KR20000004964A - Method for treating pan - Google Patents

Abstract

PURPOSE: A method for treating pain is provided, which comprises administering an onalgesic dosage of olanzapine to an animal in need of such treatment. CONSTITUTION: Olanzapine will be the Form II olanzapine polymorph having a typical X-ray powder diffraction, and is administered as the substantially pure Form II olanzapine polymorph containing less than about 0.05% content of acetonitrile and less than 0.5% of associated water. Olanzapine is administered about 0.1-30mg per day in case of the acute pain like headache, arthritis, and simple muscle strain, about 5-30mg per day in case of the neuropathic pain like chronic pain, pain associated with arthritis, and cancer associated pain, and about 5-25mg per day in case of the nociceptive like post-operation pain, cluster headaches, and dental 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") for the treatment of pain. Provides a way to use it. The present invention provides methods particularly useful for the treatment of acute pain, traumatic pain and neuropathic pain.

The present invention provides a method for treating pain.

The present invention provides, for example, a method for the treatment of self-limiting diseases, low body cavity type acute pain, including but not limited to headaches, arthritis, simple muscle contusions and menstrual irregularities. The invention also provides a method of treating neuropathic pain. The present invention also provides a method for treating trauma.

There is a need for more active analgesics that reduce side effects and toxicity and are non-toxic. Ideal analgesics reduce pain awareness, cause analgesia over a wide range of pain types, work satisfactorily whether administered orally or parenterally, with minimal or no side effects, tolerance and drug dependence. There is no tendency to cause it.

Applicants have found that olanzapine can provide many of the characteristics of an ideal analgesic for the treatment of pain.

Olanzapine can provide antipsychotic activity and is 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 in its entirety as useful for treating schizophrenia, schizophrenia disorders, acute mania, and mild anxiety conditions and psychosis. Surprisingly, in accordance with the present invention, applicants have discovered that olanzapine may be useful for treating pain. Olanzapine will meet the long-standing need for safe and effective acute pain treatment.

The present invention provides a method for treating pain, comprising administering an effective amount of olanzapine to an animal in need thereof.

The present invention provides a method for treating acute pain comprising administering an analgesic dose of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Acute pain is preferably selected from the group consisting of headache, arthritis, simple muscle suppuration, and menstrual irregularities.

The present invention provides a method for treating traumatic pain, comprising administering an analgesic dose of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The present invention provides a method of treating neuropathic pain comprising administering an analgesic dose of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The neuropathic pain is preferably selected from the group consisting of chronic lower back pain, arthritis related pain, cancer related pain, herpes neuralgia, ring pain, central pain, opioid resistant neuropathic pain, bone trauma, delivery and pain during childbirth.

Traumatic pain is selected from the group consisting of post-operative pain, cluster headache, toothache, external pain, severe burns, for example, pain caused by third-degree burns, postpartum pain, angina pain, cystitis-related urinary tract pains It is desirable to be.

Finally, the present invention may provide a method for treating inflammation comprising administering an anti-inflammatory dose of olanzapine to an animal in need thereof.

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.

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.

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 "acute pain" as used herein will refer to self-limiting, lower body cavity pain. Examples include, but are not limited to headaches, arthritis, simple muscle suppuration, and menstrual irregularities.

As used herein, the term "traumatic pain container" will refer to pain transmitted through the intact neuronal pathway.

As used herein, the term "neuropathic pain" will often refer to pain caused by damage to nerve structures, including nerve hypersensitivity.

The neuropathic pain is preferably selected from the group consisting of chronic lower back pain, arthritis related pain, cancer related pain, herpes neuralgia, ring pain, central pain, opioid-resistant neuropathic pain, bone trauma, delivery and pain during childbirth.

Trauma is selected from the group consisting of post-operative pain, cluster headaches, toothaches, external pain, severe burns, for example, pain caused by third-degree burns, postpartum pain, angina pain, cystitis-related urinary tract pains It is desirable to be.

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 arranged to be administered in a daily dose of about 1 mg to about 30 mg of olanzapine.

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.

Mouse Struggle Test

An approved standard for detecting and comparing analgesic activity of different types of analgesic compounds that correlates significantly with human analgesic activity is to prevent acetic acid-induced writhing in mice.

Grown male mouse CD-1 [Cr1: CDR-1 (ICR)] mice (approximately 4 to 5 weeks of age) were obtained from Charles River laboratories (Portage, Mich.) And tested about 2 Acclimated days ago. Only healthy mice weighing 22-35 g were included in the test. Mice were housed 10 per cage in plastic population cages and provided certified rat feed, Certified Rodent Chow and lithium-added water. Dragonfly was replaced twice a week. Room temperature was maintained at 22 +/- 4 ° C. and relative humidity was maintained at 30% -70%. Starting with about 1800 hours of darkness, the photoperiod was 12 hours during the day and 12 hours at night.

Throughout the study, suspensions were prepared at the target concentrations of olanzapine of 0, 0.3, 0.1, 0.3 and 1 mg / ml by adding 10% gum arabic in purified water. Vehicle controls included 10% gum arabic in purified water.

Olanzapine was administered as follows to evaluate analgesic activity using acetic acid induced struggle. Intraperitoneal injection of acetic acid in mice causes contraction or torsion of abdominal muscles (Siegmund et al., 1957). Administration of either opioid or non-opioid analgesics reduces the amount of writhing (Collier, 1964). Struggle was used to define the pharmacology of analgesics such as aspirin and morphine. Approximately 60 minutes after oral administration of olanzapine, each mouse was given 0.5% acetic acid (0.01 ml / g, intraperitoneal). Mice were placed in separate clean observation chambers and total writhing times by each mouse were counted between 5 and 10 minutes after acetic acid administration (see, for example, Haubrich, DR, Ward, SJ, Baizman, E., Bell, MR, Bradford, J., Ferrari, R., Miller, M., Perrone, M., Pierson, AK, Saelens, JK and Luttinger, D .: "Pharmacology of pravadoline: a new analgesic agent", The Journal of Pharmacology and Experimental Therapeutics 255 (1990) 511-522].

Surprisingly, these experiments showed that olanzapine provided significant analgesic activity at doses of 1, 3 and 10 mg / kg compared to the control.

Another standard approved for detecting and comparing analgesic activity of different kinds of analgesic compounds that correlates significantly with human analgesic activity is to prevent phenyl-p-benzoquinone induced writhing in mice [H. Blumberg et al. Proc. Soc. Exp. biol. Med., 118, 763-766 (1965)].

Mice treated with various doses of olanzapine or vehicle were injected intraperitoneally at standard procedure doses of phenyl-p-benzoquinone 5 minutes before the designated observation period. Phenyl-p-benzoquinone was prepared at about 0.1 mg / ml of a solution of about 5% by volume of ethanol in water. The dose to cause writhing was 1.25 mg / kg injected at a volume of about 0.25 ml / 10 g. To score, “writhing” was expressed as systemic stretching or abdominal contraction for about 5 minutes after the start of observation following phenyl-p-benzoquinone administration.

All ED50 values and their 95% confidence limits were determined using approved numerical methods (eg, W.F. Thompson, Bacteriological Rev., 11 115-145 (1947)).

Fishtail test

Tail stroke tests were used to define or monitor analgesia levels after exposure to various compounds [D'Amour and Smith, 1941; Harris ans Pierson, 1964]. The device can be used to assess tailing tendency by concentrating a light beam on the tail of a mouse, rat or monkey. This test has proven useful for screening mild or potent analgesics [Dewey et. al., 1969].

Tail strokes were used to evaluate the analgesic effect of olanzapine. About 60 minutes after oral administration of olanzapine (0, 0.3, 1, 3 or 10 mg / kg), mice were placed in a fixed tube and the time required for each rat to respond to heat from the light beam focused on the tail ( Tail Flick Apparatus, Columbus Instruments, Columbus, Ohio.

Olanzapine had an increased tailing tendency at 1, 3 and 10 mg / kg compared to the control trend.

The unexpected neuropathic analgesic activity of olanzapine is evidenced by the following sciatic nerve ligation model.

Sciatic Nerve Ligation Model

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. Mice were orally administered various amounts of olanzapine or placebo prior to testing. The rats were placed in a container with a clear glass bottom and shot from the bottom to the plane of the foot where the radiant heat source was applied to determine the foot's response to the harmful heat. An increased tendency to pull back hind feet is an indicator of analgesic activity. The rats are placed in a container with a straddled bottom, and the graded von Frey hairs are used to stimulate the back of the foot to measure the force required to bend the hair in grams (g) to respond to normally harmless mechanical stimuli. decided. 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 [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].

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. Remaining hydroxy propyl cellulose (total weight is 4.0% w / w of the final tablet weight) of high purity grades is selected from olanzapine (1.18% w / w), lactose (79.32% w / w) and some crospovidone (5% w / w ) And 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 (16)

A method of treating acute pain comprising administering an analgesic dose of olanzapine to a mammal in need thereof. The method 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 method of claim 1, wherein the analgesic dose of olanzapine is about 0.1 mg to about 30 mg per day. The method of claim 3, wherein the analgesic dose of olanzapine is about 1 mg to about 20 mg per day. The method of claim 2, wherein the acute pain is selected from the group consisting of headache, arthritis, simple muscle suppuration, and menstrual irregularities. A method of treating inflammation comprising administering an anti-inflammatory dose of olanzapine to an animal in need thereof. A method of treating neuropathic pain comprising administering an analgesic dose of olanzapine to a mammal in need thereof. 8. The method of claim 7, wherein the olanzapine is a type II olanzapine polymorph with a typical x-ray diffraction pattern, where d represents the interplanar spacing. 8. The method of claim 7, wherein the analgesic dose of olanzapine is about 5 mg to about 30 mg per day. The method of claim 9, wherein the analgesic dose of olanzapine is about 5 mg to about 25 mg per day. 8. The neuropathic pain of claim 7, wherein the neuropathic pain is selected from the group consisting of chronic lower back pain, arthritis related pain, cancer related pain, herpes neuralgia, ring pain, central pain, opioid resistant neuropathic pain, bone traumatic pain, delivery and pain during childbirth. How. The method of claim 11, wherein the neuropathic pain is arthritis related pain. The analgesic dose of olanzapine is a group consisting of post-operative pain, cluster headache, toothache, external pain, pain caused by severe burns, for example, third-degree burns, postpartum pain, angina pain, cystitis, and urinary tract-related pain. A method of treating trauma, comprising administering to a mammal in need thereof. The method of claim 13, wherein the olanzapine is a type II olanzapine polymorph with a typical x-ray diffraction pattern, where d represents the interplanar spacing. The method of claim 13, wherein the analgesic dose of olanzapine is about 5 mg to about 25 mg per day. A method of treating pain, comprising administering an effective amount of olanzapine to an animal in need thereof.