KR20000004965A - Method for treating pain - Google Patents

Abstract

PURPOSE: A method for treating pain is provided, which comprises administering2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno£2,3-b|£1,5|benzodiazeine(hereinafter referred as "olanzapine") and Drug Useful in the treatment of Pain. CONSTITUTION: The composition for treating pain comprises 1 part by weight of olanzapine or a pharmaceutically acceptable salt or solvate thereof and 1-1000 parts by weight of one or more Drug Useful in the Treatment of Pain. Drug Useful in the Treatment of Pain have NSAIDS, nonsteroidal anti-inflammatory drug, opioid compounds, and alpha adrenergic compounds. NSAIDS includes salicylates like aspirin, indomethacin, and ibuprofen, and opioid compounds contains morphine, codeine and meperidine. Tricylic antidepressants, anticonvulsants, and serotonin-noreinephrine reuptake inhibitors can be used as Drug Useful in the Treatment of Pain.

Description

How to treat pain

The present invention relates to 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter referred to as "olanzapine"), and pain treatment Provided are methods for treating pain, comprising administering a drug useful to the animal in need thereof.

The present invention relates to therapeutic combinations of compounds that provide analgesic activity.

Surprisingly, the inventors have found that olanzapine can be particularly useful when used in combination with drugs useful for treating pain. More specifically, the present invention provides a method of synergistically treating pain in an animal that provides a synergistic effect using olanzapine in combination with drugs useful for treating pain.

There are many drugs useful for treating pain known to the literature and those skilled in the art. Oral combinations of codeine or other anesthetic analgesics with aspirin are known to provide additional analgesic effects in humans (The Pharmacological Basis of Therapeutics, 5th edition, Macmillan Publishing Co., 1975, pp 325-358).

There is a continuing need for analgesic formulations with greater activity, as reduced doses can provide interesting possibilities for alleviating pain, thereby reducing the expected side effects and toxicity that may result from higher doses. It is particularly desirable to have a synergistic compounding effect. Such compositions are the subject of the present invention.

Olanzapine can provide antipsychotic activity and is currently known to be commercially available in the treatment of psychosis. Olanzapine is a known compound and is described in US Pat. No. 5,299,382, which is incorporated herein by reference as useful for treating schizophrenia, schizophrenia disorders, acute mania, mild anxiety conditions and psychosis. Surprisingly, in accordance with the present invention, Applicants have found that olanzapine may be useful for treating pain and may provide a synergistic effect when administered with drugs useful for treating one or more pain. Olanzapine will meet the long-standing need for safe and effective pain treatment.

The present invention provides an analgesic composition comprising olanzapine or a pharmaceutically acceptable salt thereof and a drug useful for treating one or more pains in a weight ratio of about 1 part to about 1 part to about 1000 parts of olanzapine to drugs useful for treating pain. Provided are methods of treating pain comprising administering to a patient in need.

Preferred compositions have a weight ratio of olanzapine to drug useful for treating pain from about 1 part to about 1 part to about 100 parts. A particularly preferred ratio is from about 1 part to about 1 part to about 30 parts of olanzapine to drugs useful for treating pain. A more preferred ratio may be a ratio of about 1 part to about 10 parts of the drug useful for treating olanzapine to pain. The most preferred ratio may be a ratio of about 1 part to about 1 part to about 3 parts of olanzapine to drugs useful for treating pain.

One preferred group of drugs useful for the treatment of pain is nonsteroidal anti-inflammatory agents (hereinafter "NSAIDS"), including but not limited to salicylates such as aspirin. Another preferred group of NSAIDS include indomethacin, ibuprofen, naproxen, phenpropene, tolmethine, sulindac, meclofenamate, ketoprofen, pyroxicam, flurbiprofen and diclofenac, It is not limited to this.

Particularly preferred NSAIDS is selected from the group consisting of ibuprofen and naproxen. Another particularly preferred NSAID is aspirin.

The invention also includes an olanzapine or a pharmaceutically acceptable salt thereof, or a solvent compound thereof, and a drug useful for treating one or more pains in a weight ratio of about 1 part to about 1 part to about 1000 parts of olanzapine to drugs useful for treating pain. It provides a composition for treating pain.

Olanzapine is a compound of formula (I) or an acid addition salt thereof.

It is particularly preferred that the olanzapine is a type II olanzapine polymorph with a typical x-ray powder diffraction pattern as represented by the following interplanar spacing.

A typical example of an x-ray diffraction pattern for Form II is as follows, where d represents the interplanar spacing and I / I ₁ represents a typical relative intensity.

The x-ray diffraction pattern described herein was obtained using a copper K _a radiation source Siemens D5000 x-ray powder diffractometer with wavelength l = 1.514 Hz.

It is also preferred to administer the Type II olanzapine polymorph as a substantially pure Type II olanzapine polymorph.

As used herein, “substantially pure” refers to Form II in combination with up to about 5% of Type I, preferably up to about 2% of Type I, more preferably up to about 1% of Type I. In addition, “substantially pure” Form II will preferably comprise about 5% or less of related chemicals that indicate undesirable chemical impurities or residual solvents or water. Specifically, "substantially pure" form II should include acetonitrile in an amount of about 0.05% or less, more preferably acetonitrile in an amount of about 0.005% or less. In addition, the polymorph of the present invention should contain 0.5% or less of binding water.

Polymorphs obtainable by the method taught in the patent in U.S. Pat.No. 5,229,382 will be represented by Form I, and substantially the following x-ray powder diffraction pattern obtained using a Siemens D5000 x-ray powder diffractometer ( Where d represents the distance between crystal faces).

Typical examples of x-ray diffraction patterns for Form I are as follows, where d represents the interplanar spacing and I / I ₁ represents a representative relative intensity.

Here, the x-ray powder diffraction pattern was obtained with copper K _a of wavelength L = 1.541 GHz. The distance between the crystal planes labeled "d" at the top is Angstrom. Typical relative intensities are indicated as "I / I ₁ " at the top.

As used herein, the term “drugs useful in the treatment of pain” shall mean a compound known to those skilled in the art as having clinical analgesic activity or a pharmaceutically acceptable salt thereof. Drugs useful for the treatment of pain as used herein include, but are not limited to, NSAIDS, opioid compounds, and alpha adrenergic compounds.

Drugs useful for the treatment of pain will also include traditional analgesics known to those skilled in the art (see, eg, Goodman and Gillman, The Pharmacological Basis of Therapeutics, 5 ^th edition, Macmillan Publishing Co., 1975, pp 325-358). Similar literature commonly referred to by those skilled in the art). That is to say that the term is for example Tylenol # 3, tricyclic antidepressants (e.g. desipramine, imipramine, amitriptyline, nortriptyline), anticonvulsants (e.g. carbamazepine, Gatafentin, valproate), serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine, citalopram, sertraline), mixed serotonin-norepinephrine reuptake inhibitors (e.g. venlafaxine, duloxetine), serotonin Receptor agonists and antagonists, cholinergic (muscarinic and nicotinic) analgesics, and neurokinin antagonists.

Drugs particularly useful for the treatment of pain can be selected from the group consisting of tricyclic antidepressants, anticonvulsants and serotonin-norepinephrine reuptake inhibitors.

The term "alpha-adrenergic compound" as used herein refers to a compound having central alpha-adrenergic receptor activity. Most preferred central alpha-adrenergic active compounds are clonidine or a pharmaceutically acceptable salt thereof having the chemical name 2- (2,6-dichlorophenylamino) -2-imidazoline. New alpha adrenergic activators are under pharmacological development. The present invention includes all drugs that function as central alpha-adrenergic active compounds.

Clonidine is known to be useful for treating hypertension [Physicians' Desk Reference, 45th Ed. (1991) p. 673].

As used herein, the term “opioid” or “opioid compound” has the meaning commonly associated with terms by those skilled in the art. Preferred opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorpanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, pentazosin, butorpanol, nabupine and buprenorphine It is selected from the group consisting of.

The term "NSAIDS" as used herein refers to a nonsteroidal anti-inflammatory agent that can be identified as is by those skilled in the art. For example, the well-known NSAIDS is described in the Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 1308-1309. The term includes, but is not limited to salicylic, such as aspirin. The term also includes, but is not limited to, indomethacin, ibuprofen, naproxen, phenopropene, tolmethine, sulindac, meclofenamate, ketoprofen, pyroxhamm, flurbiprofen and diclofenac It doesn't work. Particularly preferred NSAIDS are ibuprofen and naproxen. Another particularly preferred NSAID is aspirin. Particularly preferred NSAIDS are aspirin and ibuprofen. Salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic acid and sodium salicylate. The term NSAIDS will refer to all compounds that act as nonsteroidal anti-inflammatory agents. Applicant recognizes that new NSAIDS will be under development, and that synergistic compositions comprising such new drugs in addition to olanzapine are expected in the present invention.

The term "animal" as used herein will refer to vertebrates. Most preferably, the vertebrate is a mammal. The term "mammal" as used herein will refer to a mammal that is a higher vertebrate. The term "mammal" includes, but is not limited to, humans. As used herein, the term "treatment" includes the prevention of, or amelioration or cure of, a named disease once it has been demonstrated.

In the compositions of the present invention, olanzapine or a pharmaceutically acceptable salt thereof, and at least one drug useful for treating pain are combined in a weight ratio of about 1 part to about 1 part to about 1000 parts of olanzapine to drug useful for treating pain.

Preferred compositions have a weight ratio of olanzapine to drug useful for treating pain from about 1 part to about 1 part to about 100 parts. A particularly preferred ratio is about 1 part to about 1 part to about 30 parts of a drug useful for treating olanzapine to pain. More preferred ratios may be from about 1 part to about 1 part to about 10 parts of the drug useful for treating olanzapine to pain. The most preferred ratio may be from about 1 part to about 1 part to about 3 parts of the drug useful for treating olanzapine to pain.

Olanzapine is effective in a wide range of dosages, but it is desirable to administer as low a dose as possible. The amount of drug useful for treating pain present in the composition is adjusted such that the ratio to the olanzapine dosage is as described above. For example, the daily dosage of olanzapine generally ranges from about 0.1 mg to about 30 mg per day and the drug useful for treating pain present in the composition will be from about 3 to about 1000 times this amount. However, the amount of compound administered substantially will be determined by the physician in light of the circumstances involved, including the condition to be treated, the choice of compound to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, the route of administration chosen, and thus It will be understood that the dosage range is not intended to limit the scope of the invention in any way. Although the compounds of the present invention are preferably administered orally to a person suffering from or suffering from pain, the compounds may be administered by a variety of other routes such as the transdermal, parenteral, subcutaneous, intranasal, intramuscular and intravenous routes. Can be. Such formulations can be engineered to provide delayed or controlled release using formulation techniques known to those skilled in the art.

As used herein, the term “treatment” includes the prevention of physical and / or mental disorders, or the amelioration or cure of a disease state once proven, or the alleviation of certain symptoms of such a disease.

The term "pain" as used herein will refer to all kinds of pain. Preferably, the term refers to chronic pain such as neuropathic pain, postoperative pain, chronic lower back pain, cluster headache, herpes neuralgia, ring pain, central pain, toothache, neuropathic pain, opioid-resistant pain, intestinal pain, external pain, bone Traumatic pain, pain during childbirth and childbirth, pain resulting from burns including sunburn, postpartum pain, migraine, angina pain, and bladder sore throat will refer to pain associated with urethra, and the term preferably also includes trauma acceptance. It will indicate pain or pain.

Pharmacological studies have shown that olanzapine has muscarinic choline receptor activity. This compound is described in 3H-SCH233390 [Billard, et al. Life Sciences 35: 1885 (1984)] and 3H Spiferon [Seeman et al Nature 216: 717 (1976)] binding assays, as shown by IC50 <1 μM, respectively, as active on dopamine D-1 and D-2 receptors Enemy Olanzapine is also active at the 5-HT-2 receptor and the 5-HT1C receptor. The combined pharmacological profile of the compound provides a medicament that may be useful for treating pain.

The dosage administered, as well as the pharmacodynamic properties and mode and route of administration of the particular drug; The age, health and weight of the recipient; It will vary depending on known factors such as the nature and severity of the symptoms, the type of concurrent treatment, the frequency of the treatment and the desired effect. Typically, the daily dose may be set to be administered at a daily dose of about 0.2 mg to about 30 mg of olanzapine and about 0.6 to about 200 mg / kg of the drug useful for treating pain.

The term "part" as used herein in the context of the composition will optionally refer to parts by weight proportional to the drug or olanzapine useful for treating pain in the composition.

Compositions suitable for oral administration comprise from about 0.5 mg to about 600 mg of active ingredient per unit unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount from about 0.5% to about 95% by weight based on the total weight of the composition.

Typical compositions are olanzapine, or a pharmaceutical thereof, formulated with a pharmaceutically acceptable excipient or diluent, which may be a carrier, diluted with a carrier, or packaged in a carrier, which may be in the form of a capsule, sachet, paper or other container. Phase acceptable acid addition salts or drugs useful for the treatment of one or more pains. When preparing the composition, conventional techniques for preparing pharmaceutical compositions can be used. For example, the active compound will typically be mixed with the carrier, or diluted with the carrier, or packaged in a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container. If the carrier acts as a diluent, it may be a solid, semisolid or liquid which acts as a vehicle, excipient or medium for the active compound. The active compound can be adsorbed onto the granular solid container, for example. Some examples of suitable carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acids, fatty acid monoglycerides and diglycerides, pentaerytes Lytol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulation may also include wetting agents, emulsifiers and suspending agents, preservatives, sweeteners or flavoring agents. The formulations of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures well known in the art.

Pharmaceutical formulations may be sterilized and, if necessary, mixed with adjuvants, emulsifiers, osmotic control salts, buffers and / or coloring substances and the like which do not adversely react with the active compound.

For parenteral administration, particularly injectable solutions or suspensions are suitable, with aqueous solutions in which the active compound is dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules containing talc and / or carbohydrate carriers or binders and the like are particularly suitable for oral administration. Preferred carriers for tablets, dragees, or capsules are lactose, corn starch and / or potato starch. Syrup or elixir can be used when a sweet vehicle is used.

Generally, the compositions of the present invention are dispersed in unit form at about 1 mg to about 30 mg per unit dose in a pharmaceutically acceptable carrier.

Most preferably, solid oral formulations are included in packaging materials that protect the formulation from humidity and light. For example, suitable packaging materials include brown high density polyethylene bottles, brown glass bottles, and other containers made of materials that inhibit light passage. Most preferably, the packaging will comprise a dry pack. The container may be sealed with an aluminum foil foam to provide the desired protection and to maintain product stability.

Compositions of the invention may be suitable for animal administration. Such animals include poultry such as livestock, laboratory animals, domestic pets, and non-poultry such as wild animals. More preferably, it is a vertebrate. Most preferably the compound of the present invention will be administered to a mammal. As this animal, a domestic mammal or a human is specifically preferable. For this purpose, the compounds of the present invention can be administered as food / feed additives. The most preferred mammal is a human.

Usability Testing Method

The unexpectedly improved analgesic activity of the compositions of the present invention was evidenced by the first test in mice. Mice weighing about 18-22 g in the test were used in the next study. All mice received oral route with drugs useful for treating olanzapine and / or pain.

Mouse Struggle Test

An approved standard procedure for detecting and comparing analgesic activity of other classes of analgesic compounds that is of significant relevance to human analgesic activity is to prevent acetic acid-induced writhing in mice [R. Koster et al. Acetic acid for analgesic screening. Fed. Proc. 18: 412, 1959.

Mice treated with various doses of olanzapine, drugs useful for treating pain, combinations of drugs used for treating olanzapine: pain, or vehicle were injected intraperitoneally at standard procedure doses of acetic acid 5 minutes prior to the designated observation period. Acetic acid was prepared as a 0.55% solution and injected at a volume of 0.1 ml / 10 g of body weight. To score, “writhing” was expressed as a systemic stretch or abdominal contraction for about 5 minutes after the start of acetic acid administration.

Sciatic Nerve Ligation Model

The model approved for measuring neuropathic pain insensitivity is the sciatic nerve ligation model [Bennett, G.J. And Xie, Y.-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1988) 87-107; Lee, Y.-W., Chaplan, S.R. And Yaksh, T.L .: Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model. Neuroci Lett 186 (1995) 111-114]. Mice were anesthetized and neural ligation procedures were performed. The normal sciatic nerve was taken out and loosely tied around the nerve with about 4 mm of ligation. The trauma acceptance test was performed 1 to 10 weeks after surgery. The rats were placed in a container with a transparent glass bottom and the radiant heat source was shot from below the floor to the plane of the foot to determine the reaction to the harmful heat of the foot. An increased tendency to pull back hind feet is an indicator of analgesic activity. The rat is placed in a container with a screen bottom, and the graded von Frey hair is used to stimulate the back of the foot to determine the response to a normally harmless mechanical stimulus by measuring the number of grams (g) needed to bend the hair. did. Mice undergoing sciatic nerve ligation respond to lower gram mechanical stimulation with reflexive retraction of the paw than mice without surgery. Normally this response to harmless stimuli is called allodynia. Increasing the number of g of mechanical force needed to reverse the foot is an indicator of antiallodynic activity.

Formalin test

The formalin test is a well approved test for inflammation [Malmberg, A.B. And Yaksh, T.L .: Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. The Journal of Pharmacology and Experimental Therapeutics 263 (1992) 136-146]. Mice were anesthetized and when spontaneous movement was lost, mice were subcutaneously injected with 50 μl of a 5% formalin solution on the dorsal surface of the hind paw using a 30 gauge needle. The mice were then placed one by one in an open plexiglass container for observation, and within a maximum of one to two minutes, the animals were awakened from anesthesia through spontaneous behavior and normal motor function. Pain behavior was quantified by periodically counting the occurrence of spontaneous stinging / vibration of the injected foot. Withdrawal was counted for 1 minute at 1- to 2-, 5- to 6- and 5 minute intervals for 10 to 60 minutes. Inhibition of pain behavior is an indicator of analgesic activity.

The average of all ED ₅₀ values and their standard errors (SEM) was determined using approved mathematical methods (see, for example, RE Kirk (1982) Experimental Design: Procedures for the behavioral sciences, 2nd ed. Belmont, CA: Brooks / Cole Publishing Co.]. Dose interactions in the incidence of mice or rats are described in Loewe's isometric image [S. Loewe, Pharm. Rev. 9. 237-242, (1957).

The interaction of olanzapine, and drugs useful in the treatment of pain in mouse pain, was demonstrated by rowi isometric photography. In the isotope analysis, the analgesic activity of olanzapine is shown on the X axis and the analgesic activity of the other compounds used for pain treatment is shown on the Y axis. The solid line associated with the ED ₅₀ dose of olanzapine alone and the drug alone useful for pain treatment represents the “ED50 dose line”, which, with a simple addition, indicates the expected position of the ED ₅₀ value for olanzapine, and the combination of drug useful for pain treatment. To explain their combined effect.

According to Lowi's isometric theory, if the analgesic effects of olanzapine and drugs used to treat pain are a simple sum of each other, then the estimated positions of olanzapine at fixed dose ratios and ED ₅₀ of drugs used to treat pain are added ED _50. You will be on the line. ED ₅₀ ED ₅₀ of the combination is added in a significant down the line is showed an unexpectedly improved analgesic activity, ED ₅₀ ED ₅₀ in combination on the addition line would represent an unexpected analgesic effects decreased.

One way to confirm the importance of this unexpected improved or reduced activity is to calculate the SEM value for each ED ₅₀ . If the SEM value does not overlap the addition line, the ED 50 value at this time is significantly different from the addition line.

Surprisingly, these experiments demonstrate that olanzapine, and drugs useful for treating pain, provide statistically significant synergistic analgesic effects.

For example, when the ratio of olanzapine to morphine was 1 part to 10 parts, and when the ratio of olanzapine to morphine was 1 part to 30 parts, the rat struggling test showed a statistically significant synergistic analgesic effect. Similar results were obtained for the combination of olanzapine and diclofenac, olanzapine and ibuprofen with olanzapine and acetaminophen over a range of ratios.

It is to be understood that the specification and examples are intended to be illustrative, not restrictive, and that various modifications and changes may be made without departing from the spirit and scope of the invention.

Surprisingly, these experiments demonstrate that compositions comprising olanzapine and drugs useful for treating one or more pains provide a statistically significant synergistic analgesic effect.

Clinical observation

Double-blind multicenter clinical trials were planned to assess the safety and efficiency of olanzapine. Patients were randomized to olanzapine, the compositions of the present invention, drugs or placebos useful for the treatment of pain. Patients were monitored for pain perception using standard methods.

The materials of the present invention can be purchased or prepared by various procedures known to those skilled in the art. Olanzapine can be prepared as described in Chakrarabarti, US Pat. No. 5,229,382 ('382), which is incorporated herein by reference in its entirety. Moreover, the following preparation example demonstrates the manufacturing method of an especially preferable type II olanzapine polymorph.

Characterization methods for compounds include, for example, x-ray powder pattern analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), titration for water, and H ¹ -NMR analysis for solvent content. .

The following examples are provided for purposes of illustration and should not be construed as limiting the scope of the claimed invention.

Preparation Example 1

Industrial grade olanzapine

The following ingredients were added to a suitable three neck flask:

Dimethyl sulfoxide (analytic amount): 6 times volume

Intermediate 1: 75 g

N-methylpiperazine (reagent): 6 equivalents

Intermediate 1 can be prepared using methods known to those skilled in the art. For example, the preparation of intermediate 1 is taught in the patent in US Pat.

A bottom nitrogen sparge was added to remove ammonia formed during the reaction. The reaction was heated to 120 ° C. and maintained at that temperature throughout the reaction period. The HPLC reaction was then performed until 25% of intermediate 1 remained unreacted. After the reaction was complete, the mixture was slowly cooled to 20 ° C. (about 2 hours). The reaction mixture was then transferred to a suitable three neck round bottom flask and water bath. To this solution a 10-fold volume of reagent grade methanol was added with stirring and the reaction stirred at 20 ° C. for 30 minutes. Three volumes of water were added slowly over about 30 minutes. The reaction slurry was cooled to 0-5 ° C. and stirred for 30 minutes. The product was filtered off and the wet cake was washed with cold methanol. The wet cake was dried overnight at 45 ° C. vacuum. The product was found to be industrial olanzapine.

Yield: 76.7%; Efficacy: 98.1%

Preparation Example 2

Type II olanzapine polymorph

270 g of industrial grade 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample in anhydrous ethyl acetate (2.7 L) Suspended. The mixture was heated to 76 ° C. and held at 76 ° C. for 30 minutes. The mixture was cooled to 25 ° C. The product thus produced was isolated using vacuum filtration. The product was identified to be type II using x-ray powder analysis. Yield: 197 g.

The method described above for the preparation of Form II provides a pharmaceutically good product with an efficacy ≧ 97%, total relevant substance <0.5%, and isolation yield> 73%.

Example 1

A portion of hydroxypropyl cellulose was dissolved in purified water to form a granular solution. High purity grade remaining hydroxy propyl cellulose (total weight is 4.0% w / w of final tablet weight) was obtained by olanzapine (1.18% w / w), ibuprofen (3% w / w), lactose (79.32% w / w) and A portion of crospovidone (5% w / w) was combined in a high shear granulator. All ingredients were sieved safely and dry blended in a granulator before addition. This mixture was then granulated with hydroxypropyl cellulose solution in a high shear granulator. The granules were sized in the wet state using standard methods. The wet granules were then dried in a fluid bed dryer and sized. The material was then added to a tumble bin mixer. A flow powder consisting of microcrystalline cellulose (granular) (10% w / w), magnesium stearate (0.5% w / w), and the remaining crospovidone was added to the sized particles. The mixture was blended and compressed with a suitable tool in a tablet compression device.

Sub-coating:

Hydroxypropyl methylcellulose (10% w / w) was mixed with purified water to form a solution. The core tablets were divided into approximately equal fractions and spray coated with hydroxypropyl methylcellulose solution. This process was carried out in perforated coating pans.

Coating of Core Tablets:

Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80 and titanium dioxide) was mixed with purified water to form a coating suspension. The subcoated tablets were divided into approximately equal fractions and coated with the coating suspension. This process was carried out in perforated coating pans.

The carnauba wax was lightly sprayed onto the coated tablets and the appropriate recognition was imprinted out.

Claims (32)

For treating pain comprising a weight ratio of about 1 part to about 1 part to about 1000 parts of olanzapine to a drug useful for treating pain, with olanzapine or a pharmaceutically acceptable salt thereof, or a solvent compound thereof Composition. The composition of claim 1, wherein the drug useful for treating pain is NSAIDS. The method according to claim 2, wherein the NSAIDS is aspirin, indomethacin, ibuprofen, naproxen, phenopropene, tolmethine, sulindac, meclofenamate, ketoprofen, pyricampam, flurbiprofen and diclofenac or A composition selected from the group consisting of pharmaceutically acceptable salts thereof. The composition of claim 1, wherein the olanzapine is a type II olanzapine polymorph with a typical x-ray diffraction pattern, where d represents the interplanar spacing. The composition of claim 4, wherein the drug useful for treating pain is selected from the group consisting of aspirin, ibuprofen and naproxen. The composition of claim 1 wherein the weight ratio of olanzapine to drug useful for treating pain is about 1 part to about 1 part to about 100 parts. The composition of claim 6 wherein the weight ratio of olanzapine to drug useful for treating pain is about 1 part to about 1 part to about 30 parts. 8. The composition of claim 7, wherein the weight ratio of olanzapine to drug useful for treating pain is about 1 part to about 1 part to about 10 parts. The composition of claim 8, wherein the drug useful for treating pain is selected from the group consisting of morphine, acetaminophen, ibuprofen and diclofenac. The composition of claim 1, wherein the drug useful for treating pain is an opioid compound. The composition of claim 4 wherein the drug useful for treating pain is an opioid compound. 8. The composition of claim 7, wherein the drug useful for treating pain is an opioid compound. The opioid compound according to claim 10, wherein the opioid compound is morphine, codeine, meperidine, methadone, propoxyphene, levorpanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, pentazosin, butorpanol, nabuphine And buprenorphine. The composition of claim 13, wherein the opioid compound is selected from the group consisting of morphine, oxymorphine, oxycodone, hydromorphine, codeine and methadone. The drug of claim 1, wherein the drug useful for treating pain is Tylenol # 3, a tricyclic antidepressant (eg, desipramine, imipramine, amitriptyline, nortriptyline), an anticonvulsant (eg, carbamazepine , Gatapentin, valproate), serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine, citalopram, sertraline), mixed serotonin-norepinephrine reuptake inhibitors (e.g. venlafaxine, duloxetine), A composition selected from the group consisting of serotonin receptor agonists and antagonists, cholinergic (muscarinic and nicotinic) analgesics, and neurokinin antagonists. The drug of claim 4, wherein the drug useful for treating pain is selected from the group consisting of tylenol # 3, tricyclic antidepressants, anticonvulsants, serotonin reuptake inhibitors, mixed serotonin-norepinephrine reuptake inhibitor analgesics, and neurokinin antagonists Composition. The composition of claim 16, wherein the drug useful for treating pain is a tricyclic antidepressant. The composition of claim 1, wherein the drug useful for treating pain is an alpha adrenergic compound. The composition of claim 18, wherein the central alpha-adrenergic active compound is clonidine, or a pharmaceutically acceptable salt thereof. The composition of claim 4, wherein the drug useful for treating pain is an alpha adrenergic compound. 8. The composition of claim 7, wherein the drug useful for treating pain is an alpha adrenergic compound. The composition of claim 1, which can provide synergistic analgesic activity. An analgesic dose of olanzapine or a pharmaceutically acceptable salt thereof, or a solvent compound thereof and a drug useful for treating one or more pains in a weight ratio of about 1 part to about 1 part to about 1000 parts of olanzapine to drug useful for treating pain A method of treating pain, comprising administering a composition. The method of claim 23, wherein the drug useful for treating pain is NSAIDS. The method of claim 23, wherein the weight ratio of the olanzapine to drug useful for treating pain is about 1 part to about 1 part to about 100 parts. The method of claim 25, wherein the weight ratio of olanzapine to drug useful for treating pain is about 1 part to about 1 part to about 30 parts. 24. The method of claim 23, wherein the olanzapine is a type II olanzapine polymorph having the following typical x-ray diffraction pattern, where d represents the interplanar spacing. The method of claim 23, wherein the drug useful for treating pain is selected from the group consisting of alpha adrenergic compounds and opioid compounds. 24. The drug of claim 23, wherein the drug useful for treating pain is selected from the group consisting of tylenol # 3, tricyclic antidepressants, anticonvulsants and serotonin reuptake inhibitors, mixed serotonin-norepinephrine reuptake inhibitor analgesics, and neurokinin antagonists How to be. The method of claim 23, wherein the pain is neuropathic pain. The method of claim 23, wherein the pain is trauma. The method of claim 23, wherein the pain is acute pain.