HRP960600A2 - Medical treatment - Google Patents

Description

This invention relates to a method of preventing relapse in patients with chronic schizophrenia.

In accordance with the proposed invention, there is provided a method of preventing the return of the disease in patients with chronic schizophrenia, which includes administering a therapeutically effective amount of the compound of formula I

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or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently hydrogen or methyl, together with a pharmaceutically acceptable diluent or carrier for a patient in need thereof.

A preferred compound of formula I is 2-[(8-chloro-dibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine or a pharmaceutically acceptable salt thereof.

The preparation and psychotropic and neurotropic activity of compounds of formula I, such as 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, or a salt thereof, are described in British Pat. 1247067 (Fujisawa). The use of compounds of formula I, such as 2-[(8-chlorodibenzo-[b,f]-thiepin-10-yl)oxy]-N,N-dimethylethylamine and salts thereof in the treatment of gout is described in US Pat. No. 4, 443, 469 (Fujisawa) . 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)-oxy]-N,N-dimethylethylamine has been available by prescription for the treatment of schizophrenia in Japan since 1982 under the commercial name "Lodopin®", and in Germany since 1990, under the commercial name "Nipolept®". 2-[(8-chlorodibenzo-[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine is also known as zotepine.

Many drugs are known to be useful in the treatment of schizophrenia. However, in patients with chronic schizophrenia, the problem of relapse remains. The drug's ability to prevent relapse is a highly desirable feature for the treatment of schizophrenia. It has now surprisingly been found that administration of a compound of formula I is useful in preventing relapse in patients with schizophrenia.

The concept of disease relapse can be defined as the reappearance of schizophrenia symptoms, such as hallucinations, apparitions and thought disorders, which can lead to suicidal or aggressive behavior, and social withdrawal, despite treatment with a compound used to treat schizophrenia, and can result in hospitalization or the need for increased care.

A compound of formula I may be administered in any known pharmaceutical dosage form. The amount of the compound will depend on a number of factors including the age of the patient, the severity of the condition and past medical history, and will always be within the reasonable judgment of the physician, and it is generally anticipated that the dosage of the compound administered will be in the range of 0.1500 mg, preferably 75 up to 450 mg per day in one or more doses.

In the proposed invention oral dosage forms are preferred and these are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. Auxiliary means, which are used for the preparation of these compositions, are known in pharmacy. Tablets can be prepared from a mixture of the active compound with fillers, for example lactose or calcium phosphate; disintegrants, for example corn starch; a lubricant, for example magnesium stearate; binders, for example microcrystalline cellulose, hydroxypropyl cellulose or polyvinylpyrrolidone and other ingredients known in the art to enable tableting of the mixture by known methods. Tablets may be formulated in a manner known in the art to aid release of the compound of the proposed invention. Such tablets, if desired, can be provided with external coatings by known methods, for example using cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound, with or without the addition of excipients, may be prepared in a conventional manner and, if desired, may be provided with outer coatings in known manner. The contents of the capsule can be formulated by known methods, so that a tolerable release of the compound is obtained.

Other compositions for oral administration include, for example, aqueous suspensions of the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethylcellulose, and oil suspensions containing a compound of the present invention in a suitable vegetable oil, for example sesame oil. The active compound can be formulated into granules with or without the addition of excipients. The granules can be swallowed directly by the patient or they can be added to a suitable liquid carrier (eg water) before swallowing. Granules may contain disintegrants, for example, a pharmaceutically acceptable effervescent vapor formed from an acid and a carbonate or bicarbonate salt, to facilitate dispersion in a liquid medium.

The therapeutically active compounds of formula I can be formulated into compositions that the patient retains in his mouth so that the active compound is administered through the oral mucosa.

Compositions of the present invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with cocoa butter and/or polyethylene glycol bases.

Dosage forms suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in suitable solvents, for immediate or sustained release.

Dosage forms for topical administration may contain a matrix in which the pharmaceutically active compounds of the present invention are dispersed, so that the compounds are kept in contact with the skin and thus the compounds are administered transdermally. A suitable transdermal composition can be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as mineral oil, petroleum and/or a wax, for example paraffin wax or beeswax, together with a strong transdermal accelerator, such as isopropyl myristate, dimethyl sulfoxide or propylene glycol . Alternatively, the active compounds may optionally be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in the topical formulation should be such as to deliver a therapeutically effective amount of the compound during the time required for the topical formulation to remain on the skin.

The therapeutically active compound of formula I can be formulated into compositions that are dispersed in the patient as an aerosol through the oral or nasal cavity. Such aerosols can be delivered by pump or from a compressed package containing a volatile propellant.

The therapeutically active compound of formula I used in the method of the present invention may also be administered by continuous infusion, from an external source, for example by intravenous infusion or from a source of the compound located in the body. Internal sources include implanted reservoirs containing the compound to be infused and which is permanently released, for example by osmosis, and implants which may be (a) a liquid, such as an oil suspension of the compound to be infused, for example in the form of a derivative of very modest solubility in water, or (b) in the form of an embedded support for the compound to be infused, for example a synthetic resin or wax-like material. The substrate can be a single body containing the entire compound or an array of several bodies, each containing a portion of the compound to be delivered. The amount of active compound present in the internal source must be such that a therapeutically effective amount of the compound is released over a long period of time.

In some formulations, it may be advantageous to use the compounds of this invention in the form of very small particles, such as for example those obtained by vigorous liquid milling.

In the compositions of the proposed invention, the active compound, if desired, can be combined with other compatible pharmacologically active ingredients.

The present invention also includes a compound of formula I, preferably 2-[(8-chloro-dibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine for use in relapse prevention in patients with chronic schizophrenia.

The proposed invention also includes the use of a compound of formula I, preferably 2-[(8-chloro-dibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, for the manufacture of a medicament for the prevention of relapse in patients with chronic schizophrenia.

Another aspect of the proposed invention includes a pharmaceutical composition for relapse prevention in patients with chronic schizophrenia comprising a therapeutically effective amount of a compound of formula I

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or its pharmaceutically acceptable salts, in which R1 and R2 independently represent hydrogen or a metal, preferably 2-[(B-chloro-dibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, together with pharmaceutical with an acceptable diluent or carrier.

The ability of zotepin to prevent relapse in chronic schizophrenia was demonstrated by the following clinical trial.

In a clinically controlled study, patients were selected according to the DSM-III-R criteria for the diagnosis of chronic schizophrenia.

Additionally, all patients had to have relapsed within the past 18 months and had a score of 3 or more (ie, be at least moderately ill) on the Clinical Global Impression (CGI) severity scale. Patients initially received 150 mg of zotepin per day, or placebo, titrated up to 300 mg per day during the first week of treatment, which could be further reduced to 150 mg. The trial was conducted during 26 weeks of treatment.

The primary measure of zotepin's effectiveness in preventing relapse was the time to relapse. Assessments were performed at week 0 (initial), then after 2, 4, 8, 16, 20 and 26 weeks. Efficacy was also assessed using the Brief Psychiatric Rating Scale (BPRS), the Scalc for Assessment of Negative Symptoms (SANS), and the Clinical Overall Impression (CGI) severity scale for each visit, and with CGI to improve from week one onwards.

In this trial, the term "disease relapse" was defined as follows: after 2, 4, 8, 16, and 26 weeks, patients were evaluated using five rating scales, namely BPRS, CGI severity, SANS, AIMS (Abnormal Involuntary Movement Scale, Abnormal Involuntary Movement Scale) and EPMS (extrapyramidal scale according to Simpson and Angus). At each evaluation, the disease recurrence questionnaire and the CGI global improvement scale were applied. The illness return questionnaire consisted of the following three details recorded with yes or no answers.

a) Was there any deterioration that required hospitalization? This must include an increase of at least 2 units in the sum of the CGI severity with an increase in the sum of 2 units to at least 2 units of positive symptoms on the BPRS.

b) Was there a STRONG deterioration during 24 hours (ie according to the CGI severity score III), or did the patient's condition in the hospital deteriorate to such an extent that, due to suicidal or aggressive behavior, it requires special care by the caregiver?

c) Did the BPRS sum increase by 2 units for at least two positive symptoms and did the CGS sum increase by 2 units or more?

If the patient showed worsening requiring hospitalization (a) or severe worsening (b) , this was defined as disease relapse and the assessment of disease remission/relapse as well as final developmental forms was concluded. A two-unit increase in at least two positive symptoms on the BPRS sum with a two-unit increase in the CGS sum (c) was defined as moderate grade clinical worsening. In that case, 2 days later, the BPRS and CGI scales were additionally concluded. The second score of clinical deterioration of a moderate degree was defined as the relapse of the disease and the evaluation of the remission/relapse of the disease as well as the final forms of development was concluded. If the above criteria, (a) or (b) or (c) were not met, then the patient did not have a relapse and therefore remained on the trial.

A total of 121 patients entered the double-blind trial; 63 were randomly assigned to zetepin and 58 to placebo. During the 26 weeks of the study, 25 patients in the group receiving zotepin experienced a complete relapse, 4 (6.3%), and 21 (36.2%) in the placebo group. Disease relapse was more frequent in the group of patients who received placebo than in the group of patients who received zotepin, and the difference in the ratio of disease relapse between the treatment groups was statistically significant (by-treatment analysis p = 0.0001). It turns out that in the group that received the placebo, the distribution of the return of the disease was uniform between 1-16 weeks, while in the group that received zotepin, the highest number (in 3 patients out of a total of 4) of the return of the disease occurred in the week of treatment. The relapse rate in patients who received 150 mg zotepin was similar to the rate in patients who received 300 mg, that is, 1 patient out of 16 (6.3%) and 3 patients out of 45 (6.7%).

Mean BPRS total sum from baseline to endpoint (week 26, last observation carried forward (LOCF) group) decreased by 5.7 in the zotepine group and increased by 1.8 in the received placebo. This difference was statistically significant at p = - 0.0078. This result was supported by change results from baseline to week 26 for most BPRS subscores (LOFC analysis), the CGI improvement scale, and the CGI severity scale. These scales show that there was a greater improvement in the zotepin-treated group than in the placebo group.

The results of the trial are presented in Tables 112. Figure 1 (see end) shows the mean profile of change in BPRS total sum from baseline, with the last observation performed at termination, for data on patients scheduled for treatment.

Table 1.

Disease recurrence rate

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* Risk of disease relapse compared to placebo. A hazard ratio <1 indicates a lower risk of relapse at any time in patients who received zotepin. ;Table 2 ;Total BPRS ;[image] ;* Shows a statistically significant difference between zotepin and placebo at the 4.5% level.

From these results, it can be seen that the improvement in the relapse ratio in patients treated with zotepine is significant compared to those who received placebo. This demonstrates the utility of compounds of formula I, such as zotepine, for relapse prevention in chronic schizophrenia.

Claims (12)

1. A method of preventing relapse in patients with chronic schizophrenia, characterized by administering to humans in need an effective amount of a compound of formula I [image] or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 are independently H or methyl, together with a pharmaceutically acceptable diluent or carrier. 2. The method according to claim 1, characterized in that the compound of formula T is 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine. 3. Compound of formula I [image] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently H or methyl, indicated for use in the prevention of disease relapse in patients with chronic schizophrenia. 4. 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, indicated to be used for the prevention of relapse in patients with chronic schizophrenia. 5. Use of the compound of formula I [image] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently H or methyl, indicated that it is used for the manufacture of a drug for the prevention of relapse in patients with chronic schizophrenia. 6. Use of 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N dimethylethylamine, characterized in that it is used for the production of a drug for the prevention of relapse in patients with chronic schizophrenia. 7. Pharmaceutical composition for the production of a drug for the prevention of disease relapse in patients with chronic schizophrenia, characterized in that it contains a therapeutically effective amount of the compound of formula I [image] or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 8. Pharmaceutical composition for the prevention of relapse in patients with chronic schizophrenia, characterized by the fact that as the main ingredient it contains a therapeutically effective amount of 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)-oxy]-N,N - dimethylethylamine, together with a pharmaceutically acceptable diluent or carrier. 9. Use of the compound of formula I [image] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently H or methyl, for use in the prevention of relapse in patients with chronic schizophrenia. 10. Use of 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, characterized in that it is used for the preparation of a composition for the prevention of relapse in patients with chronic schizophrenia. 11. Pharmaceutical composition for the prevention of relapse in patients with chronic schizophrenia, characterized in that it contains a therapeutically effective amount of the compound of formula I [image] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently H or methyl, prepared by a method known per se, together with a pharmaceutically acceptable diluent or carrier. 12. Pharmaceutical composition for the prevention of relapse in patients with chronic schizophrenia, characterized in that it contains a therapeutically effective amount of 2-[(8-chlorodibenzo[b,f] thiepin-10-yl)oxy]-N,N-dimethylethylamine, prepared by a method known per se, together with a pharmaceutically acceptable diluent or carrier.