MXPA97004579A - Pharmaceutical composition comprising mirtazapine and one or more selective seroton reabsorption inhibitors - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising mirtazapine, a selective inhibitor of serotonin reuptake (SSRI) and pharmaceutically acceptable auxiliaries. In particular, the SSRI is selected from fluoxetine, fluvoxamine, citalopram, cericlamin, fexomethine, sertraline, paroxetine, ifoxetine, cyanodotiepin and litoxetine. The composition, which can be used to treat patients with depression, has fewer side effects than the treatment of patients with mirtazapine or the SSRI alone.

Description

PHARMACEUTICAL COMPOSITION COMPRISING MIRTAZAPINE AND ONE OR MORE SELECTIVE REABSORTION INHIBITORS OF SEROTONINE DESCRIPTION OF THE INVENTION The invention relates to pharmaceutical compositions comprising mirtazapine and elective serotonin reuptake inhibitors (SSRI 's), to a package containing a dose units comprising mirtazapine and an SSRI, and to a method for the treatment of depressive patients. Depression is a chronic disease that affects people of all ages. Although there are many effective antidepressant agents available, the current armamentarium of treatments is usually not adequate, with unsatisfactory results in approximately one third of all treated subjects. Of the various classes of antidepressants, which are currently available, selective serotonin reuptake inhibitors (SSRIs) are among the most successful. SSRIs have a high ratio of inhibition of 5HT reabsorption on the inhibition of reabsorption of noradrenaline. SSRIs have been made available since the beginning of the 1980s, and SSRI zimelidine was the first drug to be sold. Other SSRIs in the market or in development are, for example, fluoxetine, fluvoxamine, citalopram, cericlamin, femoxetine, ifoxetine, cyanodotiepin, sertraline, paroxetine, and litoxetine. Although released as new breakthrough drugs due to their favorable profiles compared to the classic antidepressant drugs that come from them, SSRI's are considered to have many problematic side effects. These usually exclude the use of SSRIs for the treatment of depression. In addition, some researchers believe that in the subpopulation of depressed melancholic patients, SSRIs may be inferior to other antidepressants. The most obvious side effects of SSRI's are headache, nausea, appetite suppression, and sexual function disorder, such as anorgasmia and loss of libido. These side effects of sexual malfunction can easily interfere with long-term condescension. It has now been found that the administration of mirtazapine, which is one of the newer antidepressant agents and has been described in the patent of E. U.A. 4,062,848, is able to prevent or at least significantly reduce the side effects that occur when SSRIs are administered. This finding is the most surprising, since mirtazapine and SSRIs share many aspects. Like the SSRIs, mirtazapine has a low affinity for muscarinic cholinergic receptors, norepinephrine absorption vehicle and alpha-1 adrenergic receptors. In addition, both improve the release of serotonin. In contrast to SSRIs, mirtazapine does not inhibit the pumping of neuron uptake for serotonin. The most significant adverse effect of mirtazapine treatment is drowsiness. A further advantage of the present invention is that the SSRIs decrease the side effects of mirtazapine when administered together. In this manner, the present invention relates to the administration of two different classes of the antidepressant drug, each drug mutually decreasing the side effects of the other drug. It has also been found that both drugs improve efficacy as an antidepressant drug. As a consequence, if the SSR I's are administered together with mirtazapine, this can be used for many patients while maintaining or improving the therapeutic effect. Thus, according to one aspect, the present invention provides a combination comprising mirtazapine or a pharmaceutically acceptable salt thereof and one or more SSRI's, or a pharmaceutically acceptable salt thereof, preferably an SSRI. Most preferably, the combination comprises mirtazapine with an SSRI. Such combinations mentioned hereinafter can be referred to as combinations according to the invention. It will be appreciated that the compounds of the combination can be administered concomitantly, either in the same pharmaceutical formulation or in a different one, or sequentially. If sequential administration is taken, the delay in the administration of the second active ingredient (or additional) should not be such that it loses the benefit of the effective effect of the combination of the active ingredients. Suitable salts include acid addition salts, for example, hydrochloric, fumaric, maleic, citric, or succinic acid, these acids being mentioned only by way of illustration and without limitation involved. It will be appreciated that mirtazapine, SSRI's and their salts may contain one or more centers of chiral capacity and exist as isomers, including diastereomers and enantiomers. The present invention includes the aforementioned stereoisomers within its scope, and each of the individual (R) and (S) enantiomers of the compounds and their salts, substantially free, i.e., associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer and mixtures of said enantiomers in any ratio, including racemic mixtures containing substantially equal amounts of the two enantiomers. The present invention also provides combinations according to the invention for use in therapy, more particularly in the treatment or prophylaxis of depression. In addition, the invention comprises the use of combinations according to the present invention for the manufacture of a medicament having antidepressant activity with a minimum of side effects. The present invention also provides the use of mirtazapine in the manufacture of a medicament to be administered concomitantly or sequentially with one or more SSRI's for the treatment of depression. It will be appreciated that an SSRI can be used in the manufacture of the above medicament to be administered concomitantly or sequentially with mirtazapine. The invention further includes the use of mirtazapine and an SSR I for the manufacture of a medicament having antidepressant activity without inducing headache, nausea, appetite suppression, or sexual function disorder. The present invention further includes a method for the treatment of an animal, for example, a mammal, including a human being, suffering from depression, which comprises administering an effective amount of a combination according to the invention. The method of this invention is suitable for all SSRI's. For example, mirtazapine or a pharmaceutically acceptable salt thereof can be combined with fluoxetine, fluvoxamine, citalopram, cericlamine, femoxetine, sertraline, paroxetine, ifoxetine, cyanodotiepin and lithoxetine, or a pharmaceutically acceptable salt thereof. Mirtazapine combinations with one or more of fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine are preferred. Preferred is the combination of mirtazapine or a pharmaceutically acceptable salt thereof with fluoxetine or a pharmaceutically acceptable salt thereof. Very preferred is the combination of mirtazapine with fluoxetine. The amount of an amount of mirtazapine (or a pharmaceutically acceptable salt thereof) and an SSRI (or a pharmaceutically acceptable salt thereof), required to produce the effective effects, will, of course, vary and is ultimately at the discretion of the physician. Factors that must be considered include the route of administration and the nature of the formulation, the body weight of the animal, its age and general condition, and the nature and severity of the disease that will be treated. In general, an appropriate dose of mirtazapine or a pharmaceutically acceptable salt thereof, to be administered to a human being, will be in the range of 0.01 to 30 mg per kilogram of the body weight of the patient, per day, preferably on the scale of 0.1 to 5 mg per kilogram of body weight per day, and most preferably on the scale of 0.3 to 1.0 mg per kilogram of body weight per day. In general, a suitable dose of an SSRI or a pharmaceutically acceptable salt thereof, to be administered to a human being, will be in the range of 0.01 to 50 mg per kilogram of the body weight of the container per day, preferably in the range of 0.1 to 3. mg per kilogram of body weight per day. In the case of fluoxetine, a suitable dose will be in the range of 0.01 to 10 mg per kilogram of the body weight of the container per day, preferably in the range of 0.1 to 1 mg per kilogram of weight per day. Unless otherwise stated, all weights of active ingredients are calculated in terms of drug per se.

The desired dose is preferably presented as two, three, four, five, or more sub-doses administered at appropriate intervals during the day. These sub-doses can be administered in unit dose forms, for example, containing from 5 to 50 mg, preferably 10 mg of mirtazapine. The SSRI can be administered in unit dosage forms of 10 to 100 mg, preferably 10 to 50 mg. Fluvoxamine is conveniently administered in unit dose forms of 50 to 100 mg, paroxetine in unit doses of 20 mg and sertraline, 50 mg. In the case of fluoxetine, a typical dose unit is 20 mg. The components of the combination, which may be referred to as the active ingredients, may be administered for therapy, to an al, v. gr. , a mammal including a human being, in a conventional manner. Since it is possible for the active ingredients of the combination to be administered as the starting chemical, it is preferable that they be presented as a pharmaceutical formulation. Pharmaceutical formulations according to the present invention comprise the active ingredients (ie, the combination of mirtazapine or a pharmaceutically acceptable salt thereof and one or more SSRI's or a pharmaceutically acceptable salt thereof) together with one or more carriers or pharmaceutically acceptable excipients and optionally other therapeutic agents. The vehicle (s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not harmful to the container thereof. When the individual components of the combination are administered separately, each is generally represented as a pharmaceutical formulation. Suitable formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations can be prepared by methods well known in the art of pharmacy, for example, using methods such as those described by Gennaro et al., In Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: "Pharmaceutical Preparations and Their Manufacturing." Said methods include the step of associating the active ingredient with the vehicle, which constitutes one or more accessory ingredients, said accessory ingredients include those conventional in the art, such as fillers, binders, diluents, disintegrators, lubricants, colorants, flavoring agents and wetting agents Formulations suitable for oral administration can be presented as discrete units such as pills, tablets or capsules, each containing a predetermined quantity of active ingredient, such as a powder or granules; as a solution or suspension. It can also be present as a bolus or paste, or it can be contained within liposomes. Formulations for rectal administration can be presented as a suppository or enema. For parenteral administration, suitable formulations include sterile aqueous and non-aqueous injection. The formulations can be presented in unit dose or multiple dose containers, for example, sealed bottles and ampoules, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid carrier, eg, water before of use. Formulations suitable for administration by nasal inhalation include fine powders or vapors, which can be generated through aerosols, nebulizers or pressurized, metered dose insufflations. The present invention further includes a process for the preparation of a pharmaceutical formulation, which comprises associating a combination of mirtazapine (or a pharmaceutically acceptable salt thereof) and one or more SSRI's (or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable vehicles thereof. In a modality, a mixture of mirtazapine or one or more SSRI's can be presented as a pharmaceutical formulation in unit dosage form, for example, administered in the form of a tablet, pill, capsule and the like. Said dosage forms are known in the art, v. gr. , as described in the standard reference by Gennaro et al., in Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: "Pharmaceutical Preparations and their Manufacturing", compounds can be compressed in unit doses solid, such as pills, tablets, or be processed into capsules or suppositories.With pharmaceutically acceptable liquids, the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, v. gr., a nasal spray To make unit doses, for example tablets, the use of conventional additives such as fillers, colorants, polymeric binders, and the like is contemplated In general, any pharmaceutically acceptable additive which does not interfere can be used. with the function of the active compounds The appropriate amounts of active ingredients are, for example, a table ta comprising 5 to 50 mg of mirtazapine and typically 5 to 100 mg of SSRI. In a specific example, a tablet is obtained comprising 15 mg of mirtazapine and 20 mg of fluoxetine. SSRI quantities greater than 100 mg may be necessary when using SSRI's with low intrinsic activity. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives, and the like, or mixtures thereof, used in suitable amounts. More commonly, these pharmaceutical formulations of days are prescribed to the patient in "patient packs" that contain the entire course of treatment in a single package, usually in a packet of ampoules. Patient packages have an advantage over traditional prescriptions, where a pharmacist divides the supply of a pharmaceutical product for patients from a bulky supply, since the patient always has access to the package insert contained in the package for the patient. patient, usually forgotten in traditional prescriptions. The inclusion of a package insert to shown improves the patient's condescension with medical instructions. An additional embodiment includes a package containing separate dose units, one or more of which containing mirtazapine or a pharmaceutically acceptable salt thereof, and one or more of which containing an SSRI or a pharmaceutically acceptable salt thereof. Unit dosages containing mirtazapine (or a pharmaceutically acceptable salt thereof) have suitable amounts of active ingredient, eg, from 5 to 50 mg of mirtazapine, have for example 10 to 30 mg of SSRI. A package contains sufficient tablets, capsules or the like for the treatment of a patient during a predetermined period, for example, 2 weeks, 1 month, or 3 months. Patients, or course, can also be treated using separate unit doses, each containing mirtazapine or an SSRI. Said separate unit doses are considered to be encompassed in the packages described herein. The present invention further includes a patient package comprising mirtazapine and an SSRI and an information insert containing the indications on the use of the active ingredients together in combination. Mirtazapine can be prepared using the method described in the patent of E.U.A. 4, 062, 843, which is incorporated herein by reference. The SSRI's can be prepared by any method known in the art. For example, fluoxetine and its pharmaceutically acceptable acid addition salts can be prepared by any method known in the art for the preparation of a compound of similar structure. Typically, the compounds are prepared by the methods described in the patent of E. U.A. 4, 314.081. Pharmaceutical compositions containing fluoxetine are described in the patent of E.U.A. 4, 194.009. The contents of the patents of E. U.A. Nos. 4,314,081 and 4, 194, 009 are incorporated herein by reference. The invention is further illustrated through the following examples.EXAMPLE 1 Disorders of Sexual Functions in Rats by Fluoxetine Male rats were individually placed in small cages. Observations were continually made. Due to the treatment of the rats with fluoxetine, these had an average of 2.1 i 0.3 spontaneous erections with ejaculations. This is in accordance with the work published by Berendsen and Broekkamp, European J. Pharmacol 135: 279-287, 1987. When the rats were treated with both fluoxetine and mirtazapine, there was a strong, statistically significant reduction in the occurrence of penile erections. A dose of 0. 1 mg / kg of mirtazapine is enough to antagonize this abnormal effect of fluoxetine on sexual function. The stockings were obtained from 1 1 rats. Fluoxetine, 22 mg / kg subcutaneously (sc): 2.1 + _0.3 erections. Fluoxetine 22 mg / kg se + mirtazapine 0.1 mg / kg sc: 0.2 + 0.1 erections. Fluoxetine 22 mg / kg scC + mirtazapine 0.22 mg / kg sc: 0.4 + 0.2 erections.

EXAMPLE 2 Reduction in Appetite Suppressant Effect by Fluoxetine For 30 minutes, rats were placed in a cage with available food, which is the preferred rats. They ate 14.5 + .1 .8 grams (average of 7 rats). The food consisted of live mealworms. Rats that were treated with 30 mg / kg of fluoxetine, ate only 3 + 0.4 grams. This is a reduction of 80%. When this comparison was made with a concomitant treatment with 2 mg / kg of mirtazapine, the reduction was only 40%. This is clear but partial appetite antagonism inhibited the effect of fluoxetine through mirtazapine.

Claims (10)

1. - A combination comprising mirtazapine or a pharmaceutically acceptable salt thereof and one or more SSRI's or a pharmaceutically acceptable salt thereof.

2. A combination according to claim 1, wherein the SSRI is selected from zimeldine, fluoxetine, fluvoxamine, citalopram, cericlamin, femoxetine, ifoxetine, cyanodotiepin, sertraline, paroxetine and lithoxetine.

3. A combination according to claim 1, comprising mirtazapine and fluoxetine.

4. A combination according to any of claims 1 to 3 for use in the treatment of depression.

5. - A pharmaceutical formulation comprising a combination according to any of claims 1 to 3 in association with one or more pharmaceutically acceptable vehicles thereof.

6. A method for the treatment of depression in an animal, which comprises treating said animal with a therapeutically effective amount of a combination as defined in any of claims 1 to 3 or a formulation described in claim 5.

7 .- The use of mirtazapine and one or more SSRI's in the manufacture of a drug that has antidepressant activity with a minimum of side effects.

8. - The use of one or more SSRI's in the manufacture of a drug to be administered concomitantly or sequentially with mirtazapine for the treatment of depression.

9. The use of mirtazapine in the manufacture of a medicament to be administered concomitantly or sequentially with one or more SSRIs for the treatment of depression.

10. A package containing separate unit doses, of which one or more unit doses comprises mirtazapine and one or more other unit doses comprises an SSR1, preferably fluoxetine.