TW200808804A - Mirtazapine for the treatment of neuropathic pain - Google Patents

Abstract

This invention relates to a method of treatment of neuropathic pain comprising administering to a subject in need of treatment for neuropathic pain a therapeutically effective dose of S(+)-mirtazapine and the use of S(+)-mirtazapine for the manufacture of a medicine for the treatment of neuropathic pain and a pharmaceutical composition for the treatment of neuropathic pain, comprising S(+)-mirtazapine.

Description

200808804 IX. Description of the Invention [Technical Field of the Invention] The present invention relates to the use of Lohas for treating neuropathic pain. [Prior Art] Clinical and preclinical evidence shows that antidepressants can effectively treat pain conditions. In particular, it can be used for the treatment of chronic pain (Ansari, Har v Rev Psychiatry, 7 (2000) 257-77; Carter and

Sullivan, Curr Opin Investig Drugs, 3 (2002) 4 5 4-8; Reisner, Curr Pain Headache Rep 9 7 (2003) 24-3 3; Matt i aet al., Minerva Anestesiologica, 68 (2002) 1 05- 1 1 4 ). In particular, tricyclic antidepressants (TCAs) are well-established for difficult conditions such as neuropathic pain and tension headache (Carter and Sullivan, Curr Opin Investig Drugs, 3 (2002) 454 -8; Lynch, J Psychiatry and Neuroscience, 26 (200 1 ) 3 0-3 6 ). However, because tricyclic antidepressants often have serious side effects and lack safety in drug overdose (Reisner, Curr Pain Headache Rep, 7 (2003) 24-3 3), the new generation is better tolerated and more Safer antidepressants with fewer side effects are increasingly being used to treat chronic pain (An sari, H arv Rev Psychiatry, 7 (2000) 257-77). It is proposed to write a 30% tricyclic antidepressant (TCA) prescription for Pain Conditions (Su, X, Gebhart, GF (1 998) Pain 7 6 : 105-114 ) And effective even without depression (Monks, R, -4- 200808804)

Psychotropic Drugs In Textbook of Pain (1 994) Eds: PD Wall & R Melzack, Churchill Livingstone, 9 6 3 -989; McQuay ? HJ and Moore, RA, Br. Med.J., 3 1 4 ( 1 997) 763 -764). In fact, Oxford Pain Clinic (Oxford Pain)

More than 50% of the patients attending the clinic are taking antidepressants. However, the mechanisms of the analgesic properties of antidepressants are still poorly understood. Since the antidepressant exerts its anti-pain effects, it is unfortunately difficult to predict which antidepressants are effective in the treatment of pain, especially neuropathic pain. While knowing that older tricyclics have a role in multiple receptors, more selective reuptake blockers, such as venlafaxine, can also effectively treat pain (Sumption, JE). And Moulin, DE, Annals of Pharmacotherapy, 3 5 (200 1 b) 5 5 7-5 5 9 ). Therefore, it is possible that the analgesic effects of these antidepressants are associated with their ability to block the reuptake of serotonin and noradrenaline in the central nervous system (CNS). Duloxetine (CymbaltaTM) (Goldstein et al., Pain 1 16 (1 -2) (2005) 1 09- 1 1 8 ), reuptake blockers such as serotonin and norepinephrine The utility of treating neuropathic pain supports this hypothesis. Mirtazapine is an antidepressant drug that is marketed for treatment in the form of a racemic mixture comprising the mirror image isomers R (-), Loxo and S (+) - Lohas. There are some clinical indications that can be speculated that Lohas can be used for pain treatment in humans (Carter and Sullivan, Curr 200808804)

Opin Investig Drugs, 3 (2002) 454-8). Brannon and

Stone, J Pain Symptom Manage, 1 8 ( 1 999 ) 3 82-5 Report on the treatment of patients with chronic back pain and depression. Bendtsen and Jensen, Neurology, 62 (2004) 1 706- 1 1 Reporting the use of Lohas to treat tension headaches; Ansari, Harv Rev Psychiatry, 7 (2 00 0) 25 7-77 reported chronic treatment with Lohas pain. The use of Lohas in the treatment of pain in cancer patients is reported by Theobald et al., J Pain Symptom Manage, 23 (2 0 0 2) 442-7. None of these disorders showed the original source of pain in the action of damaged or stimulated nerve cells. Neuropathic pain is thought to be the result of injury to the peripheral or peripheral regions of the central nervous system. Wang et al. (US 2003/096805) mentions a combination of Lohas and local anesthetics for local or regional use to reduce neuropathic pain in a range of options. SUMMARY OF THE INVENTION The present invention provides the use of S (+)-mirroromers of Lohas in the treatment of neuropathic pain. In the context of the present invention, the term "substantially free of R-mirror isomers (or R (-)") means that the content of R (-) is more than the total amount of music. 5 %, 2 %, 1 %, 0.5 % or 〇. 1 %. A specific embodiment of the invention is the use of pure S(+)-Luohuo for the preparation of a medicament for the treatment of neuropathic pain. In this category, pure S ( + ) - Lohas Worry means basically no R ( + ) - Lok Worry. In the context of the present invention, neuropathic pain means any form of pain associated with a neurological condition or a condition resulting from (partial) nerve damage or primary irritation, including degeneration, toxicity, Metabolic, ischemic, and mechanical forms of injury. Neuropathic conditions include all forms of neuritis and multiple neuritis. Neuropathic conditions can be hereditary, such as hereditary sensorimotor neuropathy and hereditary sensation and autonomic neuropathy. The neuropathy may be secondary to diabetes, rheumatic diseases or viral infections (such as infections caused by herpes viruses; post-herpetic neuralgia). Myofascial pain is a form of neuropathic pain. According to a particular embodiment thereof, the present invention relates to: - S ( + ) - the use of Lohas for the manufacture of a medicament for the treatment of neuropathic pain; and the use of S ( + ) for the treatment of neuropathic pain A pharmaceutical composition for Lohas; a method for treating neuropathic pain, comprising administering to a patient in need of treatment for neuropathic pain a therapeutically effective dose of S ( + ) - Lohas Sorrow Special, S ( + ) - Le Survival can be used to treat pain caused by diabetic neuropathy, which can include multiple neuropathies of all forms of peripheral and central neurological conditions associated with chronic diabetic metabolic diseases. In this context, the neuropathy is secondary to diabetes, in which diabetes causes nutrients such as nutrients to the nerves of the nerves, ultimately leading to damage to the nerves themselves. Accordingly, the present invention is particularly directed to the use of S ( + ) - Lohas for treating diabetic neuropathic pain, and a pharmaceutical composition for treating the pain, which includes S ( + ) - Lohas. The invention also relates to a method of treating 200808804 for the treatment of pain caused by diabetic neuropathy comprising administering a therapeutically effective dose of s (+)-Luohuo to a patient in need of such treatment. The s(+)-lewives used for the purposes of the present invention can be used in the form of a free base or one or more generally acceptable acid addition salts. Such compounds can be used in their pure form or in admixture with pharmaceutical excipients. The preferred form of Lohas is a salt form which results in a stable pharmaceutical formulation, as reported in WO 2005/05 1 7 1 4, wherein maleic acid salt is preferred. S ( + ) - Lohas can be prepared in several ways; for example, by purification from a racemic mixture. Lohas can be prepared using the method described in U S 4,0 6 2,8 4 8 . S ( + ) - Lohas can also be obtained via stereoselective synthesis (see WO 20 0 5/0 0 54 1 0 for details). In the context of the present invention, a patient is a patient, human or animal suffering from a condition associated with any one or more of the aforementioned forms of neuropathic pain; it may be administered S (+)-Live to treat the pain. S ( + ) - Lohas Worry, also referred to herein as the active ingredient, is the amount required to achieve the desired therapeutic effect, i.e., the therapeutically effective amount, which varies with the particular compound, the route of administration, and the age of the patient and other conditions. Unless otherwise indicated, the amount of Lohas, as defined in this specification, refers to the amount of free living alkali. The appropriate daily dose for human use may range from 0.5 to 140 mg, based on the weight of the test, within the range of daily doses, preferably between 5 and 90 mg of base per day. In general, parenteral administration requires lower doses than other methods of administration that rely more on absorption. In any case, -8- 200808804, the daily dose of humans is between 〇·〇1 and 3 mg/kg of patient weight. In the case of resistance formation, the treatment can be further optimized by increasing the dose up to 5 times during the slow treatment of humans. Suitable dosages can be administered in divided doses of 1, 2, 3, or more at appropriate intervals throughout the day. Treatment can be used for single sputum, by the patient on a "if needed" basis or for a limited treatment period defined by number of days, weeks, or months. Although the active ingredient can be administered in this regard, it is preferred to present it in the form of a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition for treating neuropathic pain comprising pure S(+)-lew, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the user. The invention further encompasses a pharmaceutical formulation, such as those described above, and a combination of packaging materials suitable for the pharmaceutical formulation, the packaging material including instructions for use of the pharmaceutical formulation in the treatment of pain. Blends include those suitable for oral or rectal administration. The blend can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of combining the active ingredient with a carrier which comprises one or more accessory ingredients. Such adjunct ingredients include those skilled in the art, such as elixirs, binders, diluents, disintegrating agents, lubricants, colorants, flavoring agents, and wetting agents. Formulations suitable for oral administration can be presented as discrete units such as tablets or capsules' each containing a predetermined amount of active ingredient; powder or granule; solvent or suspension -9 - 200808804 float. The active ingredient may also be presented as a cream or may be included in the vesicles or microparticles. The blend can also be administered as a large bolus. Blends to be administered parenterally (e. g., subcutaneously) can also be visualized with a suitable sustained release dosage form. In the context of the present invention, the use of S ( + ) - Lohas for the treatment of neuropathic pain is a combination of independent therapies without any other analgesics or can be combined with any other active compound for the treatment of the condition to be treated. . Other active compounds can be administered before, simultaneously, or after S ( + ) - Lohas. S ( + ) - Lohas can even be combined with other active compounds into a pharmaceutical composition. It will be appreciated by the expert that in each case of combined use or additional therapy, the dosage and/or the formulation must be adapted accordingly. [Embodiment] Example: S ( + ) - Lohas Worry in the utility of c h n n g neuropathy model

The Chung neuropathic model is an animal model of neuropathic pain. Animals that tighten the L5 spinal nerve gradually develop hyperalgesia and allodynia, which can be measured using standard behavioral paradigms.

Chung Surgery: Anesthesia was administered using isoflurane in oxygen. Under sterile conditions, a longitudinal incision (about 5 mm from the midline side) was performed at the lower lumbar humerus to expose the left paraspinal muscles. The paraspinal muscles were then isolated and a small blunt shear was used to remove the segment from the L4 spine-10-200808804 spinous process to the tibia. This opens from the ventral side to the facet joint, from the dorsal side to the L6 lumbar vertebrae, and from the middle to the ileum. Use the small roungers to remove the L6 lumbar transverse process as completely as possible. The L5 spinal nerves are then separated and tightly ligated. After the surgery is completed, hemostasis is determined and the wound is closed with multiple layers of silk sutures and metal clips. The anesthesia was then discontinued. The animals were placed in warm-filled cages until they recovered completely from anesthesia. The rat withdrawal threshold for mechanical stimulation (calibrated von Frey filament method) was measured (baseline reading). Rats were placed on a raised (~40 cm) mesh box bottom in a Perspex box and applied with increasing force filaments (2.6-167 mN) using the upper or lower method (Chaplan et al., 1 994). On the sole of the foot. The paws were touched with a series of 8 von Frey hairs with longitudinal toughness. The von Frey hair is presented vertically on the sole of the foot with sufficient force to cause bending of the paw for 1-3 seconds. If the paw is suddenly withdrawn, it is recorded as a positive reaction. A cutoff of 15 grams was chosen as the upper limit of the test because the harder hair tends to pick up the entire limb without bending, which substantially changes the nature of the stimulus. After the baseline measurement, each animal was anesthetized and tensioned to L5 spinal nerves. Animals recover from surgery for a period of at least 5 days. On the day of drug administration, the foot can be re-measured to withdraw the bottom limit (〇 minutes). Immediately after this reading, the rats were injected subcutaneously with vehicle (1 ml/kg) or S(+)-Lehuo (0.3-120 micromoles/kg) (see Table 1 for dose and group size). ). Thereafter, the reading was taken during the fixation period after the compound injection. -11 - 200808804 The data sheet is the average 値 ± standard error mean 値 (s.e.m·) and a one-way analysis of variance using Kruskal-Wallis, a non-parametric statistical test for comparison among groups. Each treatment group was compared to the vehicle group using a non-parametric Dunn test. Calculate the maximum effect time (T m ax ). The subcutaneous administration of S(+)-Live succinyl succinate significantly attenuated the mechanical abnormal pain that was gradually produced in this animal model (see Table 1). After giving 1 20 micromoles/kg of s (+)-lehive, mechanical abnormal pain reversal to 53% of baseline. It was observed that at 120 (mu)m/kg of S(+)-Live, the vocalization/struggling during injection (s.c.) and necrosis at the injection site were observed. In addition, animals were observed to exhibit hyperactivity/excitability in the 60 and 1 20 micromoles/kg groups when the rats were returned to the cage after the test. Table 1 · Compound Path Dose (micro-moma kg) Number of tested animals Tmax at Tmax withdrawal bottom line 克 (g) 10% Tween 80 Subcutaneous-kg 9 60 1.2 ± 0.2 S (10) - Lohas 5 x 1.8 1.8 0.4 S(+)-乐活忧皮下__3 8 60 1.7 士0·3 S(十)-乐活忧皮下8 60 1.3 土0·4 S(+)-乐活忧皮下9 60 5.8 士士 l.(T S(十) - Lohas erotic subcutaneous 6 60 7.4 ± 0.7** __ Table 1 shows the dose groups used in the neurologically induced mechanical abnormal pain test and the number of animals in each group. The table also shows each group

Tmax and the withdrawal threshold of Tmax (g). "Table of vehicle-treated -12- 200808804 when compared with animals in the compound-treated group, P < 〇.〇1. For comparison purposes, R ( + ) in the Chung neuropathic model lacks R ( + ) - Lohas (free base) subcutaneously (10 - 10 〇 micromol / kg) for Mechanical abnormal pain induced by spinal L5 spinal ligation in rats had no effect. Table 2 · Compound route dose (micromolar) The number of animals tested Tmax at Tmax withdrawal bottom line 克 (g) 10% Tween 80 subcutaneous 1 ml / kg 5 30 2.3 ± 0.4 R - Lohas 5 × 30 2.3 士0.4 R-乐活忧皮下· 30 3 30 2.1 士0.3 乐活忧下下100 5 30 3.2 土0.2 Table 2: shows the dose groups and each group used in the experimental study of mechanical abnormal pain induced by neuropathy The number of animals in the. The table also shows the Tmax for each group and the withdrawal threshold (g) for Tmax. No significant effects were observed. No side effects were observed after treatment with any of the doses. For comparison purposes, the effect of racemic-learning in the Chung neuropathic model was that the racemic activity (1 〇 and 30 μmol/kg) was compared 40 minutes after administration, compared with vehicle-treated rats. At the time of withdrawal, there was a small but significant effect (up to 4 grams) on the withdrawal threshold (Mann Whitney test, p < 0.05). However, this utility is not dose dependent. -13- 200808804 Conclusion: Anti-abnormal pain activity was observed in rats with mechanical allodynia after L5 spinal nerve ligation after subcutaneous administration of S-Luoxi 60 and 120 micromoles/kg. Conversely, subcutaneous administration of R to 1 〇〇 micromole/kg does not work. Reference materials:

Ansari, Harv Rev Psychiatry, 7 (2000) 25 7-77; B endts en and Jensen, Neurology, 62 (2004) 1 706- 1 1 Brannon and Stone, J Pain Symptom Manage, 18 (1999) 382-5

Carter and Sullivan, Curr Opin Investig Druge, 3 (2002) 454-8;

Goldstein et al., Pain 1 1 6 ( 1 -2) (2005 ) 1 09- 1 1 8) Lynch, J Psychiatry and Neuroscience, 26 (200 1 ) 3 0- 36)

Mattia et al., Minerva Anestesiologica, 68 (2002) 105-114).

McQuay® HJ and Moore, RA, Antidepressants and chronic pain—effective analgesia in neuropathic pain and other syndromes, B r. Med. J., 314 (1997) 763-764. Monks, R Psychotropic Drugs In Textbook of Pain ( 1 994 Eds: PD Wall & R Melzack, Churchill Livingstone, 96 3 -9 8 9; •14- 200808804

Reisner, Curr Pain Headache Rep, 7 (2003) 24-33 S u X, Gebhart GF (1998) Effects of tricyclic antidepressants on mechano sensitive pelvic nerve afferent fibers innervating the rat colon. Pain 76:1 05- 1 1 4.

Sumpton, J. E. and Moulin, D. E., Treatment of neuropathic pain with venlafaxine, Annals of Pharmacotherapy, 3 5 (2001) 557-559.

Theobald D E. Kirsh KL. Holtsclaw E. Donaghy K. Passik S D. An open—label,crossover trial of mirtazapine (15 and 3 Omg) in cancer patients with pain and other distressing symptoms. Journal of Pain & Symptom Management. Vol. 23 (5) (pp 442-447), 2 0 0 2.

Van der Burg US 4,062,848 Wang et al. (U S 2 0 0 3 / 0 9 6 8 5 ) WO 2005/05 1 7 1 4 WO 2005/0054 1 0 -15-

Claims (1)

200808804 (1) X. Patent application scope 1. A use of s (+)-Lee Worry (s(+)-mirtazaPine) for the preparation of a medicament for the treatment of neuropathic pain. 2. The use according to item 1 of the patent application, wherein the neuropathic pain is caused by a diabetic neuropathy. 3. A pharmaceutical composition for treating neuropathic pain, comprising S (+) - Lohas. 4. The pharmaceutical composition according to item 3 of the patent application, wherein the pain is caused by a diabetic neuropathy. -16 - 200808804 VII. Designated representative map: (1) The representative representative of the case is: No (2), the representative symbol of the representative figure is a simple description: No. 8. If there is a chemical formula in this case, please reveal the best display invention. Chemical formula of the feature: none