TWI297607B - The use of mirtazapine for the treatment of sleep disorders and pharmaceutical composition comprising mirtazapine - Google Patents

Description

1297607 A7 B7 V. INSTRUCTIONS (1) The present invention relates to the use of mirtazapine for the preparation of a medicament for use in a method for treating a sleep disorder in a new patient. (Please read the notes on the back and fill out this page.) Sleep difficulties are the main motivation for drug use. The most commonly used drugs are those that interact with the G A B A neurotransmitter-receptor system in the brain, the so-called minor* tranquillisers, a typical example of which is the benzodiazepine drug group. The currently available hypnotics have the disadvantage of having potential adverse effects, preserving lower sleep quality, residual effects, dependence on potential, drug breakage effects, and undesired effects on cognitive function. Sleep quality cannot be derived solely from sleep effects, such as whether sleep is refreshing and has a positive effect on the morning slumbering/alertness of the septum, and also from the characteristics of objective EEG determination, which describes the sleep stage and structure. . The discovery of different classes of benzodiazepine receptors by the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative has been used to open new insomnia medications (see CK Kirkwood: Management of insomnia for details). J Am Pharmaceut. Ass. Vol 39 pp 688-696; 1 999 ). Other mechanisms for inducing sleep are also explored. Opioids, barbituric and antihistamines have been used as sleep inducers for ten years, but their use has been eliminated because of unfavorable side effects and/or lower efficiency. . These drugs are still used in other disorders, the main effect of which is to treat the side effects of sleep disorders. In particular, drugs that antagonize histamine receptors are sedatives and are sleep-inducing, but are less selective, less potent, and less safe than benzodiazepines and today's successful drugs. From a sexual point of view, they are no longer used formally. The mirtazapine is known as an antidepressant. It is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) at 1 5 - 4 5 mg per -4- paper scale. 1297607 A7 B7 V. Invention description (3) (Please read the note on the back first) Fill out this page) exists. The present invention includes the above stereoisomers within the scope thereof and the individual (R) and (S) mirror image isomers and their salts are substantially different, that is, 'with less than 5%, preferably less At 2%, especially less than 1%, another mirror image isomer, and mixtures of such mirror image isomers in any ratio include racemic mixtures containing substantially equal amounts of the two mirror image isomers. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Consortium. The object that can be treated by the present invention can be an animal or a human. The invention is preferably applied to mammals and more preferably to humans. Men and women often respond differently to medications and have different feelings about the nature, frequency and severity of sleep disorders. In addition, there are different treatments for patients with sleep problems of different age groups. In the old age, adolescence or postmenopausal age, each group has its own different treatment needs. Certain aspects of various sleep quality improvements are more important for different age groups or genders or for different sleep disorders. These discriminating factors need to be considered when selecting the treatment of the present invention and selecting the correct dose of mirtazapine for use in the treatment. The very correct dose and method of administration of mirtazapine must be determined by the needs of the individual patient to be administered in the form of a pharmaceutical and the nature or need of the sleep disorder and the judgment of the physician. In general, parenteral administration requires lower doses than other treatments that rely more on absorption. However, the daily dose is between 005·005 and 0.07 mg/kg of the drug's weight. The patient is a patient receiving a mirtazapine to treat a sleep disorder. There are several sleep disorders in humans, of which primary insomnia is the most prevalent and preferred is to be treated with low doses of mirtazapine according to the present invention. Other sleep disorders are, for example, temporary sleep disorders and secondary sleep disorders. Sleep disorders can be applied according to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) at the Diagnostic and paper scales. 1297607 A7 ___ B7_____ V. Description of invention (4) (Please read the notes on the back and fill in the form) page)

The Statistical Manual of Mental Disorders 4th edition (DSM IV), the American Psychiatric Association, Washington, D. C (1 994), the criteria and methods described in the issuer are diagnosed. Although mirtazapine, or a pharmaceutically acceptable acid addition salt or solvate thereof, may be administered alone, it is preferably presented as a pharmaceutical composition for the treatment of sleep disorders, including mirtazapine Or a pharmaceutically acceptable acid addition salt or solvate thereof, admixed with one or more pharmaceutically acceptable adjuvants. Medicinal products including rice-flat tablets may be administered by enteral (e.g., oral, rectal, nasal or topical) or parenteral (e.g., via intramuscular, subcutaneous, intravenous or intraperitoneal injection). The unit therapeutic dose (di-administration unit) is the amount of mirtazapine administered to the patient at a specific time in the form of a pharmaceutical delivery. The daily therapeutic dose can be administered in one or more dosage units suitable for oral, rectal, sublingual or nasal route or transdermal (e.g., transdermal patch, or cream). The Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperation, and the invention further includes a patient pack for treating a sleep disorder, which comprises a dosage unit matched with a packaging material suitable for the dosage unit, wherein the dosage unit includes medical assistance. And the amount of mirtazapine in an amount between 1 and 5 mg, and if desired, the packaging material further includes means to assist the patient in administering the dosage unit in a manner most suitable for treating a sleep disorder. The above-described means for assisting the drug user to use the dosage unit in a manner most suitable for the treatment is, for example, a user of the composition. The intended use of the combination of mirtazapine in the treatment of sleep disorders in their patient kits can be applied to the National Standards (CNS) A4 (210) by helping the patient to use the paper in the most appropriate manner. X 297 mm) 1297607 A7 ____B7 _ V. INSTRUCTIONS (5) (Please read the notes on the back and fill out this page) The instructions, equipment, accessories, fittings and/or other tools used for the compound are to be notified. These measures make the patient's drug pack particularly suitable and compliant with the treatment of sleep disorders. To manufacture medications such as nine, spin, suppository, (micro) capsules, powders, lotions, creams, ointments, implants, patches, gels, and any other preparations for sustained release, sprays, When various injection preparations or the like are used in the form of a solution or suspension, a suitable adjuvant such as a carrier, a tanning agent, a binder, a lubricant, a dispersing agent, an emulsifier, a stabilizer, a surfactant, an antioxidant, a coloring agent may be used. Preservatives and the like are for example described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, in particular Part 8: Pharmaceutical Preparations and Their Manufacture). In general, any pharmaceutically acceptable adjuvant that does not interfere with the function of the active compound is suitable and can be utilized. Suitable materials or carriers for the administration of the composition include agar, alcohol, fat, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, cerium oxide, sterile saline, etc. or mixtures thereof. Use in an appropriate amount. Printed by the Ministry of Economic Affairs, the Intellectual Property Office, the Consumer Cooperative, and the adhesive used to make the pharmaceutical composition have a cohesive property to minimize the loss of the pharmaceutical composition during manufacturing and disposal. The binder is exemplified by cellulose, starch, polyvinylpyrrolidone, and the like. A suitable lubricant which can be used with the active agent of the present invention is, for example, magnesium stearate. Surfactants are available to help compounds in different physical environments such as parental paper scales applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) ^ 1297607 A7 B7 V. Description of invention (6) Aqueous and hydrophobic environments The agent used for contact and exudation. A wide variety of interfacial agents are known to those skilled in the art of making pharmaceutical compositions, such as those described in Remington's Pharmaceutical Sciences et al. (18th Edition, A. R. Gennaro; Mack Publishing Comp; Easton, Pennsylvania). The surfactant which can be used in the preparation of the pharmaceutical composition is, for example, polyethylene glycol (P E G ) or the like. Mirtazapine can be prepared by the method described in U.S. Patent 4,006,848, which is incorporated herein by reference. The following examples are illustrative of the use of the mirtazapine of the present invention. EXAMPLES Mirtazapine was formulated into dosage units containing 0.5 mg, 1.5 mg, and 4.5 mg of mirtazapine. The dosage unit (tablet) containing 0 · 5 mg has the composition shown in Table 1 below: Γ·丨丨---------β-装- (Please read the notes on the back and fill out this page) ) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Table 1 Each batch of tablet excipients gram gram of mirtazapine 0.5 7.7 Corn starch 6.5 100.0 Hydroxypropyl cellulose 1.3 20.0 Magnesium stearate 0.4875 7.5 Aerosil 0.975 15.0 Lactose 2 0 0 Μ to 65 mg to 1000 g This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -9^ 1297607 A7 B7 V. Invention description (8) The design is parallel, double Blind, placebo and active controllers, patients received 14 days of treatment, _ days given once 〇 5 mg of mirtazapine, 1.25 mg of mirtazapine, 4 · 5 mg of mirtazapine, 20 mg of temazepam or Placebo. One week of placebo treatment (washout) was used to begin recording the observations, evaluation and measurement and ending with a one-week placebo treatment after treatment to assess retraction (reb 〇 u n d )/bronchion. The assessment method was to perform a poly-somnography (PSG) recording on the night of the 2nd, 2nd, 1st, 13th, 14th, and 15th, and the first night was defined as the first treatment. One night before the day. The subjective rating using the rating scale for sleep and chalk function was performed using the evening and morning questionnaires throughout the study period (Leeds sleep assessment questionnaire, Μ 0 S sleep assessment scale, clinical total impression scale) Clinical global impression scale, Bastani mood rating scale, Cader Bond mood rating scale, mood state profile). A psychiatric assessment was performed on the mornings of days 1, 2 and 15. The first day was defined as the first day of administration of drugs or placebo at night, on the first day and the morning of the 15th day and Blood was taken at night for 15 days and assessed using signs of life and physical and laboratory measurements. Improvements in quality were observed before and after treatment in the various parameters measured by the methods shown, including sleep benefits and medication safety, adverse effects, and recurrence/bronchion effects. The PSG assessment and the subjective and objective assessment of sleep and performance the next morning, revealing information about sleep parameters such as functional EEG characteristics, sleeping time, total sleep time, nighttime wake frequency and duration, The morning paper awakening time, sleep grading, interrupted stimulation of the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -Γ ^---^------- --- (Please Read the notes on the back and fill out this page.)

一JJ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -11- 1297607 A7 B7 V. Invention Description (9) Sensitivity, refreshing feeling 'unsatisfaction or tiredness after waking up' balance and coordination of getting up Sense of 'sleep health care during the day (such as daytime nap), reflected in the daytime performance state of fatigue, staying awake during the whole day, the performance in the identification test is like simple reaction time, digital alert service (digit Vigilance task ), select reaction time, fast visual information processing, tracking, digital operational memory, text recognition, and feelings of depression, anxiety, confusion, anger, irritability and residual effects. The Lader Bond mood rating scale provides a separate assessment along the following scales: awakening/sleeping, calmness/excitement, strong/declining, coma/mind, well-coordinated/clumsy, lazy/vigorous, satisfied/dissatisfied, troubled / Quiet, slow-hearted / wit, nervous / slack, attention / good illusion, incompetent / proficient, happy / sad, antagonistic / harmonious, interested / tired, lonely / gregarious, worried / careless, depressed / Elated, and self-centered/extroverted. The Bastani Visual Analog Scale provides the following separate assessments of sleepiness: sleepiness, disgust, coma, calmness, initiative, anxiety, stimuli, depression, good overall, no tranquility, unfamiliarity, perk, and roundness. ——------ Install—(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Print -12- This paper scale applies to China National Standard (CNS) A4 specifications (2)0 X 297 public f) TIGKn! Item 2A: Patent application No. 90101408 izy/ου/ Chinese manual replacement page Republic of China December 4, 1996 amendment (here, this bureau pastes the barcode at the time of receipt)

(This statement applies to the various styles of Nao and 雠 发明 invention patent description 軎 834856 ※Application number: 90101408 ※Application date: January 31, 1990 ^PC classification: 1. Invention name: (middle) mirtazapine The use of mirtazapine for the treatment of sleep disorders and pharmaceutical composition comprising mirtazapine for the treatment of sleep disorders (English) 2. Applicant: (total of 1 person)

1. Name: (中) Ou Jialong Pharmaceutical Factory (English) NV ORGANON Representative: (middle) 1. He Clark 2. Puwensen Bick (English) l. KRAAK, Η. 2. VAN WEZENBEEK, PMGF Address: (middle) No. 6 Kluster Street, Oss, The Netherlands

(English) Kloosterstraat 6,5349 AB Oss, The Netherlands Nationality: (中英) Netherlands NEffiERLANDS III. Inventor · (Total 2 persons) 1 Name: (中) Janad Slujout

(English) RUIGT, GERARDUS STEPHANUS FRANCISCUS Nationality: € 3 Netherlands

(English) NETHERLANDS 2. Name: (middle) Fransberg

(H) VAN DEN BERG, FRANS Nationality: (middle) Netherlands

(English) NETHERLANDS IV. Declarations: ◎ Before applying for this case, you have applied for patents from the following countries (regions). Claim international priority: [Format please: Accepting country (region); application date; order number of application number] 1 .Europe;2000/02/11 ; 00200499.2 □No claim priority 1297607 Annex 3 No. 90101408 Patent application Chinese manual No underline replacement page 民丨卜年P月_ 92 September

Bao luxury fe.T V. Description of invention (2) The human daily dose is active for this purpose. It is well known that this dose is critical for effective treatment, especially for the treatment of depression. Mirtazapine has been reported to have some initial sputum effect and thus lead to an impact on sleep. It has been reported to improve temporary or situational insomnia in the range of 5 - 30 mg per person per day, while the dose of 15 mg is better than 5 mg (S 01 · enseneta 1. A cta P Sychiatr · S can d. 71-339-346; 1985). In addition, W i η ok ui. (B io 1 ogica 1 P sychia 11· y 1 998; 45(8S): p 106S) also explored 1 5 and 30 mg of mirtazapine for depressed patients with significant sleep-related pain. The utility of these drugs is recommended to further investigate the treatment of sleep disorders. It has been found that mirtazapine can be used to prepare a medicament for treating a sleep disorder in a patient, the treatment comprising treating the dose with a unit comprising more than 0.1 and less than 5 mg of mirtazapine, in other words, 〇.1 and 5 mg of rice. The unit therapeutic dose between the levels of nitrogen is given to mirtazapine. In general, these achieve therapeutic doses between 0.55 and 70.7 mg/kg for the average person. Different from the expectation, the beneficial results of using this compound as a medicinal correct substitute known to be used in the treatment of sleep disorders are based on the use and recommendations of Sorensen et al and Winokin (described above). The therapeutic dose winner under the dosage range. From the preferred quality after treatment, at least for individual patients, mirtazapine within the above dosage range may be a better choice than known sleep-modifying drugs. The amount of mirtazapine defined in the description section refers to the amount of mirtazapine free base. Mirtazapine contains a palm center and can be in the form of stereoisomers. This scale applies to Chinese national standards (CNS M4 specification (2) 0X297 mm)~~~ ------------- r (Please read the note on the back and then fill out this page) Ordered by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1297607 Α7 Β7 Amendment 5, Invention Description (7) For tablet preparation, the complete amount of mirtazapine is obtained. (alkali) and 100 g of lactose 200 Μ in a 1 liter glass container on a Turbuia mixer pre-mixed at 2 2 revolutions per minute (rpm) for 1 〇 minutes to prepare a granular batch with no composition of Table 1. The mixture was passed through 150 μm and then another 20 g of lactose 200 was added. The remaining lactose, corn starch and hydroxypropyl cellulose were mixed in a high shear mixing granulator. Granulation was carried out. The granules were dried in a tray vacuum chamber and classified by a conical sieve mill and mixed with aerosil and magnesium stearate. The 6 5 mg tablets were pressed into a 5 mm diameter and 7.5 mm. Convex radius. A lozenge containing 1.5 and 4 mg of mirtazapine was prepared in a similar manner, in which lactose was adjusted. Amount to counteract the increased mirtazapine content. A dosage unit containing 15 mg and 4.9 mg of mirtazapine was prepared in a similar manner, which counteracted the reduction in the amount of lactose 200 esh. Low dose mirtazapine The effects of sleep in patients with insomnia: a parallel double-blind comparison with placebo and temazepam. This study was conducted by a central center in several different countries in Europe. According to DS Μ IV Diagnostic criteria select patients with primary insomnia. In addition, patients must have two of the following three objective characteristics: 280 minutes of sleep latency in 8 hours, nightly > 3 awakenings, total sleep Time < 6 . 5 hours. The main exclusion criteria are: secondary insomnia, sleep suffocation syndrome, unrelated serious illness or drug abuse. This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 public) PCT) L.--------41^衣-- (Please read the notes on the back and fill out this page) Ordered by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Printed -10-

Claims (1)

1297607 A8 B8 C8 D8 丨切日耀: VI. Patent application scope Annex 4A Patent application No. 90 1 01 408 Patent application scope Replacement of the Republic of China December 4, 1996 Revision 1. A use of mirtazapine (mirtazaPine) For the manufacture of a medicament for the treatment of sleep disorders, wherein the treatment comprises administering a therapeutic dose of 1.00 to 5 mg of mirtazapine. 2. The use of claim 1 wherein the sleep disorder is primary insomnia. 3. The use of claim 1 wherein the therapeutic amount of the unit comprises 0.5 to 4.5 mg of mirtazapine. 4. For the use of the scope of claim 1, wherein the unit of therapeutic agent comprises 氮.5 to 4.5 mg of mirtazapine. 5. For the use of the scope of claim 1, wherein the unit of therapeutic agent comprises 1.5 to 4.5 mg of mirtazapine, and the sleep disorder is primary insomnia. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives. 6. A pharmaceutical composition for treating sleep disorders, which includes 0.1 to 5 mg of mirtazapine. 7. The pharmaceutical composition of claim 6, wherein the sleep disorder is primary insomnia. 8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises 0.5 to 4.5 mg of mirtazapine. 9. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises 1.5 to 4.5 mg of mirtazapine. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm). Qiao _ 1297607 as _§__ VI. Patent application scope 1 如 · The pharmaceutical composition of claim 6 of the patent scope, including 1.5 to 4.5 mg of imipenem, and the sleep disorder is primary insomnia (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -2- This paper scale applies China National Standard (CNS) A4 specification (210X297 mm)