are incorporated herein by reference in their entirety, but doxepin's depression for the treatment of chronic and non-chronic (eg, transient / short-term) insomnia. It describes use at much lower doses than those used for treatment.

Some aspects of the invention are the ability of low-dose doxepin, a pharmaceutically acceptable salt or prodrug thereof, to prevent early or early final arousal and / or to improve disrupted sleep. With respect to, this identifies an individual in need of such treatment and provides the individual with a low dose of doxepin, its pharmaceutically acceptable salt, or its prodrug, for 7 hours of an 8-hour sleep period. It can be assessed by a decrease in sleep efficiency (SE) at the eye and at 8 hours.

<u style="single">Definition</u> As used herein, the term "polysomnography" (PSG) refers to a diagnostic test that measures and records several physiological variables during sleep. Physiological sensor leads to record brain electrical activity, eye and jaw muscle movements, leg muscle movements, airflow, respiratory effort (chest and abdominal range of motion), EKG and oxygen saturation Install on the patient. It collects information from all leads, sends it to a computer, and outputs it as a series of waveform records, which allows technicians to visualize various waveforms, assign test scores, and assist in the diagnostic process. The primary efficacy variable, sleep awakening time (WTDS) and various secondary efficacy variables are all based on PSG and are defined as follows:

"Awakening time during sleep" (WTDS), typically expressed in minutes, is the number of arousal events (epochs) from the onset of sustained sleep to the final awakening divided by two. Each epoch is defined as 30 seconds on the PSG record.

"Post-sleep awakening time" (WTAS) is typically expressed in minutes, which is the number of epochs from the last awakening to the end of PSG recording (ie, the awakening epoch just before the end of recording) divided by two. It is a thing. WTAS is zero if the patient does not have an arousal epoch just prior to the end of recording.

"Awakening after falling asleep" (WASO) is the sum of WTDS and WTAS.

"Epoch to persistent sleep" (LPS) is typically expressed in minutes and is the number of epochs from the start of PSG recording (off) to the first 20 consecutive unawakening epochs divided by two. Is.

"Total sleep time" (TST), typically expressed in minutes, is the number of unawakened epochs from the start of PSG recording to the end of recording divided by two.

"Sleep efficiency" (SE) is TST divided by the time in bed (8 hours) and multiplied by 100, expressed as a percentage. This can also be divided into SEs for each sleep in one-third of the night, representing SEs at 160-minute intervals each night. Finally, the SE can be evaluated for individual times during the night or sleep period, eg, the last hour of the sleep period.

The term "divided sleep" can mean sleep interrupted during a measurement period or sleep period, eg, the time the patient is awake during the measurement period. Division can occur as a result of multiple awakenings or one or more long-term awakenings.

The term "prodrug" means a drug that is converted to an active drug in vivo. Prodrugs are often useful because they can be easier to administer than active drugs in some situations. For example, prodrugs may be bioavailable by oral administration, but active drugs are not. Prodrugs may have better solubility in pharmaceutical compositions than active drugs. Examples of prodrugs, but not limited to, are administered as esters (prodrugs) to facilitate migration across cell membranes when water solubility is detrimental to migration. Then, once inside the cell where water solubility is beneficial, it is hydrolyzed to the active substance carboxylic acid by metabolism, which is the compound of the present invention. A further example of a prodrug could be a short chain peptide (polyamino acid) attached to an acid group, where the peptide is metabolized to reveal the active moiety.

The term "pharmaceutically acceptable salt" means an ionic form of a compound that does not significantly irritate the administered organism and does not suppress the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds of the present invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Can be done. Pharmaceutical salts are prepared by reacting the compounds of the present invention with bases; ammonium salts; alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; dicyclohexylamine, N-methyl-D- It can also be obtained by producing salts of organic bases such as glutamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine and lysine.

The term "low dose" can mean a daily dose range between about 0.5 and 6 mg. In some embodiments, the daily dose of low dose doxepin can be about 1, 2, 3, 4, 5 or 6 mg. These doses have reduced side effects, are surprisingly effective, and are relatively rapid onset. In one embodiment, an initial daily dose of about 1 mg can be administered. If the desired improvement in sleep is not achieved, the dose may be gradually increased until the desired dose is achieved or the maximum desired dose is reached, for example 2 mg, 3 mg, 4 mg, 5 mg or It can be 6 mg. It should be noted that other doses of doxepin may be used in the embodiments described herein. For example, the dose can be from about 0.5 to about 10 mg.

<u style="single">Compound</u>Doxepin: Doxepin HCl is a currently approved and available tricyclic compound for the treatment of depression and anxiety. Doxepin has the following structure.<img file="JP2013237694A_D0001.tif" />

Unless otherwise stated, all compounds disclosed herein include both cis and trans stereoisomers, as well as mixtures thereof, where carbon-carbon double bonds are indicated.

Doxepin belongs to the class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds and is currently approved and prescribed for use as an antidepressant for the treatment of depression and anxiety. Doxepin has well-established safety properties and has been prescribed for over 35 years.

Doxepin, unlike most FDA-approved formulations for the treatment of insomnia, is not a Class 4 regulated substance. U.S. Pat. Nos. 5,502,047 and 6,211,229 are incorporated herein by reference in their entirety, but doxepin's depression for the treatment of chronic and non-chronic (eg, transient / short-term) insomnia. It describes use at much lower doses than those used for treatment.

It is contemplated that doxepin for use in the methods described herein can be obtained from any suitable source or prepared by any suitable method. As mentioned above, doxepin is approved and available in high doses (75-300 milligrams) for the treatment of depression and anxiety. Doxepin HCl is commercially available and may be obtained in capsule form from several sources. Doxepin is marketed under the trade name and generic form of SINEQUAN® and is commonly available in the United States in capsules at 10, 25, 50, 75, 100 and 150 mg doses, as well as in 10 mg / mL concentrates from pharmacies. can do. Doxepin HCl is Plantex Ltd. Chemical Industries (Hakadar Street, Industrial Zone, PO Box 160, Netanya 42101, Israel), Sifavitor SpA (Via Livelli 1 --Frazione, Mairano, Italy), or Dipharma SpA It is available from (20021 Baranzate di Bollate, Milano, Italy). Similarly, doxepin is PharmacyRx (NZ) (2820 1)^st Avenue, Castlegar, BC, Canada) also market in capsules in doses of 10, 25, 50, 75, 100 and 150 mg. In addition, doxepin HCl is available from the CVS Online Pharmacy Store (CVS.com) in capsules in amounts of 10, 25, 50, 75, 100 and 150 mg, and in 10 mg / ml concentrates.

Doxepin can also be prepared according to the method described in US Pat. No. 3,438,981, and this disclosure is incorporated herein by reference in its entirety. Many of the embodiments described herein specifically refer to "doxepin," such as pharmaceutically acceptable salts, prodrugs, metabolites, doxepin insitu salts produced after administration, etc. It should be noted and understood that other doxepin-related compounds may also be used, including polymorphs and solid forms containing hydrates.

Metabolites: In addition, doxepin metabolites can be prepared and used. For illustration purposes, some examples of doxepin metabolites include desmethyldoxepin, hydroxydoxepin, hydroxyl-N-desmethyldoxepin, doxepin N-oxide, N-acetyl-N-des. Methyl doxepin, N-desmethyl-N-formyldoxepin, quaternary ammonium linked glucuronide, 2-O-glucronyldoxepin, didesmethyldoxepin, 3-O-glucronyldoxepin, or Includes, but is not limited to, N-acetyldidesmethyldoxepin. Doxepin metabolites can be obtained or prepared by any suitable method, including those described above for doxepin.

Desmethyldoxepin has the following structure.<img file="JP2013237694A_D0002.tif" />

Desmethyldoxepin is commercially available as a forensic standard. For example, it is available from Cambridge Isotope Laboratories, Inc. (50 Frontage Road, Andover, MA). Desmethyldoxepin for use in the methods described herein can be prepared by any suitable method. For example, desmethyldoxepin is taught in US Pat. No. 3,509,175 from 3-methylaminopropyltriphenylphosphonium bromide bromide and 6,11-dihydrodibenz (b, e) oxepin-11-one. This disclosure is incorporated herein by reference in its entirety.

Hydroxydoxepin has the following structure.<img file="JP2013237694A_D0003.tif" />

2-Hydroxydoxepin can be prepared by any suitable method, including that taught by Shu et al. (Drug Metabolism and Disposition (1990) 18: 735-741), the disclosure of which is in its entirety. Is incorporated herein by reference.

Hydroxy-N-desmethyldoxopine has the following structure.<img file="JP2013237694A_D0004.tif" />

2-Hydroxy-N-desmethyldoxopine can be prepared by any suitable method.

Doxepin N-oxide has the following structure.<img file="JP2013237694A_D0005.tif" />

Doxepin N-oxide can be prepared by any suitable method. For example, doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol (1969) 18: 1941-1954), the disclosure of which is incorporated herein by reference in its entirety.

N-Acetyl-N-desmethyldoxopine has the following structure.<img file="JP2013237694A_D0006.tif" />

N-Acetyl-N-desmethyldoxopine can be prepared by any suitable means. For example, (E) -N-acetyl-N-desmethyldoxepin is used in filamentous fungi incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27: 1157-1164). As produced, this disclosure is incorporated herein by reference in its entirety.

N-desmethyl-N-formylmethixepine has the following structure.<img file="JP2013237694A_D0007.tif" />

N-desmethyl-N-formylmethixepine can be prepared by any suitable means. For example, (E) -N-desmethyl-N-formylmethionide xepin is produced in filamentous fungi incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27: 1157-1164). This disclosure is incorporated herein by reference in its entirety.

N-Acetyl didesmethyldoxepin has the following structure.<img file="JP2013237694A_D0008.tif" />

N-Acetyl didesmethyldoxepin can be prepared by any suitable means. For example, (E) -N-acetyldidesmethyldoxepin is produced in filamentous fungi incubated with doxepin as taught by Moody et al. (Drug Metabolism and Disposition (1999) 27: 1157-1164). This disclosure is incorporated herein by reference in its entirety.

Didesmethyldoxepin has the following structure.<img file="JP2013237694A_D0009.tif" />

Didesmethyldoxopine can be prepared by any suitable means. For example, (Z)-and (E) -didesmethyldoxepin are plasma of depressed patients taking doxepin as taught by Deuschle et al. (Psychopharmacology (1997) 131: 19-22). And isolated from cerebrospinal fluid, this disclosure is incorporated herein by reference in its entirety.

3-O-Glucronyldoxepin has the following structure.<img file="JP2013237694A_D0010.tif" />

3-O-Glucronyldoxepin can be prepared by any suitable means. For example, (E) -3-O-glucuronyl doxepin is simply derived from the bile of rats treated with doxepin, as described by Shu et al. (Drug Metabolism and Disposition (1990) 18: 1096-1099). Separated, this disclosure is incorporated herein by reference in its entirety.

2-O-Glucronyldoxepin has the following structure.<img file="JP2013237694A_D0011.tif" />

2-O-Glucronyldoxepin can be prepared by any suitable means. For example, (E) -2-O-glucuronyl doxepin is described by Shu et al. (Drug Metabolism and Disposition (1990) 18: 1096-1099) in the bile of rats treated with doxepin, and It has been isolated from doxepin-treated human urine, the entire disclosure of which is incorporated herein by reference.

Doxepin quaternary ammonium linked glucuronide (doxepin N⁺-Glucuronide) has the following structure.<img file="JP2013237694A_D0012.tif" />

N⁺-Glucuronide can be obtained by any suitable means. For example, doxepin N⁺-Glucuronide can be prepared as taught by Luo et al. (Drug Metabolism and Disposition, (1991) 19: 722-724), the disclosure of which is incorporated herein by reference in its entirety.

Pharmaceutically acceptable salt: As mentioned above, the methods and other embodiments described herein can use any suitable pharmaceutically acceptable salt or prodrug of doxepin, or a salt or prodrug of a doxepin metabolite. Therefore, substitution or use of a combination of salt and prodrug is specifically contemplated in the embodiments described herein. Pharmaceutically acceptable salts and prodrugs can be prepared by any suitable method.

The term "pharmaceutically acceptable salt" means an ionic form of a compound that does not significantly irritate the administered organism and does not suppress the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds of the present invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Can be done. Pharmaceutical salts are prepared by reacting the compounds of the present invention with bases; ammonium salts; alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; dicyclohexylamine, N-methyl-D- It can also be obtained by producing salts of organic bases such as glutamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine and lysine. Pharmaceutically acceptable salts are described in more detail in the following paragraphs.

Acids that can be used to prepare pharmaceutically acceptable acid additions include, for example, non-toxic acid additions such as acetates, benzenesulfonates, benzoates, hydrogen carbonates, hydrogen sulfates. , Hydrogen tartrate, borate, bromide, calcium edetate, cansilate, carbonate, chloride, clavolanate, citrate, dihydrochloride, edetate, dislyate, estrate, esylate, ethyl succinate Acid, Fumalate, Gluceptate, Gluconate, Glutamate, Glycolyl alsanylate, Hexylresorcinato, Hydrabamine, Hydrobromide, Hydrochloride, Iodine, Isothionate, Lactate, Lactobion Acid, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucat, napcilate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, Pantothenate, phosphate / diphosphate, polygalacturoate, salicylate, stearate, basic acetate, succinate, tannate, tartrate, theocrate, tosylate, trietiodode ( Triethiodode), and those that produce salts containing pharmacologically acceptable anions such as valerate.

Bases that can be used to prepare pharmaceutically acceptable base addition salts include, for example, non-toxic base addition salts, ie, bases produced with metals or amines such as alkaline and alkaline earth metals or organic amines. Includes those that produce salt. Non-limiting examples of metals used as cations include sodium, potassium, magnesium, calcium and the like. Also included are heavy metal salts such as, for example, silver, zinc, cobalt, and cerium. Non-limiting examples of suitable amines include N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

Prodrug: The term "prodrug" means a drug that is converted to an active drug in vivo. Prodrugs are often useful because they can be easier to administer than active drugs in some situations. For example, prodrugs may be bioavailable by oral administration, but active drugs are not. Prodrugs may have better solubility in pharmaceutical compositions than active drugs. Examples of prodrugs, but not limited to, are administered as esters (prodrugs) to facilitate migration across cell membranes when water solubility is detrimental to migration. Then, once inside the cell where water solubility is beneficial, it is hydrolyzed to the active substance carboxylic acid by metabolism, which is the compound of the present invention. A further example of a prodrug could be a short chain peptide (polyamino acid) attached to an acid group, where the peptide is metabolized to reveal the active moiety. Examples of prodrug groups include, for example, T. Higuchi and V. Stella, in'' Pro-drugs as Novel Delivery Systems,'' Vol. 14, ACS. Symposium Series, American Chemical Society (1975); H. Bundgaard,'' Design of Prodrugs,'' Elsevier Science, 1985; and'' Bioreversible Carriers in Drug Design: Theory and Application,'' edited by EB Roche, Pergamon Press: It can be found in New York, 14-21 (1987), each of which is incorporated herein by reference in its entirety.

<u style="single">How to use low dose doxepin</u> Some aspects relate to methods for reducing or preventing premature arousal in patients in need of it. The method is the step of identifying a patient with a sleep disorder who experiences a given sleep period of desired sleep, eg, a sleep period ending during or before the last 60 minutes of that period during 8 hours. And the patient may include the step of administering a dose effective for prolonging sleep, preferably between 1 and 6 mg of doxepine. In some aspects, the patient may experience a sleep period ending within the last 60, 45, 30 or 15 minutes. In other aspects, the sleep period can end even earlier, eg, the last 90 minutes, the last 120 minutes, or longer. In some aspects, the sleep period is by administering low doses of doxepin to extend the sleep period so that it ends during or after the 7th hour of the 8-hour sleep period (eg, 7.5 hours). It may be lengthened. Patients can also be identified as needing to reduce awakening time during (or after) sleep.

In addition, some embodiments relate to methods of improving fragmented sleep during the last hour of a patient's sleep period, preferably the last hour or eighth hour of sleep. The method is to identify, for example, a patient who suffers from or experiences fragmented sleep during the last hour or longer of the sleep period; and to that patient about 1 mg to 6 mg of doxepin. Includes the step of administering in between doses. Preferably, this method can be used to reduce or ameliorate fragmented sleep during the 8th hour of sleep. In some aspects, the dose of doxepin can be about 1 mg, 3 mg or 6 mg.

Some aspects relate to the use of low dose doxepin to reduce WTAS in early awakening individuals. Individuals in need of such need can be identified and low doses of doxepin can be administered to the individual, eg, before the sleep period.

The methods described herein can be used to treat individuals suffering from sleep disorders such as insomnia. Individuals suffer from chronic or non-chronic insomnia. Due to chronic (eg, longer than 3-4 weeks) or non-chronic insomnia, patients fall asleep, maintain sleep (interruption due to sleep awakening period at night), sleep duration, sleep efficiency, early morning awakening, or its. You may also have difficulty in combining. Insomnia may also be caused, for example, by concomitant use of other drugs. Non-chronic insomnia can be, for example, short-term insomnia or transient insomnia. Chronic or non-chronic insomnia can be primary insomnia or another condition, eg, secondary to a disease such as depression or chronic fatigue syndrome, or insomnia caused by it. In some aspects, the patient may be free of insomnia, a component of the disease, or may treat a otherwise healthy patient. As mentioned above, chronic or non-chronic insomnia can be due to primary insomnia, ie another psychiatric disorder, general medical condition, or substance. Often, such conditions are associated with chronic insomnia, including diagnosable DSM-IV disorders, disorders such as anxiety or depression, or insomnia caused by disorders of the physiological sleep-wake system. However, it is not limited to them. In some aspects, insomnia can be non-chronic or short-lived (eg, less than 3-4 weeks). Examples of causes of such insomnia may be extrinsic or intrinsic, according to the International Classification of Sleep Disorders (ICSD), such as inadequate sleep hygiene, high altitude insomnia, or adaptive sleep disorders (eg, bereavement). Includes, but is not limited to, environmental sleep disorders as defined. Short-term insomnia can also be caused by disorders such as shift work sleep disorders.

<u style="single">Doxepin administration</u> In carrying out the method, doxepin, a pharmaceutically acceptable salt of doxepin, or a prodrug of doxepin can be administered using any suitable route or delivery method. Similarly, doxepin, a pharmaceutically acceptable salt or prodrug thereof, can be administered in the composition.

Suitable routes of administration include oral, oral, sublingual, transdermal, rectal, topical, transmucosal, or intestinal; intramuscular, subcutaneous, intravenous, intramedullary injection, and submucosal, direct intraventricular. Includes parenteral delivery, including intraperitoneal, intranasal, or intraocular injection.

For oral administration, the compounds can be readily formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like for oral ingestion by treated patients. To do. Administration by the oral route can be performed using, for example, capsules, tablets, granules, sprays, syrups, liquids, powders, granules, pastes (eg, for application to the tongue). Oral administration can be performed using, for example, an immediate melting preparation. Pharmaceutical formulations for oral use mix one or more solid excipients with the pharmaceutical combination of the invention, optionally grind the resulting mixture, and optionally supplement with a suitable adjunct. It can be obtained by processing the mixture of granules after addition to make it the center of a tablet or dragee. Suitable excipients are sugars, especially those containing lactose, sucrose, mannitol, or sorbitol; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanto gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, And / or fillers such as cellulose preparations such as polyvinylpyrrolidone (PVP). If desired, a disintegrant such as crosslinked polyvinylpyrrolidone, agar, or a salt thereof such as alginic acid or sodium alginate may be added.

Pharmaceutical formulations that can be used orally, including sublingually, include, for example, bulk or unit dose dosage forms of solutions, powders, and suspensions. Similarly, oral formulations include, for example, pills, tablets, granules, sprays, syrups, pastes, powders, giant pills, pre-measured ampoules or syringes, gelatin pushfit capsules, and gelatin and glycerol or Sealed soft capsules made of plastics such as sorbitol may be included. Pushfit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. All formulations for oral administration should be at appropriate doses for such administration.

For oral administration, the composition may take any suitable dosage form, such as tablets or lozenges.

For topical administration, the compounds may be formulated for administration to the epidermis as ointments, gels, creams, pastes, ointments, gels, creams or lotions, or as transdermal patches. Ointments and creams may be formulated with an aqueous or oily base, for example, with the addition of appropriate thickening and / or gelling agents. Lotions may be formulated with aqueous or oily bases and generally also include one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.

For injection, the substances of the invention may preferably be formulated in aqueous solutions in physiologically compatible buffers such as Hanks, Ringer, or saline buffers. For transmucosal administration, a penetrant suitable for the penetrating barrier is used in the formulation. Such penetrants are generally known in the art.

A pressurized pack of compounds for use in accordance with the present invention for administration by inhalation, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Alternatively, it is conveniently delivered from the nebulizer in the form of an aerosol spray. In the case of pressurized aerosols, the dose unit may be determined using a valve for delivering the measured amount. Capsules or cartridges made of, for example, gelatin for use in inhalers or injectors may be formulated with a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, eg, bolus injection or continuous infusion. Injectable formulations may be provided, for example, in ampoules or unit dose forms in multi-dose containers, with the addition of preservatives. The composition may be in the form of a suspending agent, liquid or emulsion in an oily or aqueous medium and may contain a formulation substance such as a suspending agent, stabilizer and / or dispersant.

Pharmaceutical preparations for parenteral administration include aqueous solutions of water-soluble active compounds. In addition, suspensions of active compounds may be prepared as suitable oily suspensions for injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspending agent may contain a suitable stabilizer or a substance that enhances the solubility of the compound so that a high concentration solution can be prepared.

In addition, any of the compounds and compositions described herein can be formulated as depot formulations. Such long-acting formulations may be administered by transplantation (eg, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymers or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, eg, sparingly soluble salts. Good. In addition, any of the compounds and compositions described herein can be formulated as immediate melting formulations. The compounds and compositions can also be formulated and administered as absorbent materials such as infusions, suppositories, ointments, ointments, transdermal patches and the like.

The compounds of the present invention can also be administered in sustained release dosage form or sustained release drug delivery system. Remington: The Science and Practice of Pharmacy (20)^th It can be found in the materials incorporated in ed, Lippincott Williams &amp; Wilkens Publishers (2003)), which are incorporated herein by reference in their entirety.

Remington: The Science and Practice of Pharmacy (20)^th It can be found in ed, Lippincott Williams &amp; Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety.

<u style="single">Composition</u> As mentioned above, doxepin, its pharmaceutically acceptable salts, and / or prodrugs alone or in combination with other substances, such as other insomnia or sleeping pills, or other drugs that treat the underlying disorder. It can be used in combination with. Doxepin alone or in combination can also be included as part of the composition. Compounds and compositions can include any form of compound suitable for pharmaceutical delivery, as discussed in more detail herein.

The compositions and formulations disclosed herein can also include one or more pharmaceutically acceptable carrier materials or excipients. Such compositions can be prepared for storage and for subsequent administration. Acceptable carriers or diluents for therapeutic use are well known in the technical field of pharmacy, for example Remington: The Science and Practice of Pharmacy (20).^th ed, Lippincott Williams &amp; Wilkens Publishers It can be found in the materials incorporated in (2003)), which are incorporated herein by reference in their entirety. The term "carrier" material or "excipient" herein is not a therapeutic agent in itself, but is a carrier and / or a diluent and / or an adjunct, or a vehicle for delivering a therapeutic agent to a subject. To improve the handling or storage properties of pharmaceutical compositions, or to allow or facilitate the formation of dosage units of compositions into separate articles such as capsules or tablets suitable for oral administration. Means any substance added to a pharmaceutical composition. Excipients mask diluents, disintegrants, binders, adhesives, wetting agents, polymers, lubricants, slip agents, unpleasant tastes or odors, for illustration purposes only, not for limitation. Alternatively, it may include substances added to offset, fragrances, pigments, fragrances, and substances added to improve the appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, corn starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid. Includes sodium and calcium salts, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. Examples of excipients suitable for gelatin soft capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols. Excipients suitable for the preparation of liquids and syrups include, but are not limited to, water, polyols, sucrose, invert sugar and glucose. Suitable excipients for injectable solutions include, but are not limited to, water, alcohols, polyols, glycerol, and vegetable oils. Pharmaceutical compositions also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, It can contain colorants, fragrances, buffers, coatings, or antioxidants. Sterilized compositions for injection are Remington: The Science and Practice of Pharmacy (20)^th It can be formulated according to the usual pharmaceutical practices described in the materials incorporated in ed, Lippincott Williams &amp; Wilkens Publishers (2003)). For example, it may be desirable to dissolve or suspend the active compound in water or natural vegetable oils such as sesame oil, peanut oil, or cottonseed oil, or synthetic fatty media such as ethyl oleate. Buffers, preservatives, antioxidants, etc. can be incorporated according to accepted pharmaceutical practices. Compounds can also be prepared in microencapsulated dosage forms. In addition, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents. Absorption-enhancing preparations (eg, liposomes) can also be used if desired.

Compositions and formulations can also include any other substance that improves transfer, delivery, tolerability, and the like. These compositions and formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cations or anions) including vesicles (such as Lipofectin®), DNA conjugates, anhydrous absorption. Includes pastes, oil-in-oil and water-in-oil emulsions, emulsion carbowax (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any mixture described above is suitable for the treatment and therapy of the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation, the formulation is physiologically compatible and route of administration tolerated. possible. For more information on formulations, excipients and carriers well known to those skilled in the art of pharmaceutical chemistry, see Baldrick P. `` Pharmaceutically intensive development: the need for preclinical guidance`` Regul. Toxicol. Pharmacol. 32 (2): 210-8 (2000), Charmant WN `` Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts Major J Pharm Sci.89 (8): 967-78 (2000), Powell et See also al.''Compendium of preferablys for parenteral formulations'' PDA J Pharm Sci Technol 52: 238-311 (1998) and references therein.

The compounds of the present invention can also be administered in sustained release dosage form or sustained release drug delivery system. Remington: The Science and Practice of Pharmacy (20)^th It can be found in the materials incorporated in ed, Lippincott Williams &amp; Wilkens Publishers (2003)), which are incorporated herein by reference in their entirety.

<u style="single">dose</u> As mentioned above, in some embodiments, the preferred dose can be between about 1 mg and 6 mg. Preferably, the dose can be about 0.5 mg, 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg. It should be noted that in some embodiments, the dose is between about 0.01 mg and 20 mg, or between about 0.5 mg and 10 mg. In addition, the dose can be about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

The dose level selected may depend, for example, on the route of administration, the severity of the condition being treated, and the condition and past history of the patient being treated. However, it is within the skill of the art to start the dose of the compound at a lower level than required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained. However, specific dose levels for any particular patient may include genetic properties, body weight, general health, diet, time and route of administration, concomitant use with other drugs, and specific conditions during treatment, and their severity. It will be understood that it can depend on various factors, including degree. For the treatment of insomnia, a single dose is preferably given before bedtime.

The dose selected can also be determined by targeting the mean plasma concentration characteristics involved in improving sleep variables in one or more PSGs, including LPS, WASO, TST, SE, WTDS, or WTAS. Yes (Fig. 1). An example of such plasma concentration characteristics is shown in FIG. Target plasma concentration characteristics are oral, oral, sublingual, transdermal, rectal, topical, transmucosal, or intestinal administration; intramuscular, subcutaneous, intravenous, intramedullary injection, and submucosal, direct intraventricular, It can be achieved with any suitable formulation by any suitable route of administration, including parenteral delivery, including intraperitoneal, intranasal, or intraocular injection.

<p>Example<u style="single">Example 1</u> Doxepin is prepared by the following method.</p><p> (a) Grignard compounds are prepared in the usual manner from magnesium (4.8 g, 0.2 g-atoms) in ether (100 mL), (3-chloropropyl) -tertbutyl ether (30 g, 34 ml) and ether (100 mL). 6,11-Dihydrodibenzo- [b, e] -oxepine-11-one (16.40 g, 0.078 mol) dissolved in is added dropwise so that the contents of the flask are slightly boiled. The mixture is heated in a reflux condenser for 1 hour with stirring to complete the reaction and then decomposed with ammonium chloride solution. When the ether residue (24.0 g) is extracted with ligroin, the product 11- (3-tert-butyloxypropyl) -11-hydroxy-6,11-dihydro having a melting point of 124-126 ° C by separation, drying and solvent removal Obtain dibenzo- [b, e] -oxepin (20.3 g, 80.0% of theory). Then (3-chloropropyl) -tert-butyl ether is obtained in the following manner: 1-chloropropanol- (3) (19 g, 0.2 mol), liquid isobutylene (50 mL) and concentrated sulfuric acid (0.5 mL) in an autoclave 24 Leave for hours, then add to excess sodium hydrogen carbonate solution and extract with ether. The ether solution is dried with calcium chloride and distilled. Recover (3-chloropropyl) -tert-butyl ether with a boiling point of 150-156 ° C (23.6 g, 78% of theory).</p><p> (b) 11- (3-tert Butoxypropyl) -11-hydroxy-6,11-dihydrodibenzo- [b, e] -oxepin (30.8 g) and anhydrous alcoholic hydrochloric acid (150 ml) obtained according to (a) above. ) Is heated to the boiling point for 1 hour. After removing the solvent by evaporation, the residue was crystallized with ligroin and 11- (3-hydroxypropyridene) -6,11-dihydrodibenzo- [b, e] -oxepin (21.0 g,) with a melting point of 108-111 ° C. 88.5% of the theory) was obtained. After recrystallization from acetic acid ester, the melting point of the compound is 112-114 ° C.</p><p> (c) Thionyl chloride (5.0 ml) dissolved in benzene (5 mL) was obtained in (b) above at room temperature. 11- (3-Hydroxypropyridene) -6,11-dihydrodibenzo- [b, e]- Drop into oxepin (12.6 g, 0.05 mol). After leaving for 1 hour, the contents of the flask are heated to the boiling point for 2 hours. The volatile components are then removed and the residue is distilled under high pressure. 11- (3-chloropropylidene) -6,11-dihydrodibenzo- [b, e] -oxepin (10.6 g, 78.5% of theory) with BP0.1 of 169-172 ° C and melting point of 106-111 ° C ). After recrystallization from acetic acid ester (20 ml), a pure product with a melting point of 113-115 ° C (9.1 g, 67.5% of theory) is obtained. However, crude products can be used very easily for further processing.</p><p> (d) 11- (3-chloropropylidene) -6,11-dihydrodibenzo- [b, e] -oxepin (5.4 g, 0.02 mol) and ethanol prepared according to (c) above in tetrahydrofuran (20 mL). Dimethylamine (5.5 g, 0.12 mol) in (20 mL) is heated together in a glass autoclave at a temperature of 95-100 ° C (boiling water bath) for 3 hours. Water and 6N hydrochloric acid are added to the contents of the autoclave and the mixture is extracted with ether. The separated aqueous acid component is made alkaline with a dilute caustic solution, thereby dissolving the separated oil in ether. After distilling the ether residue under high pressure, BP_0.1Obtains 11- (3-dimethylamino-propylidene) -6,11-dihydrodibenzo- [b, e] -oxepin (4.1 g, 73.5% of theory) at 147-150 ° C. The melting point of hydrochloride is 182 to 184 ° C (recrystallized from isopropanol).</p><p><u style="single">Example 2</u><u style="single">Preparation of desmethyldoxepin</u> Desmethyldoxopine is prepared according to the following method. Anhydrous bromide 3-methylaminopropyltriphenylphosphonium hydrobromide (1530 g) prepared according to US Pat. No. 3,509,175 was suspended in anhydrous tetrahydrofuran (4.5 L), and butyllithium (6.0 mol) in heptane was added. Add in 1 hour. After an additional 30 minutes, 6,11-dihydrodibenz [b, e] oxepin-11-one (483 g) is added to the dark red solution and the reaction mixture is maintained under reflux for 10 hours. Water (500 mL) is added at room temperature and the solvent is removed under reduced pressure. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2), then benzene (1.5 L) is added. After stirring, the mixture separates into three phases (insoluble hydrochloride product phase, aqueous phase and organic phase). The benzene layer is decanted, the remaining mixture is basicized with 10% sodium hydroxide solution and extracted with benzene (3 x 1500 mL). The benzene extract is washed, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a solid residue of desmethyldoxopine.</p><p><u style="single">Example 3</u><u style="single">(E)-Preparation of desmethyldoxepin</u> E) -Desmethyldoxepin is prepared from doxepin hydrochloride as follows. Doxepin hydrochloride (E / Z = 85/15) (55.0 g, 0.174 mol) H₂Dissolve in O (600 mL), base with 6M NaOH, CHCl₃Extract with (3 x 600 mL). CHCl₃Combine the extracts and Na₂SO₄Dry with and remove the solvent under reduced pressure. The resulting oil is dissolved in EtOH (250 mL), then maleic acid (21.15 g, 0.182 mol) dissolved in EtOH (100 mL) is added slowly with stirring, followed by the addition of EtOH (350 mL). The resulting turbid solution is refluxed until clear and then left at room temperature overnight. The obtained crystals are isolated by vacuum filtration. Further, recrystallization is performed from EtOH to obtain a white crystalline product ((E) -doxopine maleate) having an E / Z ratio of 98/2. Then, (E) -doxepine maleate (2.50 g, 6.32 mmol) was added to H.₂Partially dissolved in O (60 mL), basicized with 6M NaOH, CHCl₃Extract with (3 x 60 mL). CHCl₃Combine the extracts, wash with saline (60 mL) and Na₂SO₄Dry with and remove the solvent under reduced pressure. CHCl the obtained oil₃Dissolve again in (10 mL), add triethylamine (1.8 mL, 13 mmol), add 2,2,2-trichloroethyl chlorogiate (1.8 mL, 13 mmol), and add N to the reaction mixture.₂Stir in an atmosphere for 3.5 hours. Then the completed reactant is Et₂Dilute with O (140 mL), 0.5 M HCl (2 x 140 mL), H₂Wash sequentially with O (140 mL) and saline (140 mL), then MgO₄Dry with and remove the solvent under reduced pressure. The resulting material is eluted by silica gel column chromatography with EtOAc / Hex (20/80) and further purified to give the desired product (1.48 g, 3.36 mmol) in clear oil. Next, N-protected (E) -desmethyldoxepine intermediate (1.44 g, 3.27 mmol) was dissolved in THF (12 mL), zinc powder (2.88 g) was added, and 1 M sodium phosphate (pH = 5.5, 2.3 mL) is added and the reaction is stirred for 17 hours. The reaction mixture is filtered under reduced pressure, the solvent of the filtrate is removed under reduced pressure, and the obtained residue is obtained by silica gel column chromatography in THF / MeOH / NH.₄OH (85/15 / 0.4), then THF / MeOH / NH₄Elute with OH (75/25 / 0.4) and purify to give the desired product (744 mg, 2.80 mmol) as a pale yellow solid.</p><p><u style="single">Example 4</u><u style="single">(Z)-Preparation of desmethyldoxepin</u> Z)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows. Doxepin hydrochloride (E / Z = 85/15) (100g, 0.317mol) H₂Dissolve in O (800 mL), base with 6M NaOH, CHCl₃Extract with (3 x 800 mL). CHCl₃Combine the extracts and Na₂SO₄Dry with and remove the solvent under reduced pressure. The resulting oil is dissolved in EtOH (700 mL), then maleic acid (36.7 g, 0.317 mol) dissolved in EtOH (600 mL) is added slowly with stirring. The resulting turbid solution is refluxed until clear and then left at room temperature overnight. Crystals are isolated by vacuum filtration and the mother liquor is set aside. The crystals are recrystallized two more times as described above, the mother liquor for three times is set aside and combined, and the solvent is removed under reduced pressure. The mother liquor material is recrystallized from reflux EtOH to finally give the mother liquor product (24 g) which is the 65% Z isomer in the composition. This material is recrystallized from EtOH (450 mL) to give crystals (9.1 g) that are 80% Z isomers. CHCl this material₃/ CCl₄Recrystallize from (50/50) (170 mL) at 4 ° C to give a crystalline material (7.65 g) that is 87% Z isomer in the composition. CHCl₃/ CCl₄Is recrystallized three more times to finally give the desired product ((Z) -doxepine maleate) (5.12 g, 12.9 mmol) with an E / Z ratio of 4/96; melting point: 162 ~ 163 ° C. Then (Z) -doxepine maleate (1.00 g, 2.53 mmol) was added to H.₂Partially dissolved in O (35 mL), basicized with 6M NaOH, CHCl₃Extract with (3 x 35 mL). CHCl₃Combine the extracts, wash with saline (35 mL) and Na₂SO₄Dry with and remove the solvent under reduced pressure. CHCl the obtained oil₃Dissolve again in (4 mL), add triethylamine (0.65 mL, 4.7 mmol), add 2,2,2-trichloroethyl chlorogiate (0.65 mL, 4.7 mmol), and add N to the reactants.₂Stir in an atmosphere for 3.5 hours. The completed reaction mixture is then Et.₂Dilute with O (50 mL), 0.5 M HCl (2 x 50 mL), H₂Wash sequentially with O (50 mL) and saline (50 mL), then MgO₄Dry with and remove the solvent under reduced pressure. The resulting material is eluted by silica gel column chromatography with EtOAc / Hex (20/80) and further purified to give the desired product (710 mg, 1.61 mmol) in clear oil. Next, N-protected (Z) -desmethyldoxepine (679 mg, 1.54 mmol) was dissolved in THF (5.7 mL), zinc powder (1.36 g) was added, and 1 M sodium phosphate (pH = 5.5, 1.1 mL) was added. ) Is added and the reaction is stirred for 17 hours. The reaction mixture is filtered under reduced pressure, the solvent of the filtrate is removed under reduced pressure, and the obtained residue is obtained by silica gel column chromatography in THF / MeOH / NH.₄OH (85/15 / 0.4), then THF / MeOH / NH₄Elute with OH (82/18 / 0.4) and purify to give the desired product (364 mg, 1.37 mmol) as a pale yellow solid.</p><p><u style="single">Example 5</u><u style="single">Preparation of (Z) -2-Hydroxy-11- (3-Dimethylaminopropyridene) -6,11-dihydrodibenzo [be] oxepin</u> 2-Methoxy-11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo [b, e] oxepine (165 mg, 0.005 mol) and glacial acetic acid (0.2 mL) and hydroiodic acid (0.2 mL, 57%) ) Was stirred and heated at 90 ° C. for 5 hours. The product was then extracted, poured into ice water (25 mL) for purification, made alkaline with sodium hydroxide (2N) and extracted with ether (2 x 10 mL). The aqueous layer was then adjusted to pH 6.8 with hydrochloric acid (6N). A sodium hydrogen carbonate solution (5%) was added to the mixture to adjust the pH to 7, and the mixture was extracted with chloroform (2 × 10 mL). The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a yellowish solid. The crude reaction product was purified by TLC for preparation (chloroform / toluene / methanol / ammonia, 4: 3: 2: 1, v / v).</p><p><u style="single">Example 6</u><u style="single">Preparation of (E) -2-Hydroxy-11- (3-Dimethylaminopropyridene) -6,11-dihydrodibenzo [b, e] oxepin</u> (Z) -2-Hydroxy-11- (3-Dimethylaminopropyridene) -6,11-dihydrodibenzo [b, e] Oxepin (2.5 mg, 8.5 × 10)^-6The mixture of mol) was dissolved in a mixture of hydrochloric acid (1 mL) and methanol (9 mL) and heated at 140 ° C (oil bath) for 4 hours. The product was isolated by HPLC and evaporation of solvent.</p><p><u style="single">Example 7</u><u style="single">Preparation of (Z) -2-Hydroxy-11- (3-Methylaminopropyridene) -6,11-dihydrodibenzo [b, e] oxepin</u> 2-Methoxy-11- (3-methylaminopropyl) -6,11-dihydrodibenzo [b, e] with oxepine (0.005 mol) and glacial acetic acid (0.2 mL) and hydroiodic acid (0.2 mL, 57%) The mixture is stirred and heated at 90 ° C for 5 hours. The product is then extracted, poured into ice water (25 mL) for purification, made alkaline with sodium hydroxide (2N) and extracted with ether (2 x 10 mL). The aqueous layer is then adjusted to pH 6.8 with hydrochloric acid (6N). Add sodium hydrogen carbonate solution (5%) to the mixture to pH 7, and extract with chloroform (2 x 10 mL). The extract is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a yellowish solid. The crude reaction product is purified by TLC for preparation (chloroform / toluene / methanol / ammonia, 4: 3: 2: 1, v / v).</p><p><u style="single">Example 8</u><u style="single">Preparation of (E) -2-Hydroxy-11- (3-Methylaminopropyridene) -6,11-dihydrodibenzo [b, e] oxepin</u> Mixture of (Z) -2-hydroxy-11- (3-methylaminopropyridene) -6,11-dihydrodibenzo [b, e] oxepin (2.5 mg) into a mixture of hydrochloric acid (1 mL) and methanol (9 mL) Melt and heat at 140 ° C (oil bath) for 4 hours. The product is isolated by HPLC and evaporation of solvent.</p><p><u style="single">Example 9</u><u style="single">Preparation of doxepin-N-oxide</u> The aqueous solution of doxepin hydrochloride was made alkaline and extracted with methylene chloride. The solvent was removed and the residue was dissolved in methanol and treated with excess 30% hydrogen peroxide for 5 days. Chromatographic tests showed that doxepin was completely transformed into a more polar substance, and its mass spectrometry revealed it to be an N-oxide.</p><p> Hobbs, DC, Distribution and Metabolism of Doxepin (1969) Biochem Pharmacol 18: 1941-1954; the entire body is incorporated herein by reference.</p><p><u style="single">Example 10</u><u style="single">(Z) Preparation of doxepin-N-oxide</u> An aqueous solution of purified (Z) -doxepin hydrochloride is made alkaline and extracted with methylene chloride. The solvent is removed, the residue is dissolved in methanol and treated with excess 30% hydrogen peroxide for 5 days. Chromatographic tests show that doxepin has been completely transformed into a more polar substance, and its mass spectrometry reveals that it is the N-oxide of the (Z) isomer of doxepin.</p><p><u style="single">Example 11</u><u style="single">Preparation of (E) -doxepin-N-oxide</u> The purified aqueous solution of (E) -doxepin hydrochloride is made alkaline and extracted with methylene chloride. The solvent is removed, the residue is dissolved in methanol and treated with excess 30% hydrogen peroxide for 5 days. Chromatographic tests show that doxepin has been completely transformed into a more polar substance, and its mass spectrometry reveals that it is the N-oxide of the (E) isomer of doxepin.</p><p><u style="single">Example 12</u><u style="single">Isolation of (E) -N-Acetyl-N-Desmethyldoxepin, (E) -N-Desmethyl-N-Formylmethixepin, and (E) -N-Acetyldidesmethyldoxepin</u> Cunninghamella-elegance with (E) -N-acetyl-N-desmethyldoxepin, (E) -N-desmethyl-N-formylmethixepin, and (E) -N-acetyldidesmethyldoxepin Isolate from Cunninghamella elegans, C. elegans) as described in the material incorporated by Moody et al. (Drug Metabolism and Disposition (1999) 27: 1157-1164). Simply put, cultures of C. elegans ATCC 9245 were incubated at 26 ° C for 48 hours with a rotary stirrer operating at 125 rpm and then doxepin hydrochloride (E /) dissolved in sterile saline (0.5 mL). Z ratio 83: 16%) (10 mg) is added. After incubating for 96 hours, the contents of each flask are filtered through a glass wool into a separatory funnel and extracted 3 times with the same amount of ethyl acetate. The organic extract is dried over sodium sulfate and evaporated to dryness under reduced pressure at 34 °. For HPLC analysis, the residue is dissolved in methanol and concentrated to about 100 μL.</p><p> The extract is repeatedly injected into a semi-prepared scale HPLC system consisting of a Beckman model 100A pump, a Waters 486 turntable UV absorption detector, and a Shimadzu model CR601 Chromatopac integrator. Compounds are eluted on a 10.0 × 250 mm column over 30 minutes at 1.0 mL / min using a linear gradient of 30-75% methanol-buffer (v / v). The buffer used is 25 mM ammonium acetate, pH 7.2. Collect compounds with similar retention times. By NMR and mass spectrometry, (E) -N-acetyl-N-desmethyldoxopine, (E) -N-desmethyl-N-formylmethionepine, and (E) -N-acetyldidesmethyldoxepine Confirm the isolation of.</p><p><u style="single">Example 13</u><u style="single">Isolation of (Z) -N-Acetyl-N-Desmethyldoxepin, (Z) -N-Desmethyl-N-Formylmethixepin, and (Z) -N-Acetyldidesmethyldoxepin</u> (Z) -N-Acetyl-N-Desmethyldoxepin, (Z) -N-Desmethyl-N-Formylmethyxepin, and (Z) -N-Acetyldidesmethyldoxepin Kunning Amera-Elegance ( C. elegans) to isolate the (E) isomer as described above in Example 12. However, unlike Example 13, the culture is first incubated with doxepin, which is rich in cis (Z) -isomers of doxepin with a Z / E ratio greater than 85:15. By NMR and mass spectrometry, (Z) -N-acetyl-N-desmethyldoxepin, (Z) -N-desmethyl-N-formylmethionexepin, and (Z) -N-acetyldidesmethyldoxopine Confirm the isolation of.</p><p><u style="single">Example 14</u><u style="single">Isolation of (E)-and (Z) -N-didesmethyldoxepin</u> Patients treated with (E)-and (Z) -N-didesmethyldoxepin with doxepin according to the method described in the material incorporated by Deuschle et al. (Psychopharmacology (1997) 131: 19-22). Isolate from serum and cerebrospinal fluid. Simply put, blood and cerebrospinal fluid are collected from patients being treated with doxepin. After centrifugation (15000 g for 5 minutes), 100 μl of sample is injected directly into a cleanup column (10.0 × 4.0 mm) packed with Lichrospher RP-8 DIOL. Interfering plasma or CSF components are washed with water containing 5% acetonitrile at a flow rate of 1.5 mL / min and discarded. After 5 minutes, the flow is switched to the analytical column and the drug of interest is separated using methanol: acetonitrile: 0.008 M phosphate buffer, pH 6.4 (188: 578: 235; V / V) for elution. Isolation of (E) -N-didesmethyldoxepin and (Z) -N-didesmethyldoxopine is confirmed by NMR and mass spectrometry.</p><p><u style="single">Example 15</u><u style="single">Isolation of (E) -2-O-Glucronyldoxepin and (E) -3-O-Glucronyldoxepin</u> (E) -2-O-Glucronyldoxepin and (E) -3-O-Glucronyldoxepin, Shu et al. (Drug Metabolism and Disposition (1990) 18: Isolate from rat bile according to the method described in 1096-1099) incorporated material. Simply put, a sample of rat bile is taken from rats within 4 hours after intraperitoneal injection of doxepin hydrochloride (28 mg / kg). Samples are chromatographed on a gradient HPLC system consisting of two solvent delivery pumps (Waters M045), a system controller (Waters Model 720), a UV absorption detector (Waters Model 441), and an integrator (Hewlett 3390A). Chromatography is performed on a column (3 μm, 0.46 × 15 cm) packed with Spherisorb nitrile and maintained at 50 ° C. Analysis begins with an initial uniform solvent period (1 minute) with 95% solvent A (water) and 5% solvent B (acetonitrile / methanol, 75:25, v / v). Then, linear gradient elution is established by increasing the proportion of solvent B from 5% to 100% from 1 minute to 16 minutes, followed by the final period (4 minutes) of uniform solvent elution with 100% solvent B. Flow rate is 1.5 mL / min, UV absorption at 254 nm is 0.005 Monitor with AUFS sensitivity. Isolation of (E) -2-O-glucuronyldoxepin and (E) -3-O-glucronyldoxepin is confirmed by NMR and mass spectrometry.</p><p><u style="single">Example 16</u><u style="single">Isolation of (Z) -2-O-glucronyldoxepin and (Z) -3-O-glucronyldoxepin</u> Doxepin cis (Z) -isomer with (Z) -2-O-glucuronyl doxepin and (Z) -3-O-glucuronyl doxepin in rats with a Z / E ratio greater than 85:15 Isolate from rats according to the method described above in Example 16, except for injection of body-rich doxepin. Isolation of (Z) -2-O-glucuronyldoxepin and (Z) -3-O-glucronyldoxepin is confirmed by NMR and mass spectrometry.</p><p><u style="single">Example 17</u><u style="single">(E)-and (Z) -Doxepin N</u>^{<u style="single">+</u>}<u style="single">-Preparation of glucuronide</u> Doxepin quaternary ammonium linked glucuronide (doxepin N⁺-Glucuronide) is obtained by the organic synthesis described in the incorporated material of Luo et al. (Drug Metabolism and Disposition, (1991) 19: 722-724). Simply put, the synthetic method is the quaternization of methyl (2,3.4-tri-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranoside) ulinate, a commercially available sample of doxepin, followed by sodium hydroxide. Includes removal of protecting groups by treatment. Therefore, doxepin N⁺To prepare the (Z) -isomer of glucuronide, (Z) -doxepin is used as a starting material. To prepare the (E) -isomer of doxepin, (E) -doxepin is used as a starting material.</p><p><u style="single">Example 18</u><u style="single">Phase II study to evaluate sleep-maintaining effects of three dose levels of doxepin hydrochloride (HCl) compared to placebo in elderly patients with primary insomnia</u> Phase II randomized, multicenter, double-blind, placebo-controlled, 4-period cross-dose to evaluate the effect of doxepin (1 mg, 3 mg, and 6 mg) compared to placebo in patients aged 65 years and older with primary sleep-maintaining insomnia A reaction test was planned. Patients received single-blind placebo for two consecutive nights of the PSG screening period and double-blind study drug for two consecutive nights of each of the four treatment periods. After each study drug administration, patients recorded PSG for 8 consecutive hours in a sleep facility. The day after each PSG evaluation was completed, the patient was discharged from the sleep facility. There was a 5 or 12 day non-study period between each PSG evaluation visit. The duration of study participation for each patient was approximately 7 to 11 weeks.</p><p> Based on the evaluation of screening PSG, patients who were eligible for study enrollment were randomized in treatment sequence using a Latin square design. The final study visit was performed for either patients after the completion of the four treatment periods or after the study was discontinued. Efficacy evaluation was performed at each visit and safety evaluation was performed throughout the study period.</p><p> 71 patients were included in the protocol-compliant analysis population. The main registration criteria are Diagnostic and Statistical Manual of Mental Disorders, 65 years or older with a history of at least 3 months of primary insomnia as defined in the fourth edition (DSM-IV) and reporting each of the following in 4 of the 7 nights prior to PSG screening: Male and / or female patients with good general health: total sleep time (TST) 6.5 hours, awakening after insomnia (WASO) 60 minutes, and latency to insomnia (LSO) 20 minutes .. In addition, patients had to meet the following enrollment criteria based on PSG assessment during the screening PSG: night sleep awakening time (WTDS) 60 minutes for PSG screening, &lt;45 No nights of minutes; TST&gt; 240 minutes and 410 minutes on both nights of PSG screening; Latent to persistent sleep (LPS) 10 minutes on both nights of PSG screening, PSG screening first night Regular limb movements with awakening every hour of sleep &lt;15, and PSG screening apnea / decreased breathing every hour of sleep on night 1 &lt;15. Doxepin HCl 1 mg, 3 mg and 6 mg capsules, as well as placebo capsules, were provided in single doses for oral administration.</p><p> The primary efficacy assessment was WTDS. Secondary efficacy assessments included WASO, TST, SE and WTAS. All objective efficacy assessments were performed on the first and second nights.</p><p> For the effectiveness analysis, a population conforming to the protocol (PP; primary analysis population) was used. The PP analysis population included all patients who provided WTDS data from each of the four treatment periods without significant protocol derivations that could affect efficacy assessment. Primary and secondary efficacy analyzes were based on the PP analysis population.</p><p> Within each treatment period, the average of the two data points was used in the analysis, where appropriate. Primary efficacy variables, WTDS, and secondary objective parameters were analyzed using an analysis of variance (ANOVA) model for order, patients within order, treatment and duration. A pair comparison between each active therapeutic agent and placebo was performed using Dunnett's test. All randomized patients who took at least a single dose of the double-blind study drug were included in the safety analysis, and this analysis was based on the observed data.</p><p><u style="single">Effectiveness result</u><u style="single">once</u> WTDS showed a statistically significant reduction at dose levels of doxepin 1 mg (p = 0.0001), 3 mg (p &lt;0.0001) and 6 mg (p &lt;0.0001) compared to placebo in the PP analysis population. The mean values (± SD) observed were as follows: placebo: 86.0 (38.15); doxepin 1 mg: 70.1 (32.78); doxepin 3 mg: 66.4 (31.56) and doxepin 6 mg: 60.2 (28.00). Results using the ITT analysis population were consistent with those from the PP analysis population.</p><p><u style="single">secondary</u> Table 1 summarizes the effectiveness assessment of secondary PSG. WASO showed a statistically significant reduction at dose levels of doxepin 1 mg (p &lt;0.0001), 3 mg (p &lt;0.0001), and 6 mg (p &lt;0.0001) compared to placebo. SE showed a statistically significant increase in all three dose levels of doxepin (1 mg, p &lt;0.0001; 3 mg, p &lt;0.0001; 6 mg, p &lt;0.0001) compared to placebo. TST showed a statistically significant increase in all three dose levels of doxepin (1 mg, p &lt;0.0001; 3 mg, p &lt;0.0001; 6 mg, p &lt;0.0001) compared to placebo. All WTAS showed statistically significant reductions at doxepin 3 mg (p = 0.0264) and 6 mg (p = 0.0008) dose levels and numerically at doxepin 1 mg dose levels compared to placebo.</p><p>(Table 1) Efficacy evaluation of secondary PSG: Protocol-compliant analysis population<img file="JP2013237694A_D0013.tif" />[1] the active therapeutic agent and placebo using Dunnett's test ratio compare the P value</p><p> SE was also analyzed at each time of the night. The results are summarized in Figure 2. Table 2 summarizes the data for the 7th and 8th hours. Except for the 1-hour value of 1 mg, all three doxepin doses showed a numerical increase in SE at each time of the night compared to placebo, and SE was statistically significant at some point in the 3 and 6 mg dose levels. Ascended to. At the doxepin 6 mg dose level, SE showed a statistically significant increase at 2, 4, 5, 6, 7 and 8 hours. At the doxepin 3 mg dose level, SE showed a statistically significant increase at 5, 6, 7 and 8 hours. At the doxepin 1 mg dose level, SE showed a statistically significant increase at 5 and 6 hours.</p><p>(Table 2) Sleep efficiency at 7 and 8 hours: Protocol-compliant analysis population<img file="JP2013237694A_D0014.tif" />[1]: Measured values on the first and second nights were averaged. If one night's value was a yawning value, the n non-yawning side value was used. [2]: P-value comparing each active therapeutic agent with placebo.</p><p><u style="single">Conclusion</u> Doxepin 1 mg, 3 mg and 6 mg showed efficacy for sleep maintenance parameters in elderly patients with primary sleep maintenance insomnia (65 years and older), which appeared to be dose-related. Also effective in delaying early final arousal, as evidenced by a statistically significant reduction in WTAS at dose levels of doxepin 3 mg and 6 mg and a numerical reduction at dose levels of doxepin 1 mg, all compared to placebo. Doxepin was shown at 1 mg, 3 mg and 6 mg. Also, doxepin 1 mg, 3 mg, as evidenced by a statistically significant increase in SE at 7 and 8 hours at dose levels of doxepin 3 mg and 6 mg, and a numerical increase at 1 mg, all compared to placebo. And 6 mg were shown to be effective in improving fragmented sleep at 7 and 8 hours. All doxepin doses were well tolerated and exhibited adverse effect properties similar to placebo. There was no significant effect on residual sedation the next day. Sleep construction was largely maintained.</p><p><u style="single">Example 19</u><u style="single">Phase II study to evaluate sleep-maintaining effects of three dose levels of doxepin hydrochloride (HCl) compared to placebo in adult patients with primary insomnia</u> A phase II randomized, multicenter, double-blind, placebo-controlled, 4-period cross-dose-response study was planned to evaluate the effects of doxepin (1 mg, 3 mg, and 6 mg) compared to placebo in patients with primary sleep-maintaining insomnia. did.</p><p> Patients received single-blind placebo for two consecutive nights of the PSG screening period and double-blind study drug for two consecutive nights of each of the four treatment periods. After each study drug administration, patients recorded PSG for 8 consecutive hours in a sleep facility. The day after each PSG evaluation was completed, the patient was discharged from the sleep facility. There was a 5 or 12 day non-study period between each PSG evaluation visit.</p><p> Based on the evaluation of screening PSG, patients who were eligible for study enrollment were randomized in treatment sequence using a Latin square design. The final study visit was performed for either patients after the completion of the four treatment periods or after the study was discontinued. Efficacy evaluation was performed at each visit and safety evaluation was performed throughout the study period.</p><p> Sixty-one patients were included in the protocol-compliant analysis population. The main enrollment criteria are a history of at least 3 months of primary insomnia as defined by DSM-IV, reporting each of the following in 4 of the 7 nights prior to PSG screening, 18 Male and / or female patients aged 64 years to good general health: total sleep time (TST) 6.5 hours, WASO 60 minutes, and LSO 20 minutes. In addition, patients had to meet the following enrollment criteria based on PSG assessment during the screening PSG: WTDS 60 minutes on the night of PSG screening, no &lt;45 minutes night; PSG TST&gt; 240 minutes and 410 minutes on both nights of PSG screening; LPS 10 minutes on both nights of PSG screening, regular limb movements with awakening every hour of sleep on the first night of PSG screening &lt;10 , And PSG screening 1 night sleep apnea / hypoventilation every hour &lt;10. Doxepin HCl 1 mg, 3 mg and 6 mg capsules, as well as placebo capsules, were provided in single doses for oral administration.</p><p> The primary and secondary efficacy assessments were as described above in Example 1. All objective efficacy assessments were performed on the first and second nights of each treatment period. The statistical method was as described above in Example 1.</p><p><u style="single">Effectiveness result</u><u style="single">once</u> WTDS showed a statistically significant reduction at dose levels of doxepin 3 mg (p &lt;0.0001) and 6 mg (p = 0.0002) compared to placebo. At the doxepin 1 mg dose level, WTDS was numerically reduced but not significant. The mean values (± SD) observed were as follows: placebo: 51.9 (42.25); doxepin 1 mg: 43.2 (28.21); doxepin 3 mg: 33.4 (21.87) and doxepin 6 mg: 35.3 (25.17).</p><p><u style="single">secondary</u> Table 3 summarizes the effectiveness evaluation of secondary PSG. SE showed a statistically significant increase in all three dose levels of doxepin (1 mg, p = 0.0004; 3 mg, p &lt;0.0001; 6 mg, p &lt;0.0001) compared to placebo. TST showed a statistically significant increase in all three dose levels of doxepin (1 mg, p = 0.0004; 3 mg, p &lt;0.0001; 6 mg, p &lt;0.0001) compared to placebo. WTAS showed a statistically significant reduction at the doxepin 6 mg dose level (p = 0.0105) compared to placebo. There was a numerical reduction in WTAS at dose levels of doxepin 1 mg and 3 mg compared to placebo, but these differences were not significant. WASO showed a statistically significant reduction at dose levels of doxepin 1 mg (0.0130), 3 mg (p &lt;0.0001), and 6 mg (p &lt;0.0001) compared to placebo.</p><p>(Table 3) Efficacy evaluation of secondary PSG: Protocol-compliant analysis population<img file="JP2013237694A_D0015.tif" />[1] P-value comparing each active therapeutic agent and placebo using Dunnett's test</p><p> SE was also analyzed at each time of the night. The results are summarized in Figure 3. All three doxepin doses showed a numerical increase in SE at each time of the night compared to placebo, and SE was statistically significantly increased at several time points at the 3 and 6 mg dose levels. All three doxepin doses showed a statistically significant increase in SE at night 7 and 8 hours. Table 4 summarizes the data for the 7th and 8th hours.</p><p>(Table 4) Sleep efficiency at 7 and 8 hours: Protocol-compliant analysis population<img file="JP2013237694A_D0016.tif" />[1]: Measured values on the first and second nights were averaged. If one night's value was a yawning value, the non-yawning value was used. [2]: P-value comparing each active therapeutic agent with placebo.</p><p><u style="single">Conclusion</u> Doxepin 1 mg, 3 mg and 6 mg have been shown to be effective against sleep maintenance parameters in adult patients with primary sleep maintenance insomnia. Doxepin 1 mg, 3 mg and 6 mg prevent early final arousal or as evidenced by a significant reduction in WTAS at the doxepin 6 mg dose level and a numerical reduction at the doxepin 1 mg and 3 mg dose levels, all compared to placebo. It also showed its effectiveness in delay. Also, for doxepin 1 mg, 3 mg, and 6 mg at 7 and 8 hours of fragmented sleep, as evidenced by a significant improvement in SE at 7 and 8 hours for all three doses compared to all placebo. The effectiveness in improvement was shown. All doxepin doses were well tolerated and exhibited adverse effect properties similar to placebo. There was no significant effect on the clinically significant changes observed in residual sedation and sleep construction the next day.</p><p><u style="single">Example 20</u><u style="single">Phase III study to evaluate the sleep-maintaining effect of doxepin hydrochloride (HCl) compared to placebo in patients with primary insomnia</u> A phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was conducted to evaluate the efficacy and safety of two doses of 3 mg and 6 mg of doxepin HCl in patients with primary insomnia who have difficulty maintaining sleep. did. Patients with a 3-month history of primary insomnia were enrolled according to the primary insomnia specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR).</p><p> The study was a randomized, double-blind, placebo-controlled parallel group designed to evaluate the efficacy and safety of two-dose levels of 3 mg and 6 mg of doxepin in subjects with primary insomnia and sleep maintenance difficulties. It was a test. Efficacy and safety assessments were performed throughout the study period. Doxepin 3 mg and 6 mg capsules, as well as placebo capsules, were provided in single doses for oral administration. Sleep efficiency (SE) was evaluated. The data were randomized and analyzed based on the observed cases.</p><p><u style="single">Diagnosis and main registration criteria</u> Subjects have a history of at least 3 months of primary insomnia (as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) and at least 4 of 7 consecutive nights prior to PSG screening. Reported that they experienced awakening after falling asleep (WASO) 60 minutes, latency to fall asleep (LSO) 20 minutes, and total sleep time (TST) 6.5 hours, between the ages of 18 and 64. They were women and men.</p><p><u style="single">Evaluation criteria:</u> Primary Validity Variable: The primary validity variable was WASO on the first night.</p><p> Other objective variables: recording of each PSG during double-blind treatment The other efficacy variables obtained at night were sleep awakening time (WTDS), TST, general sleep efficiency (SE), and night 3 SE by minute, SE by night time, latency to continuous sleep (LPS), latency to second stage sleep, number of awakenings after falling asleep (NAASO), total awakening time (TWT) , Post-sleep awakening time (WTAS), and sleep building (1st, 2nd, and 3-4 stages of sleep percentages and minutes; rapid eye movement (REM [REM]) sleep and non-REM sleep percentages; and REM sleep Including the latency up to).</p><p> Subjective Variables: Subjective effectiveness variables were subjective TST (sTST), subjective WASO (sWASO), LSO, subjective NAASO (sNAASO), and sleep quality. These variables were evaluated using a questionnaire completed the morning after each PSG recording night. Dizziness, ability to work, and total daytime doze were assessed using night questionnaires completed on the 2nd, 16th, and 30th nights. The other secondary subjective efficacy variables were 2 items for severity and therapeutic effect entered by the clinician Clinical Global Impressions (CGI); 5 items for therapeutic effect entered by the subject CGI; entered by the subject. Also included was the Insomnia Severity Index (ISI); and a subjective assessment of the mean total sleep time per night after administration of the study drug at home.</p><p> A total of 229 subjects were randomized to study (77 on placebo, 77 on 3 mg, and 76 on 6 mg). These groups were comparable in weight, height, gender, and baseline sleep characteristics. A total of 203 (89%) subjects completed the study and had similar early arrest rates across treatment groups.</p><p><u style="single">Summary of results:</u> Of the 229 randomized subjects, 203 (89%) completed the study and 26 (11%) discontinued the study. Early arrest rates and baseline characteristics were comparable across treatment groups. The study population was female (73%) and male (27%). The average age was 44.5 years. Subjects were Caucasian (48%), Black / African American (33%), Latin American (16%), Asian (1%), and others (2%).</p><p><u style="single">Validity result:</u> Primary efficacy variable using the a priori ITT analysis population (WASO on night 1).</p><p> Mean WASO on night 1 was statistically significantly reduced compared to placebo for approximately 25-30 minutes after doxepin 3 mg and 6 mg. In addition, mean WASO was statistically significantly reduced in each doxepin-treated group for approximately 15-20 minutes compared to placebo throughout the 29 nights of treatment. Also for the averages for the 1st, 15th, and 29th nights, as well as the averages for the corresponding exam nights (1st and 2nd nights; 15th and 16th nights; and 29th and 30th nights). , WASO similar results were observed.</p><p> There was a consistent statistically significant improvement in doxepin 3 mg and 6 mg compared to placebo in SE in the second third and SE in the last third of the night. In particular, SE at 7 and 8 hours of the 8-hour sleep period surprisingly showed a statistically significant increase with treatment with low-dose doxepin. These results are shown in Tables 5 to 7, respectively. The results are also shown in the graphs in Figures 4 and 5.</p><p>(Table 5) Key objective efficacy variables for nights 1 and 29<img file="JP2013237694A_D0017.tif" />The data shown are average (SD). The p-value comparing each active therapeutic agent to placebo was determined from the ANCOVA model using Dunnett's test, which included the main effects of treatment and institution along with baseline values as covariance.¹Analysis performed with log conversion data.</p><p><u style="single">Sleep efficiency</u><u style="single">Overall sleep efficiency</u> There was a statistically significant increase in overall mean SE between the doxepin group on night 1 and the 3 mg and 9 mg groups on night 29 compared to placebo. In addition, there was a statistically significant increase in overall mean SE for nights 1, 15, and 29 in each doxepin group compared to placebo.</p><p>(Table 6) Reference line, 1st night, 29th night, and 1st night, 15th night, and 29th night mean general SE: ITT analysis population<img file="JP2013237694A_D0018.tif" />¹The p-value comparing each active therapeutic agent to placebo was determined from the ANCOVA model using Dunnett's test, which included the main effects of treatment and institution along with baseline values as covariance.</p><p>Sleep efficiency: the last third of the night Statistically significant improvements were observed in the 3 mg and 6 mg doxepin groups compared to placebo in mean SE values in the last third of the first night, night 15 (3 mg and 6 mg groups) and It lasted until the 29th night (6 mg group).</p><p>(Table 7) SE: ITT analysis population at baseline, night 1 and last third of night 29<img file="JP2013237694A_D0019.tif" />¹The p-value for each active therapeutic agent compared to placebo was determined from the ANCOVA model using Dunnett's test, which included the main effects of treatment and institution along with baseline values as covariance.</p><p><u style="single">Hourly sleep efficiency at night</u> Figure 7 shows the hourly sleep efficiency of the first night, adjusted for multiple comparisons using Dunnett's test.</p><p> The hourly sleep efficiency of each of the 3 mg and 6 mg doxepin groups compared to placebo was significantly improved at most evaluation points on the first night, including the 8th hour (p &lt;0.0001).</p><p>8th hour sleep efficiency As shown in Table 8, the mean SE at 8 hours for doxepin 3 mg and 6 mg was 87.8% and 88.4%, respectively, compared with 74.5% in the placebo group.</p><p>(Table 8) SE: ITT analysis population at 8 hours on reference line, night 1 and night 29<img file="JP2013237694A_D0020.tif" />¹The p-value for each active therapeutic agent compared to placebo was determined from the ANCOVA model using Dunnett's test, which included the main effects of treatment and institution along with baseline values as covariance. [1]: p-value comparing each active therapeutic agent with placebo</p><p><u style="single">Example 21</u><u style="single">Phase III study to evaluate the sleep-maintaining effect of doxepin hydrochloride (HCl) compared to placebo in patients with transient insomnia</u> A phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was conducted to evaluate the efficacy and safety of doxepin HCl for the treatment of transient insomnia in adult subjects.</p><p> This randomized, double-blind, placebo-controlled, parallel-group, single-dose study was designed to evaluate the effect of doxepin 6 mg in adult subjects. A laboratory-adapted model (ie, first night effect) and a 3-hour phase advance were performed to induce transient insomnia in healthy adult subjects.</p><p><u style="single">Diagnosis and main registration criteria:</u> Subjects were healthy females and males aged 25 to 55 years with an Epworth Sleepiness Scale score of 12 at screening and a normal nighttime sleep history of 3 months. Similarly, eligibility was determined using protocol regulatory criteria based on sleep diary information obtained during the 7 days prior to randomization.</p><p>Evaluation criteria: once<u style="single">Effectiveness</u>Variable: The primary efficacy variable was latency (LPS) to sustained sleep on the first night.</p><p><u style="single">Key secondary effectiveness variables:</u>The primary secondary efficacy variable was arousal (WASO) after falling asleep on the first night.</p><p> Other objective variables: Other PSG variables obtained on night 1 are total sleep time (TST); general night and total awakening time per hour (TWT); general night, every third of night, night Hourly and sleep efficiency (SE) in the last quarter of the night; latency to second stage sleep; wake time during sleep (WTDS); wake time after sleep (WTAS); general night And hourly post-sleep awakenings (NAASO); and percentages and minutes of sleep in stages 1, 2, and 3-4, percentages of rapid eye movement (REM) and non-REM sleep, and latency to REM sleep. It was sleep building, including time.</p><p> Subjective variables: The subjective variables obtained from the questionnaire completed on the morning of the second day are latency to fall asleep (LSO), subjective TST (sTST), subjective NAASO (sNAASO), and subjective WASO (sWASO). ), And the quality of sleep.</p><p>Summary of results: All 565 randomized subjects (282 in the placebo group and 283 in the doxepin 6 mg group) completed the study. Demographic and other baseline characteristics were similar between the two treatment groups. The testers were female (55%) and male (45%). The average age was 35.5 years. Subjects were Caucasian (50%), Latino American (32%), Black / African American (15%), Asian (1%), Native Hawaiians or other Pacific Islanders (1%), and others. It was (2%).</p><p>Validity result:<u style="single">Primary and major secondary objective effectiveness variables</u> Administration of doxepin 6 mg resulted in a statistically significant improvement in LPS (primary efficacy variable) and WASO (major secondary efficacy variable) on night 1 compared to placebo. Improvements in LPS and WASO were independent of gender and race / ethnicity.</p><p>(Table 9) Variables of primary and major secondary objective PSG on night 1: ITT analysis population<img file="JP2013237694A_D0021.tif" />¹The p-values comparing treatments were determined from the ANOVA model, which included the main effects of treatment and institution.</p><p><u style="single">Other secondary objective effectiveness variables</u> Statistically significant improvement in objective efficacy variables including TST, TWT, SE, latency to second-stage sleep, WTDS, and WTAS was observed after doxepin 6 mg administration compared to placebo. .. Nighttime analysis of SE and TWT was statistically significant at 6 mg doxepin compared to placebo at all time points. Improvements in TWT were evenly distributed across all hours of the night in the doxepin 6 mg group.</p><p> Doxepin 6 mg had no clinically significant effect on sleep construction; sleep stages were conserved compared to placebo. The time (minutes) spent in stages 2 and 3-4 sleep was longer in the doxepin 6 mg group than in the placebo group, and the time (minutes) spent in REM sleep was different between the treatment groups. There wasn't.</p><p>(Table 10) Other objective PSG variables on night 1: ITT analysis population<img file="JP2013237694A_D0022.tif" />¹The p-value comparing doxepin 6 mg treatment with placebo was determined from the ANOVA model, which included the main effects of treatment and institution.</p><p> Step-down method of primary and major secondary efficacy variables: Comparison of LPS with placebo in the doxepin 6 mg group was statistically significant. Therefore, a comparison was made regarding WASO. Similarly, after administration of doxepin 6 mg, there was a statistically significant improvement in WASO compared to placebo.</p><p> Sensitivity analysis of primary and major secondary efficacy variables: For both LPS and WASO susceptibility analyzes, the results compared to placebo in the doxepin 6 mg group were statistically significant (p &lt;0.0001) and included the ITT analysis population. It was similar to the results of the cases observed using.</p><p> Subjective efficacy variables: Statistically significant improvement in all subjective efficacy variables (LSO, sTST, sWASO, sNAASO, and sleep quality) compared to placebo on day 2 after doxepin 6 mg administration It was observed.</p><p>Conclusion: Doxepin 6 mg was statistically significant and clinically significant on the objective and all subjective scales used in this study to assess sleep onset, sleep maintenance, and prevention of early-morning awakening compared to placebo. It had a meaningful effect. Doxepin 6 mg was safe and well tolerated after a single dose and had adverse adverse effects comparable to placebo.</p><p> Efficacy and safety results comparing doxepin 6 mg to placebo include:</p><p> Statistically significant effect (p &lt;0.0001) on both objective and subjective measures of falling asleep, as assessed by LPS (primary efficacy variable) and LSO. The mean square of LPS was 13.0 minutes shorter in the doxepin 6 mg group than in the placebo group. The mean geometric least squares of LSO was 23.4 minutes in the doxepin 6 mg group, compared with 31.7 minutes in the placebo group.</p><p> Multiple objective and sleep maintenance objectives, including WASO (major secondary efficacy variable), TST, general SE, night hour SE, WTDS, general TWT, night hour TWT, sTST, and sWASO. Statistically significant effect on subjective scale. Objective and subjective evaluation results were consistent, but in some cases (ie, TST and WASO) subjective scores underestimated the strength of the effect seen on the PSG scale of the same variable. It was.</p><p> Statistically significant improvement in early-morning awakening prevention as assessed using PSG variables, including SE at 7 and 8 hours, WTAS, and SE in the last quarter of the night.</p><p> The number of awakenings and TWT were evenly distributed over night time with doxepin after the first hour.</p><p> There was no clinically significant effect on sleep building; sleep stages were conserved.</p><p> There were no clinically significant sequelae / residual effects the next day.</p><p> There were no reports of potential anticholinergic or memory-impaired adverse effects in the doxepin 6 mg group.</p><p> Laboratory values, life sign measurements, ECG, physical examination, or neurological evaluation showed no clinically significant changes. The incidence of laboratory-related adverse effects was low in both treatment groups.</p><p><u style="single">Sleep efficiency</u><u style="single">Overall sleep efficiency</u> There was a statistically significant improvement in the overall mean SE in the doxepin 6 mg group compared to placebo. Least squares mean SE was 10.6% higher (improved) in the doxepin 6 mg group than in the placebo group. The SE results are shown in Table 11.</p><p>(Table 11) SE: ITT analysis population in the first night in general and in the first, second, and last thirds of the night<img file="JP2013237694A_D0023.tif" />¹The p-values comparing treatments were determined from the ANOVA model, which included the main effects of treatment and institution.</p><p>Sleep efficiency: the last third of the night A statistically significant improvement was observed in the doxepin 6 mg group compared to placebo in mean SE in the last third of the night. Least squares mean SE was 9.5% higher (improved) in the doxepin 6 mg group compared to the placebo group.</p><p><u style="single">Sleep efficiency in the last quarter of the night</u> Table 12 outlines SE in the last quarter of the night for each treatment group using the ITT analysis population.</p><p> A statistically significant improvement was observed in the doxepin 6 mg group compared to placebo in mean SE in the last quarter of the night. Least squares mean SE in the last quarter of the night was 10.4% higher (improved) in the doxepin 6 mg group compared to the placebo group.</p><p>(Table 12) SE: ITT analysis population in the last quarter of the first night<img file="JP2013237694A_D0024.tif" />¹The p-values comparing treatments were determined from the ANOVA model, which included the main effects of treatment and institution.</p><p><u style="single">Hourly sleep efficiency at night</u> The hourly sleep efficiency of the doxepin 6 mg group compared to placebo was statistically significantly improved at all time points (p 0.0003). Figure 6 shows the hourly sleep efficiency of the first night.</p><p> Table 13 shows the sleep efficiency at 7 hours using the ITT analysis population.</p><p> Table 14 shows the sleep efficiency at 8 hours using the ITT analysis population.</p><p>(Table 13) SE: ITT analysis population at 7 hours on the first night<img file="JP2013237694A_D0025.tif" />¹The p-values comparing treatments were determined from the ANOVA model, which included the main effects of treatment and institution.</p><p>(Table 14) SE: ITT analysis population at 8 hours on the first night<img file="JP2013237694A_D0026.tif" />¹The p-values comparing treatments were determined from the ANOVA model, which included the main effects of treatment and institution.</p><p> As will be apparent to those skilled in the art, the embodiments described herein may be modified and modified in many ways without departing from their scope. The specific embodiments described herein are provided by way of illustration only.</p>