MXPA00002837A - Treatment of oppositional defiant disorder - Google Patents

Abstract

Norepinephrine reuptake inhibitors are used to treat oppositional defiant disorder.

Description

TREATMENT OF OPPOSITION REBELLION DISORDER DESCRIPTION OF THE INVENTION The invention pertains to the fields of pharmaceutical chemistry and psychiatric medicine, and provides a method for the treatment of the psychiatric disorder known as oppositional rebelliousness disorder. Children and adolescents who suffer from an oppositional rebellion disorder exhibit a pattern of hostile, rebellious, and negative behavior, most commonly observed in other individuals of the same mental age. They are argumentative with adults, are often angry and resentful, frequently lose their temper, swear, challenge adult rules and requests, and deliberately engage in annoying behavior. They also tend not to see themselves as a problem, but justify their behavior as a response to unreasonable circumstances. The opposition rebellion disorder (ODD) is often treated with the same therapies used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), for example ethylphenidate REF .: 32810 (RitalinMR), which exhibits noradrenergic and dopaminergic effects. Gross has shown that certain symptoms of ODD can be improved by increasing standard ADHD therapies with buspirone in certain patients (Gross, J. Am. Acad. Chi ld Adol esc. Psychi a try, 2 (10), 1260 (1995 )). Many patients do not accept these treatments, or discontinue treatment due to intolerable side effects. In addition, due to the high potential for substance abuse in patients with oppositional rebellion disorder, the use of stimulants such as methylphenidate is problematic. The need for a safe and effective treatment for oppositional rebellion disorder, without the disadvantages of current therapies, continues to be a problem of the psychiatric community. The present invention provides a method for treating oppositional rebuffing disorder comprising administering to a patient, in need of such treatment, an effective amount of a norepinephrine reuptake inhibitor. Many compounds, including those discussed below, are inhibitors of norepinephrine reuptake and there is no doubt that many more will be identified in the future. In the practice of the present invention, it is proposed to include reuptake inhibitors that show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al. , Drug Devel opmen t Research, _6, 397 (1985). The norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of reuptake of neurotransmitters in relation to their ability to act as direct agonists or antagonists in other receptors. Norepinephrine reuptake inhibitors useful for the method of the present invention include, but are not limited to: Tomoxetine, (R) - (-) - N-methyl-3- (2-methylphenoxy) -3-phenylpropylamine is usually administered. as the hydrochloride salt. Tomoxetine is first described in U.S. Patent # 4,314,081. The word "tomoxetine" will be used herein to refer to any acid addition salt or free base of the molecule. See, for example, Gehlert, et al. , Neurosci ence Let ters, 157, 203-206 (1993), for a discussion of the activity of tomoxetine as a norepinephrine reuptake inhibitor; The compounds of the formula I: wherein X is C 1 -C 4 alkylthio, and Y is C 1 -C 2 alkyl or a pharmaceutically acceptable salt thereof. The compounds of the formula I are described in U.S. Patent 5,281,624, Gehlert, Robertson, and ong, and in Gehlert, et al. , Li fe Sci ences, 5_5 (22), 1915-1920, (1995). The compounds are taught to be inhibitors of norepinephrine reuptake in the brain. It is also explained that the compounds exist as stereoisomers, and that therefore they include not only the racemic mixtures, but also the isolated individual isomers as well as mixtures of the individual isomers. For example, the compounds of the formula I include the following exemplary species: N-ethyl-3-phenyl-3- (2-methylthio-phenoxy) propyl benzoate; (R) -N-methyl-3-phenyl-3- (2-propylthiophenoxy) propylamino hydrochloride; (S) -N-ethyl-3-phenyl-3- (2-butylthiophenoxy) propyl-amine; malonate of N-methyl-3-phenyl-3- (2-ethylthio-phenoxy) propylamine; Naphthalene-2-sulfonate (S) -N-methyl-3-phenyl-3- (2-tert-butylthiophenoxy) propylamine; (R) -N-methyl-3- (2-methylthiophenoxy) -3-phenyl-propylamine; Reboxetine is usually given (Edronax®), 2- [α- (2-ethoxy) phenoxy-benzyl] orpholine, as the racemic mixture. It was first taught by U.S. Patent 4,229,449, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor. The term "reboxetine" will be used herein to refer any acid addition salt or free base of the molecule that exists as the racemic mixture or whether it is enantiomer; Duloxetine, N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent 4,956,388, which shows its high potency. The word "duloxetine" will be used herein to refer to any acid addition salt or free base of the molecule; Venlafaxine is known in the literature, and its method of synthesis and its activity as a serotonin inhibitor and norepinephrine uptake are taught by U.S. Patent 4,761,501. Venlafaxine is identified as compound A in that patent; and Milnacipran (N, N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught by U.S. Patent 4,478,836, which prepares milnacipran as its Example 4. The patent discloses its compounds as antidepressants. Moret et al., Neuropharma col ogy 2_4_, 1211-19 (1985), describes its pharmacological activities as a reuptake inhibitor of serotonin and norepinephrine. All United States patents that have been mentioned in the foregoing in connection with the compounds used in the present invention are incorporated herein by reference. A preferred duloxetine enteral formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separation layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. The following example demonstrates the preparation of a preferred formulation.

Example mg of Duloxetine base / capsule List of Materials Drops or beads Sucrose - incomparable starch, mesh 20-25 60.28 mg Duloxetine layer Duloxetine 11.21 Hydroxypropylmethylcellulose 3.74 Separation layer Hydroxypropylmethylcellulose 2.51 Sucrose 5.00 Talc, mesh 500 10.03 Enteric layer HPMCAS, grade LF , Shin-Etsu Chemical 25.05 Co. , Tokyo, Japan Triethyl citrate 5.00 Talc, mesh 500 7.52 Finish layer Hydroxypropylmethylcellulose 8.44 Titanium dioxide 2.81 Talc traces 141.60 mg The duloxetine layer is formed by suspending duloxetine in a 4% w / w solution of hydroxypropylmethylcellulose in water, and grinding the suspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden, Switzerland) model MS-12. A fluid bed dryer with a Wurster column is used to make this product, in a batch size of 1.0 kg. The separation layer is added from a 4% w / w solution of the hydroxypropylmethylcellulose in water, in which the sucrose is also dissolved. In order to prepare the enteric coating suspension, purified water is cooled to 10 ° C and polysorbate, triethyl citrate and silicone emulsion are added and dispersed or dissolved. Then HPMCAS and talc are added and stirred until homogeneity is obtained, and the HPMCAS is completely neutralized by the addition of ammonium hydroxide until the polymer solution is complete. For this suspension, an aqueous solution of carboxymethylcellulose, 0.5% w / w, is added and thoroughly mixed. The enteric suspension is maintained at 20 ° C during the coating process. The enteric suspension is then added to the partially filled pellets in the Wurster column at a spray rate of approximately 15 ml / minute., keeping the inlet air temperature at approximately 50 ° C. The product is dried on the Wurster column at 50 ° C when the enteric suspension has been fully added, and then it is dried in trays for 3 hours in a dry housing at 60 ° C. A finishing layer is then applied consisting of a 4.5% w / w hydroxypropylmethylcellulose solution containing titanium dioxide and propylene glycol as a plasticizer. The pellets are completely dried in a fluid bed dryer and then filled into size 3 gelatin capsules. While all compounds exhibiting inhibition of norepinephrine reuptake are useful for the method of the present invention, certain are preferred. It is preferred that the norepinephrine reuptake inhibitor be selective for norepinephrine over other neurotransmitters. It is also preferred that the norepinephrine reuptake inhibitor be selected from tomoxetine, reboxetine, or a compound of the formula I. Se. he especially prefers that the norepinephrine reuptake inhibitor of tomoxetine, reboxetine or (R) -N-methyl-3- (2-methylthiophenoxy) -3-phenylpropylamine be selected.

It will be understood by an expert reader that most or all of the compounds used in the present invention are capable of forming salts, and that forms of the pharmaceutical salt are commonly used, often because they are more easily recrystallized and purified than free bases. In all cases, the use of the pharmaceuticals described above as salts are contemplated in the description herein, and is frequently preferred, and pharmaceutically acceptable salts of all compounds are included in the names thereof. Many of the compounds used in this invention are amines, and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically room temperature oils, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid to room temperature. The acids commonly used to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p -bromophenylsulphonic, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts of this form are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, ethoxybenzoate, fatalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.

Administration The doses of the drugs used in the present invention should, in the final analyzes, be indicated by the attending physician, using the knowledge of the drugs, the properties of the drugs in combination, as determined in clinical trials, and the characteristics of the patient, including different diseases for which the doctor is treating the patient. The general guidelines of the doses, and some preferred doses, can and will be provided in the present. Tomoxetine: from about 5 mg / day to about 100 mg / day; preferably in the range of about 5 a. approximately 70 mg / day; more preferably from about 10 to about 60 mg / day; and even more preferably from about 10 to about 50 mg / day; Compounds of the formula I: of approximately 0. 01 mg / kg to approximately 20 mg / kg; the daily preferred doses will be from about 0.5 mg / kg to 10 mg / kg; ideally from about 0.1 mg / kg to about 5 mg / kg; Reboxetine: from about 1 to about 30 mg, once to four times a day; it is preferred, from about 5 to about 30 mg once a day; Duloxetine: from about 1 to about 30 mg once / day; it is preferred, from about 5 to about 20 mg once / day; Venlafaxine: from about 10 to about 150 mg one to three times / day; it is preferred, from about 25 to about 125 mg three times / day; and Milnacipran: from about 10 to about 100 mg once to twice a day; it is preferred, from about 25 to about 50 mg twice / day. All the compounds mentioned herein are orally available and are normally administered orally, and therefore oral administration is preferred. However, oral administration is not the only route or even the only preferred route. For example, transdermal administration may be very desirable for patients who are forgetful or morose about taking oral medicine. The drugs can also be administered percutaneously, intravenously, intramuscularly, intranasally or intrarectally, in particular circumstances. The route of administration can vary in any way, limited by the physical properties of the drugs and the convenience of the patient and the care given. The best description of oppositional rebellion disorder is the diagnostic criteria published by the American Psychiatric Association in the DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (1987)), as follows.

Diagnostic Criteria for Opposition Rebellion Disorder A. A disturbance of at least six months, during which at least five of the following occur: (1) frequently loses temperament (2) frequently discusses with adults ( 3) frequently actively challenges or rejects requests or rules of adults, for example, refuses to do homework (4) often does things deliberately that harm other people, for example, sticks on the heads of children (5) ) often blames others for their own mistakes (6) often touches or easily annoys others (7) is often angry and resentful (8) is often spiteful and vindictive (9) often swears or uses obscene language B. Does not meet the criteria for Behavior Disorder, and does not occur exclusively during the course of a psychotic disorder, Dysthymia, or Major Depressive, Hypomanic, or Manic Episode. Patients suffering from Oppositional Rebellion Disorder also commonly suffer concomitantly from Attention Deficit Hyperactivity Disorder. The patient will benefit from the use of norepinephrine reuptake inhibitors in the improvement of the symptoms of Oppositional Rebellion Disorder unrepaired of these or other co-morbid conditions. In addition, a patient suffering from Opposition Rebellion Disorder and Hyperactivity Disorder deficient in Attention will benefit in improving the symptoms of both conditions through the method of the present invention.

The method of the present invention is effective in the treatment of patients who are children or adolescents, and there is no significant difference in the symptoms or details of the form of treatment among patients of different ages. Generally speaking, however, for purposes of the present invention, a child is considered to be a patient under the age of puberty, and a teenager is considered to be a patient from the age of puberty to approximately 18 years of age .

Inhibition or reuptake of norepinephrine The ability of the compounds to inhibit the reuptake of norepinephrine can be measured by the general procedure of Wong, et al. , supra. Male Sprague-Dawley rats weighing 150-250 gm are decapitated and the brain is immediately removed. The brain slices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. The unpurified synaptosomal preparations are isolated after differential centrifugation at 1,000 x g for 10 minutes and 17,000 x g for 28 minutes. The final pellets are suspended in the same medium and kept on ice until they are used within the same day.

The synaptosomal uptake of norepinephrine-3H is determined as follows. Cortical synaptosomes (equivalent to 1 mg of protein) are incubated at 37 ° C for 5 minutes in a 1 ml Krebs bicarbonate medium that also contains 10 mM glucose, 0.1 mM iproniazide, 1 M ascorbic acid, 0.17 mM EDTA and norepinephrine- 3H 50 nM. The reaction mixture is immediately diluted with 2 ml of ice-cold Krebs bicarbonate buffer and filtered under vacuum with a cell harvester.

(Brandel, Gaithersburg, MD). The filters are rinsed twice with approximately 5 ml of saline solution 0. 9% cooled with ice and the uptake of norepinephrine-3H is evaluated by the liquid scintillation count. It is considered that the accumulation of norepinephrine-3H at 4 ° C as background and is extracted from all measurements.

The concentration of the test compound required to inhibit 50% accumulation of norepinephrine-3H (IC5o values) is determined by linear regression analysis. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (6)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Use of a norepinephrine reuptake inhibitor for the preparation of a medication to treat opposition rebellion disorder.

2. use according to claim 1, characterized in that the norepinephrine reuptake inhibitor is selected from the group consisting of tomoxetine, reboxetine, duloxetine, venlafaxine, milnacipran, and a compound of the formula I: wherein X is C 1 -C 4 alkylthio, and Y is C 1 -C 2 alkyl or a pharmaceutically acceptable salt thereof.

3. Use according to claim 2, characterized in that the norepinephrine reuptake inhibitor is tomoxetine, reboxetine or a compound of the formula I.

Use in accordance with the claim 3, characterized in that the norepinephrine reuptake inhibitor is tomoxetine.

5. Use according to claim 3, characterized in that the norepinephrine reuptake inhibitor is tomoxetine hydrochloride.

6. Use according to claim 3, characterized in that the norepinephrine reuptake inhibitor is reboxetine. 7 _ Use in accordance with the claim 3, characterized in that the norepinephrine reuptake inhibitor is (R) -N-methyl-3- (2-methylethiophenoxy) -3-phenylpropylamine. TREATMENT OF OPPOSITION REBELLION DISORDER SUMMARY OF THE INVENTION Norepinephrine reuptake inhibitors are used to treat oppositional rebellion disorder.