TW483757B - A pharmceutical formulation containing melatonin for use in treating preventing symptoms of dependence on, tolerance of, or addiction to benzodiazepine drugs - Google Patents

Abstract

The invention relates to a pharmaceutical formulation, for use in treating addiction to benzodiazepines in a multidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, which comprises at least one diluent, carrier or adjuvant, and as an active ingredient melatonin, wherein said pharmaceutical formulation contains at least an amount of melatonin effective for any of said treatments, but no more than 5 mg melatonin.

Description

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (1) The present invention relates to melatonin used in the manufacture or treatment of or prevention of benzodiazepine leather agent dependence, or Symptoms of addiction, medicines used to treat multiple drug addictions, and incontinence compositions for such treatments. Dependence on benzodiazepines usually occurs in patients with insomnia who use them to slander sleep, and Patients who become addicted to benzodiazepines to relieve anxiety and spasm during the withdrawal of sleeping pills. However, the habitual prohibition of benzodiazepines (and benzodiazepines usually have long half-life values) may be due to an unknown mechanism, which is manifested by an ineffective increase in dose. Furthermore, it has been observed in animals and humans that recovery or " removal, which often occurs after abrupt stopping of these agents, can lead to addiction (Greenbiatt, D.J., and

Shader, R.I., Drug Metab. Rev., 1978, 8: 13_28). In the 1990 US Family Survey of the Use of Psychotherapy Medicine, approximately 8% of sleeping pill users increased their own pre-dose, which is a 25% increase from the previous report in 1979. Taking this survey into account, 2.6% of the American population was taking benzodiazepines for incontinence (compared with 2.4% in 1979), compared with an estimated 560,000 people in the United States who experienced tolerance and dependence. These figures do not include substance use and multiple drug abuse outside the limits of medical bans or social norms. It has not been reported that patients with dependence on benzodiazepine sleeping pills have rapid withdrawal after effective treatment changes, and this problem is a major obstacle to the rehabilitation and recovery of narcotic drug addicts. It is known that melatonin (a hormone derived from the pineal gland that is derived from the pineal gland at night) participates in the cyclic sleep-wake cycle and regulates sleep. This paper applies the Chinese National Standard (CNS) Α4 specification. (210 X 297 mm) (Please read the notes on the back before filling this page)

483757 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. The invention description (2) plays a major role. There is also some evidence that melatonin can increase the efficacy of benzodiazepines. 'See, for example, Cardinali, DP. Et al., Adv. Biochem. Psychopharm.? 1986, 42: 155-164; Acuna Castroviejo, D. Et al., J. Pineal Res., 1986, 3: 101-102; and Niles, LP, et al., J. Neural Transm. 70: 117-124]. In addition, melatonin can increase the anxiolytic effect of benzodiazepine in mice (Guardiola-Lemaitre, B. et al., Pharmacol. Biochem. Behav., 1992, 41, 405-4080>. On the other hand, It is suggested that benzodiazepine (in some species, including humans) can enhance the inhibitory effect of melatonin synthesis and secretion by GABA (McIntyre, Ι · Μ · et al., Biol · Psychiat ·, 1988 , 24: 105 -108), and the nocturnal increase in plasma melatonin in humans is suppressed by benzodiazepines, thus disrupting the melatonin cycle during the day (Kabuto, M. et al., Endocr. Japon · , 1986, 33, 405-414). However, it has been observed that chronic treatment with oxazepam can change the night-time changes in the density of melatonin receptors in rabbit brains. Observed in pineal gland-removed animals (Anis, Y. et al., J. Neural Transm., 1992, 89: 155-166). The present invention has surprisingly found that melatonin is simultaneously associated with benzodiazepine Prohibition together can potentially free patients from dependence on these drugs, addiction Tolerance and prevention in patients who have been diagnosed with the need for benzodiazepines (and these undesired symptoms have not yet occurred) to prevent these symptoms from occurring. Wei Zuo of Invention · Paper Size Applicable to China National Standard (CNS) A4 (21〇X 297 mm) (Please read the precautions on the back before filling this page) ▼ 483757

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. This document provides-melatonin is used in the manufacture of multiple forbidden substances, or it has a resilience to dinitrogen transfer agents, which has a tolerant second or upper sign. Patients, or patients who have been clinically cherished as having a condition that can be easily treated with benzodiazepine _ to alleviate painful conditions, and prevent patients from becoming dependent on the benzodiazepine drug, have tolerance, or Use of medicines with the symptoms of sacrifice. In another aspect, the present invention provides a patient for the treatment of multiple contraceptive addictions, or a patient who has become dependent on benzodiazepine drugs, has tolerance, or has symptoms of addiction, or is clinically diagnosed as having an easy loan A benzodiazepine drug to alleviate painful conditions in a patient, and at the same time prevent the patient from developing a dependence on the benzodiazepine drug, which is tolerant, or addictive, which contains at least one diluent, Carrier or adjuvant and active benzodiazepine agent and melatonin. The medicine can be a medically contraindicated formulation suitable for oral, rectal, parenteral or transdermal administration, and it contains at least one diluent, carrier or adjuvant, and can be characterized by the following properties: (i) its Unit dosage forms, each unit dose containing melatonin in a range of 0.0025-100 mg; (a) in the form of a controlled release formulation, wherein melatonin is preferably at a predetermined controlled rate Release; (iii) it also contains at least one melatonin receptor modulator and / or melatonin action profile modulator. The medical contraindication may also include, and the pharmaceutical formulation according to the present invention comprises at least one benzodiazepine contraceptive, such as at least one Alprazolam, Limening, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Helazepam, Qi chicken go Methalazine, Normoxazol, Prazepam, Temazepam, Triazole This paper is sized for the Chinese National Standard (CNS) A4 (210x297 mm) (Please read the precautions on the back before filling this page),? Τ • J— n —J. · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 483757 A7 --- __B7 V. Description of the invention (Π 一 ----— Benzodiazepine. Formulation containing at least one benzodiazepine leather agent The substance can further be characterized by-or a plurality of properties as described above, (ii) and (iii). In the application of the present invention to the treatment of multiple drug addiction or having dependence on a benzodiazepine drug, For patients with symptomatic or addictive symptoms, benzodiazepine medication is continuously administered to patients (at least at the beginning), and at the same time melatonin is effectively banned to relieve at least one of these symptoms . In a particular embodiment of this treatment, the benzodiazepine agent or melatonin may be in the form of a medically contraceptive formulation suitable for oral, rectal, parenteral or transdermal administration, and contains at least one diluent , Carrier or adjuvant. In addition, the benzodiazepine and melatonin formulated can be administered separately or combined into a single pharmaceutical formulation including diazepine drugs and melatonin. '' About fading For administration of melanin, whether administered separately or co-administered with one or more benzodiazepines, the effective amount of the ban can be a daily dose rate of, for example, 0.001 to 100 mg Fangu; It can be administered in the form of a controlled release formulation. For example, 1-2 mg of melatonin in the form of a controlled release formulation can be administered at night. Melatonin can be used with melatonin receptor modulators or fading. The melatonin action profile regulator is co-administered with Tsai. An example of a saver is a short-range action benzodiazepine, such as formazan; the body; the melatonin action profile modifier is benzodiazepine, beta-block Agents and serotonin absorption inhibitors. In addition to other effects, other regulators, the melatonin effect profile can allow patients to receive light before, after or during melatonin administration. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 Mm) (Please read the notes on the back before filling out this page}

Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs IT-I 483757 A7 ___—__ B7 V. Description of the Invention (5) The benzodiazepines referred to in this article may cause dependence, tolerance and / or the risk of cancer symptoms . Without any prejudice to this overview, such drugs may be one or more of the aforementioned Alprazolam, Limening, Clorazepate 'Diazepam' Flunitrazepam, Flurazepam, Helazepam, Qi-Nordiazepam, Normexyl-Diazepam, Prazepam, Temazepam and tribenzidine. In another embodiment in which the above symptoms are treated using the present invention, the benzodiazepine drug is initially maintained (at the same time as melatonin) at substantially the same level as that previously recommended for patients receiving melatonin treatment. The dose is administered to the patient. In another embodiment in which the present invention is used to treat these symptoms, the benzodiazepine (at the same time as melatonin) is compared to the daily dose received by patients who have previously been recommended to treat melatonin Reduced doses are banned from administration to patients. In this specific embodiment, the gradually decreasing daily application rate may continue (for example) to reach a predetermined stable dosage rate, or otherwise (for example) until the dosage of benzodiazepine is zero. In the application of the present invention for prevention purposes, it is used to treat patients who have been clinically diagnosed as having a condition to ease pain by administration of benzodiazepines, while preventing patients from developing the benzodiazepines Symptoms of dependence, tolerance, or addiction are those in which the benzodiazepine agent is administered in an amount effective to slow the condition, while melatonin is administered to the patient in an amount effective to prevent at least one of these symptoms. The above items can be applied to specific examples of treating patients with the indicated symptoms, and can be correspondingly applied to preventive purposes, unless those skilled in the art have a reason for their inapplicability, for example, benzodi In the case where the nitrogen treatment is urgently needed, it is obvious that the size of the benzene paper to be applied is in accordance with the Chinese National Standard (CNS) A4 (2) 10 × 297 mm. (Please read the precautions on the back before filling this page) Order 483757 A7 V. Description of the invention (6) The amount of the two will not be reduced to zero, and in any particular case A may be reduced by the physician's decision. However, in the prophylactic bacteria of the present invention, not only to the applicator, but also melatonin, the benzodiazepine agent achieves a specific purpose at the conventional dose rate, and it is also applied to the same Or, it is still within the scope of the present invention to administer the agent to a patient in a dosage of less than a conventional dose. As indicated above, the invention also extends to pharmaceutical formulations comprising at least one benzodiazepine and melatonin. Because benzodiazepines are usually administered 1-4 times per day, the daily rate of melatonin is 0.001 to 100 mg (typically at night), so the same formulation of benzodiazepine is used. Benzodiazepines were achieved with the following examples: Therefore, the unit dose of benzodiazepines was 1 2 3 4 0 · 100 mg 0.05-50 mg 0.033-33.3 mg 0.025 -25 mg Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. When the pharmaceutical formulation of the present invention is in the form of a unit dose, each dosage unit is preferably applied at night and preferably contains a content range of 0.000. 25-100 mg of melatonin. The following table gives the benzodiazepine doses used to treat the above conditions in adults. For further information, such as restrictions, half-life, suitable for children or this, in the application of Zhang's scale) from the specifications (2 males 483757 A7 B7 V. Description of the invention (7) infants' application forms and dosages, see Goodman & Gilman's " The Pharmacological Basis of Treatment ", 7th edition, 1985 (MacMillan Publishing Company), chapter on the use of benzodiazepines (eg pages 352, 437), all of which are incorporated This article serves as a reference. Benzodiazepine unit oral dose 値, one milligram (X per day) sedative amount sleep-like daily oral dose *, anxiety relief Alprazolam 0.75-1.5 rimienine 10-100 (1-3) 50 -100 15-40 Clorazepate 3.75-15 (2-4) 15-30 30 Diazepam 5-10 (3-4) 5 -10 4-40 Flurazepam 15-30 Helazepam 60-160 Dimethoate diazepam 2-4 2 -6 Normidine Diazepam 15-30 (3-4) 15-30 30-60 Prazepam 20-40 Temazepam 15-30 Triazole benzodiazepine 0.25-0.5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please Read the notes on the back before filling out this page) * mg, usually divided into 2-4 unit doses For further information (including parenteral dose rates), please refer to the Goodman & Gilman quoted above. The preparation and release profile of the formulation according to the invention or its application is illustrated below. (A) Powdery substance to be 2 mg / tablet melatonin (Biosynth, Switzerland) and acrylic resin carrier (Rohn Pharma), which is the standard of this paper and applies the Chinese National Standard (CNS) A4 (210X 297 mm) 483757 Central Standard of the Ministry of Economic Affairs A7 B7 printed by the Bureau's Consumer Cooperatives V. Invention Description (8)

Eudrgit RS100 (Recipe SR-Ms) or Eudragit RSP0 (Recipe SR-

Mf) ’In addition to the other components shown below: Formula SR ~ Ms: Eudragit RS100 48 · 8%, lactose 50%, melatonin 1.2%; formula SR-Mf:

Eudragit RSP0 35.3%; lactose 16.7%, calcium hydrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%, after drying and mixing, compress in a 7 mm cylindrical perforator at 2.5 tons. SR-Ms and SR-Mf are sustained release formulations. '' The conventional dosage form (RM) was prepared similarly to the formulation SR-Mf, but used lactose instead of Eudrgit as a carrier. (b) The possible release profile of the tablets prepared as described in paragraph (a) was first studied with the dissolution of melatonin in distilled water at 37¾ in vitro. The results in Table A are shown at the set time interval. Dissolved melatonin content% (average of 6 tablets). &Quot; "

4__A Time (hours) 1 2 4 6 8 10 Melatonin (%) is released by: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100 ^ ^ ^ (C) If The in vivo cross-sectional view of the SR-Mf tablets prepared in paragraph (a) was taken orally at 10 am (ie when circulating melatonin could not be detected) to a healthy man (age 36). The drug was studied twice. Melatonin Yu, Tongue 10 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) ----------- Sliding ------- Order ----- (Please Read the precautions on the back before filling this page] 483757 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) The amount released in the body is based on its main metabolite (6-sulfate oxygen Based on radioimmunoassay in urine. The 6-sulfate oxymelatonin content in urine closely reflects the blood concentration of the hormone. The results in Table B show the measured melatonin. % Of total administered melatonin (average of 2 tablets). A__B_ Release time of melatonin from SR-Mf in vivo (hours) 1 2 4 6 8 10 Released at% of interval 10.7 25.7 40.6 14.0 7.0 1.9 Cumulative release% 10.7 36.4 77.0 91.0 98.0 99.9 Note that due to the phenomenon that active compounds are absorbed by tissues in the early stages of release, the release of melatonin in vitro (as described in Table A) is only provided An approximate indication of the cross-section of the release in vivo. The content can be changed to, for example, 0.5, 1 or 5 mg / tablet without affecting the release pattern found in melatonin containing 2 mg / tablet. In the present invention, as substantially in the human body Melatonin analogues known to mimic the action of melatonin will be considered to be the obvious chemical equivalent of melatonin. According to the present invention, one or more benzodiazepines can be treated as described above. The amount is incorporated into the above-mentioned formulation. The present invention will be illustrated by the following examples. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

483757 A7 ______B7 V. Description of the Invention (10) Example 1 Study the interaction between benzodiazepine and melatonin administration on melatonin and benzo-nitrogen leather sensory body in the brain and melatonin The ability to reverse these effects. The male rats were maintained at 24 ± 2ec for 14 hours a day: 10 hours dark schedule (light: 05.00h; cold white fluorescent lighting). Unlimited food and water supply. The animals (2 months old) were divided into 4 groups, each containing 5 animals. One group of animals (CON) was injected with i.P. vehicle (200 microliters of saline) daily at 16:00. Animals of the second group (VAL) were stabilized i.p. injection at 16:00 every day (1 mg in 2000 microliters of vehicle; Roche). Animals in the third group (MEL) were injected with vehicle at 16:00 daily; drinking water in this group contained melatonin (4 mg dissolved in 100 microliters of ethanol and diluted to 1 liter). Animals in the fourth group (VAL / MEL) were injected with diazepam at 16:00 (1 mg in 200 microliters of vehicle); the water in this group contained melatonin (4 mg was dissolved in 100 microliters of ethanol and diluted) To 1 liter). The treatment was terminated after 21 days and the animals were weighed. The mean body weights in the VAL (274 ± 20g) and VAL / MEL groups (239 ± 30g) were found to be slightly lower than those in the CON (292 ± 30g) or MEL groups (285 ± 30g). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The animals are decapitated at 18-19.00 the next day (at this time, 2-125 iodine in the impurity bridge fades The hormone concentration should be maximal); quickly remove the brain and prepare coarse synaptosome pellets as described, and analyze as described by Laudon, M. and Zisapel, N., FEBS Lett., 1986, 197: 9-12 Melatonin receptor. Analysis of benzodiazepines by measuring the combination of 3 Hf lunitrazepam (3 H-FNZ) and 3 h-RO 15-1788 as described by Amiri, Z · et al., Brain Res ·, 1991, 553: 155-158 body. Calculate the combination from the balanced combination data -12-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 483757 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of invention (η) parameters. Bmax 値 represents 2- 丨 25 I-iodine melatonin, 3 H-FNZ or 3 H-RO 15-1788 is a specific combination under saturation, and Kd 値 is the apparent dissociation constant. By analyzing the scatter of Student-Newman-Keul's test for multiple comparisons, the binding parameters of each group were compared. If P < 0.05, it is considered to be significantly different. Diazepam (1 mg i · P at 16:00) was injected into male rats for 3 weeks, which significantly reduced the density of the 2-norbiodine melatonin binding site in the medullary bridge (Table 1), while benzodiazepines The combination of rhenium was not significantly affected (Table 2). If the melatonin receptor is related to the sleep-wake cycle, these results suggest that the habitual administration of benzodiazepines leads to the mechanism of melatonin response and subsequent decrease in physiological activity. Melatonin, given orally by drinking water for 3 weeks, significantly enhanced the binding of 3 H-RO 15-1788 to the medullary bridge (Tables 2, 3), while the binding of 2-N-I-iodine melatonin was not affected . The density of benzodiazepine-binding sites in the medullary bridges elicited by melatonin treatment increased with apparent Kd, consistent with the increase previously observed in rat cortex, and showed an intervening involvement of opioid peptides ( Gomar, M.D. et al. Neuroendocrinology 1993, 4: 987-990). The fact that this increase is retained even in animals treated with stabilization may preclude competition between melatonin and benzodiazepine at the benzodiazepine binding site for daily dosing of stability and melatonin, stubborn 3 H -R0 15-1788 binding in the medullary bridge and reversed the suppression of 2-I-25 I-melatonin binding in this region by diazepam (Table 1, 2). These results are surprising as shown previously (Anis, Υ · et al., Melatonin binding site in hamster brain: the impact of melatonin. Molec · Cell. Endocrinol., -13-paper size Applicable to Chinese National Standards (CNS> A4 specifications (21057 mm Ding " (Please read the notes on the back before filling this page)) Assembling and ordering 483757 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (12) 1989, 67: 121-128; Oaknin-Bendahan, S. et al., J.

Basic Clin. Physiol. Pharmacol., 1992, 3: 253 ^ 268), and it was also determined in this study that banning melatonin by morning or evening injection or oral administration via drinking water will not affect melatonin Melatonin density or day-to-day changes in parts of the brain (including medullary bridges). However, pineal glandectomy does not abolish the diurnal changes in 2-iodine-melatonin binding sites, although it affects their phase positions (Oaknin-Bendahan et al., 1992, at the same place). Therefore, changes in the density of melatonin-binding sites may not be due to receptor self-regulation by melatonin. In the cerebral cortex, melatonin slightly reduces the combination of 3 H-R0 15-1788 and 3 H-FNZ. Treatment with diazepam did not significantly affect the combination of 3 h-R0 15-1788 and 3 H-FNZ, but prevented the reduction of melatonin involvement (Tables 2, 3). These data first suggest that the effect of melatonin on benzodiazepine binding sites is limited, rather than the general suppression or promotion of binding, and second, that melatonin replacement therapy can resist some chronic Harmful effects of benzodiazepine treatment. Table 1 shows the average values of Kd (unit nM) and Bmax (units of micromolar / mg protein) and S · D · 値. Equilibrium binding parameters of 2-125 I-iodine melatonin binding sites in synaptosome preparations obtained from rat medulla bridge regions. There are no significant differences in Table 1 indicated by the same symbols. (Symbols with the same meaning are also used in Tables 2 and 3, as follows.) This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 × 297 mm) | Installation-(Please read the precautions on the back first Refill this page) Order. 1.483757 A7 B7 V. Description of the invention (13) Table 1 Group Kd ± sd Bmax ± sd C0N 0 · 87 ± 0 · 2 a 7.9 ± 1.0a MEL 1 · 16 ± 0 · 3 a 7.7 soil 1.0a YAL 0 · 98 ± 0 · 21a 5 · 1 soil 0.5b YAL / MEL 2 · 27 ± 0.75b 12.5 soil 2.0c Table 2 uses Kd (unit nM) and Bmax (unit: micromole / mg protein) The average and SD 値 terms list the 3 H-R0 15-1788 binding sites in synaptosome preparations obtained from the medullary bridge region of stabilized and / or melatonin treated and untreated rats Balance binding parameters ο Table 2 Group Kd soil sd Bmax ± sd C0N 2 · 3 soil 0 · 4a 310 soil 22a MEL 2.8 ± 0.2a 476 soil 26b VAL 2 · 5 ± 0.4a 295 soil 34a YAL / MEL 2 · 6 Taxi 0 · 5a 375 Soil 87b (Please read the precautions on the back before filling out this page) SD 値 terminology ( Units of micromoles per milligram of protein) show the effects of diazepam or melatonin on the binding of 3 H-FNZ and 3 H-RO 15-1788 to rat cerebral cortex. This paper size is applicable to China National Standard (CNS) A4 (210X297 mm), invention description (14). Table 3 3 H-FNZ — One-~ 3 H-R0 15-1788 — · — — _ 935 soil 31a 1354 Soil 48a 765 Soil 78b 1060 Soil 26b 870 People 22a 1264 Soil 99a 980 Soil 16a 1362 Soil 155a

Group — 、-一 _ CON MEL VAL VAL / MEL (Please read the precautions on the back before filling this page) Example 2 Order printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Benzamidine diazepam has a surprising effect on fine tolerance and often rapid withdrawal. A 43-year-old married with two children and only suffered from insomnia for 10 years and had frequent and severe migraines. 2 A complete neurological assessment is negative. Problems with mental or other organs are also eliminated. After these years, she has received benzodiazepine, tricyclic anti-anxiety agent # 2 diazepam analgesics, and biofeedback and relief methods, but no significant improvement. In recent years, she has taken 4 to 8 mg of qi to nortriprolidone per night and the complete spirit of the sleep laboratory at Tel Aviv University has been evaluated. No obvious symptoms have been revealed. The nature of sleep is analyzed by tracking the action map of the type of asleep-wake during sleep through a small device connected to the wrist. This track records green for 3 consecutive days and shows disturbed sleep patterns. • Reduced efficiency, long sleep latency, and multiple wake insertions. Urine was collected at every hour (36 hours) and the main melatonin metabolites were analyzed: human acid oxymelatonin, as a day-to-day secretion of plasma melatonin. The results showed that 6_ sulfate melatonin excretion was more than the same age 16-

483757 A7 B7 V. Description of the invention (15) Individuals are low and lack typical cycle rules (Table 4). Began oral administration of a controlled release melatonin formulation in the form of a tablet containing 1 mg melatonin (Neurim Prohibition Company, Israel) to correct defects and distortions in the melatonin cycle. One tablet is administered daily at 8:30 AM. The patient was asked to gradually reduce the number of benzodiazepine tablets that were taken every night. Unexpectedly, within 2 days, the patient completely stopped using benzodiazepine sleeping pills and claimed that her insomnia had improved significantly. In addition, his headache gradually subsided. Tracking of the repetitive effect spectrum after 3 weeks of treatment showed significant improvement in sleep patterns. Treatment was discontinued, and urine was collected again every 3 hours (36 hours) after 2 weeks and 6-sulfate oxymelatonin was analyzed. The results (Table 4) indicate an increase in the amount of 6-sulfateoxymelatonin in the urine and a significant nighttime peak. A follow-up of 5 months confirmed that the patient still maintained his sleep and rarely had headaches. After 6 months of no treatment, the nature of sleep worsened and melatonin was given again. This case report may indicate a breakthrough to relieve the suffering of many patients whose nature of life has been disrupted by benzodiazepine addiction. Administration of exogenous melatonin can also be used as a rapid and symptom-free method to remove p-benzodiazepine-bearing patients. (Please read the notes on the back before filling this page)

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) M specification (21 × 297 mm). 5. Description of the invention (16 ^--benzo ~ azepine-dependent patients) Urine 6 'sulfate oxymelatonin (micrograms / hour) before and after melatonin treatment--time before treatment ~ -------after treatment 15.00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11 24.00 0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.21 12.00 0.13 0.01 15.00 0.22 0.04 (Please read the notes on the back before filling out this page} I. Ordering and Printing by the Central Standards Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs Example 3 This Example The effects of long-term administration of melatonin treatment on insomnia in benzodiazepine-dependent patients are described. Two volunteers, YL · (80-year-old male) and E · L · (73-year-old female) have suffered from insomnia. Waking up at night and / or at night and having difficulty falling asleep afterwards. Both have been found to have low melatonin secretion (by measuring the amount of metabolite 6-sulfateoxymelatonin in the urine). All patients took 2 mg of flunitrazepam orally every night before going to bed. Each patient was scheduled to reduce the dose of f 1uni trazePam to this paper. This paper applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 483757 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (17 ^ and at the same time melatonin (12 mg per E12 in a controlled release) was administered for more than 2 months. Since the end of this period, every Patients continued to take melatonin in the same form and at the same dose rate for about 2 years. Each patient reportedly subjectively reported good sleep defamation and substantial improvement in the nature of sleep. In particular, patient EL was scheduled At the beginning of the period, there was an improvement in sleep quality in the nature of sleep, and YL · had a similar effect in recording green when entering the second period of about two questions. Each patient reported a reduction in fatigue in white peony within a few days after starting the rest period, It was also pointed out that melatonin had left no fatigue or no hangover sensation in the morning. Neither patient reported any side effects. Example 4 This example, Randomized, double-blind, and cross-study studies show that melatonin replacement therapy improves sleep performance in older patients who are habitually using benzodiazepines. A group with an average age of 78 years (SD = 9 · 7) Consists of eight men and five women, all of whom suffer from chronic insomnia and use various benzodiazepines to provoke sleep. Urine was collected for approximately 15 hours approximately every 4 hours, and weighted as RiA. Analysis of 6-sulfate oxymelatonin, the major melatonin urine metabolite, was performed at night. Urinalysis of these patients showed low and delayed 6-sulfateoxymelatonin excretion (<14 micrograms per night, compared to 25 micrograms per minute in young adults). The study plan included two treatment periods of three weeks each, and a weekly wash-out interval between the two treatment periods. During the treatment period, patients were orally administered 2 mg of controlled-release melatonin tablets or placebo before bedtime. Five patients continued to fade outside of the initial experiment time. The paper size applies the Chinese National Standard (CNS) A4 (210X297 mm) (please read the precautions on the back before filling this page) f. Binding 483757 A7 B7 V. Description of the invention (18) Melanin treatment for 2 months. At the end of each treatment period, a wrist-loaded effect map was used to objectively analyze the patient's sleep for three consecutive nights. Neurini algorithm was used to analyze exercise log green to determine sleep latency, sleep efficiency, total sleep time, and the number of wakes and awakenings after sleep onset as the average of three nights in the individual. Six-pair marker-array analysis showed statistically significant differences in sleep parameters between the array of melatonin and placebo-treated periods. The results are shown in Table 5. Table 5: Effect of melatonin-substituted benzodiazepine on sleep parameters Parameter of melatonin placebo after 3 weeks of treatment + 82% of sleep after 2 months of melatonin treatment 75% efficiency (ζ = -2.82, ρ = 0.005) Sleep latency 17 minutes 39 minutes 7 minutes (ζ = _2 · 12, ρ = 0 · 03) 59 minutes 39 minutes and 7 minutes wake up after sleep onset (ζ = -2 · 00, ρ = 0.04) Number of awakenings 11 17 10 (ζ = -2.70, ρ = 0.007) Total sleep time 386 minutes 375 minutes 348 minutes (ζII-0.57, ρII 0.58) by From the above results, it is concluded that melatonin replacement therapy can improve the printing of consumer cooperatives with employees of the Central Standards Bureau of the Ministry of Economic Affairs ^^^ 1 '^ il · · ϋϋ mV —ϋ mi 士 ιϋ_— ϋϋ In ϋϋ mu- —ϋ ϋ ^ (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 483757 A7 B7 V. Description of the invention (19) The use of endogenous melatonin Sleep Initiation and Persistence of Diazepam in Older Patients. The benefits of melatonin therapy increase over time, suggesting that reorganization of the cyclic system has occurred. The present invention further includes manufacturing patients for treating multiple addictions, or patients who have become dependent on benzodiazepines, have tolerance, or have symptoms of addiction, or have been clinically diagnosed by the treatment industry as having an easy-to-use drug. A method of diazepine medicine to alleviate painful patients and prevent patients from relying on the benzodiazepine medicine, having tolerance, or symptoms of addiction; the method comprises using melatonin and At least one diluent, carrier or adjuvant is mixed and formulated in a unit dosage form suitable for oral, rectal, parenteral or transdermal administration, each unit dose containing 0.0025-2 mg (preferably 0.01-2 mg) of melatonin, and is preferably adapted to release melatonin at a predetermined controlled rate. In addition, at least one melatonin receptor modulator and / or melatonin action profile modulator, and / or at least one benzodiazepine inhibitor such as Alprazolam, Limening, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Helazepam, qi chicken nor nail stability, norrinthidine stability, Prazepam, Temazepam and three. Sitting benzodiazepine is mixed with melatonin. (Please read the notes on the back before filling out this page) ϊ m .1 ^ 1. V —ϋ —ϋ m ϋϋ ϋϋ ml I I. —ϋ— ^ 二 = 印 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 483757

A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description () ROC Patent Appln. No. 85104319 Patent Application No. 85104319 Supplemental Examples in Chinese-Enel. I (Republic of China 90 (Submitted on May 4, 2001) Example 5: To study the effects of melatonin on 34 adult patients aged 40-90 years is to defend the first six cycles (Phase I) and subsequent In the second six cycles (phase n), these patients initially took 1 or 2 quasi-rotors selected from the following agents for insomnia each night: Alprazolam, Brotizolam, Flunitrazepam, Lorazepam, Nitrazepam, Oxazepam, and Triazolam, These patients were required to take 2 mg of CRM (controlled release formulation) melatonin (n = 18) or the same type of placebo (n = 16) two hours before bedtime each week for the first six weeks, In addition, take the standard dose of benzodiazepine (first week), 50% of the standard dose (second week), 25% of the standard dose (third and fourth weeks), and avoid taking benzodiazepine (No. Five and six weeks) The treatment of patients which dan stopped taking benzodiazepines rate significantly exceeds that of patients after placebo treatment (4/16 to 14/18). In Phase Π, CRM was administered to CRM patients in Phase I (15/18) and patients in Placebo (15/16) at the same rate, and failed to stop taking benzodiazepines in Phase I. Patients are encouraged to further reduce the amount of benzodiazepines by 50%, 75%, and 100% in weeks 8, 9-10, and 11-12, respectively; as a result, after entering the first week of period Π, Six of the patients in the initial placebo group discontinued benzodiazepines. No significant association with the specific class of benzodiazepines administered was found in cases of successful discontinuation of benzodiazepines. • 22- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------- 1 · ----------------------- ------- (Please read the notes on the back before filling in this page) 483757 r A7 B7 V. The day of invention is finished ▲ 30 individuals of Phase Π (24 of them have stopped taking benzodiazepine Generation) was selected to continue taking melatonin. After six weeks, 19 of the 24 people were still exempt from benzodiazepine, but 5 of them resumed taking it (some reduced doses). During the 12-week test period, compared with the patients taking melatonin in Phase I, they were all taking Panyaji for the entire period: they had consistent sleep quality scores for a full 11 weeks. 'The sleep quality scores of the two groups of patients were consistent. 0 Conclusion: Treatment with melatonin according to this embodiment will result in the removal of dependence, tolerance or addiction to benzodiazepine in a significant majority, and In some cases where good sleep quality is supported, the dose of benzodiazepine can be reduced. Supplementary note: In this example, it is clear that the patient is taking the individual doses of benzodiazepine and melatonin. Selectively, it can be administered in the form of a single medicinal composition in the same amount according to the present invention. Benzodiazepine and Melatonin 0 (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-23- H: \ EVA \ 85155-claims.doc This paper standard applies Zhongguanjia Standard (CNS) A4 size ⑵q χ tear public hair>

Claims (1)

483757 A8 B8 C8 D8 Patent Application No. 85104319 VI. Scope of Patent Application κυυ raieiu ΛΡΡ 丄 1NO. 03iU4〇Uy Amended Claims in Chinese-Annex I Amended Claims in Chinese-Enel · I ~~ (Feb. 91, Republic of China (Submitted on February Y, 2002) (Submitted on February Y, 2002) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1. A pharmaceutical composition used to treat benzodiazepine drug addiction in people with multiple drug addictions, or Patients who have become dependent, tolerant, or addicted to benzodiazepine drugs, or patients who have been clinically diagnosed as having a condition to ease pain by benzodiazepine drugs, and prevent patients The benzodiazepine drug is dependent, tolerant, or addictive, and includes at least one diluent, carrier or adjuvant and melatonin as an active ingredient, wherein the medicinal composition contains a treatment for the aforementioned diseases An effective amount of melatonin, but not more than 5 mg of melatonin. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the pharmaceutical comprises a pharmaceutical formulation suitable for oral, rectal, parenteral or transdermal administration and containing at least one diluent, carrier or adjuvant. 3. The pharmaceutical composition according to item 2 of the scope of patent application, wherein the pharmaceutical composition is further characterized by at least one of the following properties: (i) It is in the form of a unit dose, and each unit dose contains a content ranging from 0.00025- 5 mg (preferably 0.025-2 mg) of melatonin; (ii) it is in the form of a controlled release formulation in which melatonin should be released at a predetermined controlled rate; -22- this paper size Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 90. 11. 2,000 1ϋ _ϋ &quot; 1 ΙΒ1 βϋ nn. ^ 1 na— · — tmi in n * 1_1 n an n · nt§§ \ " VI n 11 ϋ · · ϋ -I 1 · 1 I (Please read the precautions on the back before filling out this page) 483757 A8 B8 C8 D8 111 6. Application for patent scope It also contains at least one melanin receptor modulator and And / or melatonin effect profile regulator. 4. The pharmaceutical composition according to item 2 or 3 of the scope of patent application, wherein the medical music composition also contains at least one benzodiazepine. 5. According to the application The pharmaceutical composition of item 4 of the patent, wherein the benzodiazepine agent contains at least One is selected from Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam, Flanitrazepam, Flurazepam ), Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam, and Triazole Benzodiazepine ( Triazolam) 6. The pharmaceutical composition according to item 丨 of the scope of patent application, wherein the treatments include the combination of a benzodiazepine drug and melatonin at a significantly reduced ratio (as compared to patients before melatonin treatment). The doses received are compared) until the predetermined stabilization rate achieved when the benzodiazepine agent is administered. 7. The pharmaceutical composition according to item 丨 of the patent application scope, wherein these treatments include benzophenone Diazine agents and melatonin are administered at a significantly reduced ratio (compared to the dose received by humans before melatonin treatment) until the patient is completely exempt from benzodiazepines. -23 -^ --- ----------- Order --------- line (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs' paper rule money ffl + Group (GNS) A4 specification ⑵ "297 mm" H: \ EVA \ 85155-claims.doc 90. 11. 2,000 483757 A8 B8 C8 D8 VI. Application for patent scope (Please read the precautions on the back before filling this page ) 8. — A medicinal composition used for the treatment of benzodiazepine drug addiction or having dependence on benzodiazepine drugs, with tolerance or addictive symptoms Patients, or patients who have been clinically diagnosed as having a condition to ease pain by administering a benzodiazepine drug, while preventing the patient from developing symptoms of dependence, tolerance, or addiction to the benzodiazepine drug, comprising: At least one diluent, carrier or adjuvant, and benzodiazepine agent and melatonin as active ingredients, wherein the medicinal composition contains melatonin in an amount effective for treating the aforementioned diseases, but not more than 5 mg of melatonin, And the content of benzodiazepine is not more than just Start with the daily dose administered at the time of melatonin treatment. 9. The pharmaceutical composition according to item 8 of the scope of patent application, which is suitable for oral, rectal, parenteral or transdermal administration, and is further characterized by at least one of the following properties: (0 is a unit dosage form, Each unit dose contains melatonin in the range of 0.025-5 mg (preferably 0.025-2 mg); printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (ii) it is a controlled release formulation In a form in which melatonin is preferably released at a predetermined controlled rate; (iii) it also contains at least one melatonin receptor modulator and / or melatonin action profile modulator. 10. According to patent application No. 8 Or the medicinal composition of item 9, wherein the benzodiazepine medicament contains at least one selected from apozazole H: \ EVA \ 85155-claims.doc This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) Printed by 483757 A8 B8 C8 D8 8, Intellectual Property Bureau, Intellectual Property Bureau, Ministry of Economic Affairs, patent application scope Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam ) , Fleni Flamitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Blazepan Prazepam), Temazepam, and Triazolam. 11. A pharmaceutical composition for the treatment of benzodiazepine drug addiction in people with multiple drug addictions, or with Patients who become symptomatic of benzodiazepine drug dependence, tolerance, or palpitations, comprising at least one diluent, carrier or adjuvant and melatonin as an active ingredient, wherein the medicinal composition Contains an effective amount of melatonin for the treatment of the aforementioned diseases, and the amount used is adjusted so that the daily dose is in the range of 0.01-100 mg. 12. A pharmaceutical composition for clinical diagnosis in the treatment industry Patients who are at ease with benzodiazepine medications to reduce pain, while preventing patients from developing symptoms of dependence, tolerance, or addiction to the benzodiazepine medications, which contains at least one diluent, carrier Adjuvant and melatonin as an active ingredient, wherein the medicinal composition contains melatonin 'which is effective for treating the aforementioned diseases, and the amount used is adjusted so that the dosage is between 0.01 to 10 mg Within the range of -25-K: \ EVA \ 85155-claims.doc This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 90. 11. 2,000 nnn an 11 in nn 1_1 · in I— —I I ϋ ny T an · ϋ I · ϋ · ϋ —ϋ II Xikou (Please read the precautions on the back before filling this page)