The pharmaceutical composition, the production method, a method of treating mammals

 

(57) Abstract:

The pharmaceutical composition is intended for rectal injection in the form of a suppository. The composition contains as the active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one in the form of its free base or pharmaceutically acceptable MES. Pharmaceutically acceptable carrier is terrazitovoj basis, having a hydroxyl number in the range of 60-70. The number of the specified active ingredient is from 0.05 to 20% by weight. To prepare the composition in the form of a suppository specified active ingredient is thoroughly mixed with the specified media. The composition is used for treating conditions due to exposure to 5-hydroxytryptamine on 5-HT3the receptors. These States are nausea and vomiting. The technical result consists in the implementation of composition assignments. 3 S. and 3 C.p. f-crystals, 2 tab.

The object of the present invention is a pharmaceutical composition containing as active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one, in particular a composition for rectal administration.

1,2,3,9-tetrahydro-9-methyl-3-[(2-matichesky acceptable salt and solvate described. The compound of formula (I) described as potent and selective antagonist of 5-hydroxytryptamine (5-HT) in the "neuronal" 5-HT receptors related to the type of receptors, localized on the endings of primary afferent nerves. Receptors of this type is designated as 5-HT3receptors, they are also in the Central nervous system. 5-HT is widely represented in the neural pathways in the Central nervous system, it is also known that damage to these 5-HT-containing conductive pathways alter behavioral syndromes such as mood, psychomotor activity, appetite and memory.

The specified connection has been described as applied to the treatment of the human or animal subject suffering from a condition caused by violation of neural 5-HT function, for example for treating a human subject suffering from migrainebuy pain or psychotic disorders like schizophrenia. It was also established that this compound can be used to treat such conditions as anxiety, obesity and mania.

Published later patent applications describe the use of compounds of formula (I) and other 5-HT3antagonists for the treatment of a number of other state the ical studies have shown, the effectiveness of the compounds of formula (I) in the treatment of vomiting, in particular nausea and vomiting associated with cancer chemotherapy and radiotherapy, as well as nausea and vomiting observed in patients after operations. To date the medication was always introduced in the form of a salt, in particular in the form of hydrochloride dihydrate, either by injection or orally.

Oral administration is a preferred route of administration of pharmaceutical preparations, because it is the most convenient and acceptable to patients. Unfortunately, the oral compositions may be accompanied by certain disadvantages, in particular, in the treatment of conditions involving nausea and/or vomiting. It is very important, especially in the treatment of acute conditions, to pharmaceutical compositions had a fast and stable initial action in combination with prolonged activity and good bioavailability. Rapid absorption can be achieved by parenteral administration, but it is unacceptable for some patients, especially in those cases where the drug must be entered without direct medical supervision, that is, when Samovodene.

Possible ways wideselection drugs containing as the active ingredient hydrochloride dihydrate 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-4H-carbazole-4-it, specific suppozitornyj preparation for rectal administration, containing this active ingredient has also been described.

In the present invention offer a very promising pharmaceutical drug, not specifically described to date, which is suitable for rectal injection of compounds of formula (I).

For example, according to the invention offer a pharmaceutical composition for rectal administration, which contains as an active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one in the form of its free base or its pharmaceutically acceptable MES in conjunction with one or more pharmaceutically acceptable carriers or excipients.

In contrast to the compositions known from the prior art, the compositions according to the invention contain the active ingredient in the form of its free base or its pharmaceutically acceptable MES. Applicants have found that by rectal injection of active ingredient in advantage is, ironically, the use of free on the change in the form of retention enemas, solid dosage forms such as suppositories or soft gelatin capsules, or semi-solid dosage forms, such as rectal gel or cream. Preferably, the compositions were skompanovany in the form of a solid unit dose forms of the appropriate type, such as conical, cylindrical or torpedo-shaped form, convenient for rectal administration. Solid dosage forms may either dissolve at body temperature, or to dissolve or dissolve in the mucous secretions of the cavity.

Standard media that may be used in the compositions according to the invention include theobromine oils, solid fats, glycerides of fatty acids, glycerin-gelatin basis, macrogol (glycols) and their mixtures. Preferred compositions contain such fundamentals of solid fats, as esterified hydrogenated or fractionated vegetable oil, and a mixture of synthetic triglycerides, produced under the name solid pork fat.

Preferred verdirame the basics are solid fats containing a mixture of mono-, di - and triglycerides of saturated9-C18fatty acid. Preferably, tverdova the basis of cm, macrography ether containing from 20 to 24 oxyethylene groups in polyoxyethylene circuit, for example, polyoxy-20-cetosteatil ether, and glycerides such as ricinoleic glycerine. Preferably, tverdova basis had a high hydroxyl number (USP chemical test), for example a hydroxyl number in the range between 20 and 100, such as from 40 to 80, in particular from 60 to 70.

Solid dosage forms such as suppositories that can be prepared in a standard way, for example, by thoroughly mixing the active ingredient with the carrier, preferably the molten media. Preferably, before the introduction of the molten carrier of the active ingredient was permalot or sifted. The molten composition may then be filled in the appropriate forms, such as PVC, polyethylene or aluminum forms. Pets that before packing suppositories were covered, for example, etilovym alcohol, macrogol or polyvinyl alcohol and Polysorbate to increase time decomposition or greased to reduce sticking together when stored.

Preferably, the total weight of the solid dose form was about 1 or 2 grams, and the active ingredient m is from 0.2 to 5% of the composition by weight, for example from 0.4 to 3.2%.

The amount of free base 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-it is used in the compositions according to the invention should preferably lie in the range from approximately 0.1 mg to approximately 100 mg, more preferably from about 1 mg to about 50 mg, for example from about 2 mg to about 35 mg, in particular from approximately 5 mg to approximately 20 mg

The following aspect of the invention offer a method of treating mammals, including humans, suffering from or prone to the condition, caused by the action of 5-hydroxytryptamine on 5-HT3receptors, which includes rectal administration of a pharmaceutical composition containing as active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)- methyl] -4H-carbazole-4-one in the form of its free base or its pharmaceutically acceptable MES in conjunction with one or more pharmaceutically acceptable carriers or excipients. It should be noted that reference to treatment includes prevention and alleviation of established symptoms.

To the States, due to the action of 5-HT at 5-HT3reciproke (including senile dementia, Alzheimer's disease, syndrome Peak horey's disease, Parkinson's disease Creutzfeldt-Jakob disease) and vascular dementia (including multi-infarction dementia), as well as dementia associated with lesions covering the intracranial space, trauma, infections and related conditions (including HIV infection), metabolism, toxins, hypoxia and vitamin deficiency; and mild reduction of cognitive activity associated with aging, including memory loss associated with age; psychotic disorders such as schizophrenia and manic syndrome; anxiety, including panic, agoraphobia, social phobia, common phobia, obsessive compulsive condition, posttraumatic stress, a combination of fear and depression and General state of fear; nausea and vomiting, particularly associated with cancer chemotherapy and radiotherapy, as well as observed after operations; the syndrome of painful sensitivity of the intestine and drug dependency, and substance abuse. Among other due to similarly States include gastric stasis; symptoms of gastrointestinal dysfunction observed, for example, when poptical and depression.

The pharmaceutical compositions according to the invention have the private use for the treatment of nausea and vomiting, particularly associated with cancer chemotherapy and radiotherapy, as well as observed after operations.

It should be borne in mind that the precise therapeutic dose of the active ingredient depends on the age and condition of the patient and the nature of the condition which must be treated and must be installed permanently treating physician.

In General, however, the effective dose for treating conditions caused by the action of 5-hydroxytryptamine on 5-HT3receptors, such as postoperative nausea and vomiting, lie in the range from 0.1 to 200 mg, preferably from 0.5 to 100 mg, most preferably from 1 to 50 mg, such as 4, 8, 16, or 32 mg of the active ingredient generic dose, which can be entered as a single or divided doses, for example from 1 to 4 times a day.

Further, the invention is illustrated by the following specific examples.

Example 1 (table. 1).

Preparing a suspension of the active ingredient in the molten basis and introduced her properly templates suppositories 1 g

Examples 2, 3, 4, and 5.

Suppositories, spodnie base), prepared as described for suppositories example 1.

Example 6 (table. 2).

Preparing a suspension of the active ingredient in the molten basis and was entered accordingly in the templates suppositories 2,

Examples 7 and 8.

Suppositories containing 8 or 32 mg 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H - carbazole-4-one (sifted free base) was prepared as described for suppositories from example 6.

Example 9.

Suppositories containing 4 mg 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one (sifted free base), prepared as described for suppositories of example 6.

1. Pharmaceutical composition for rectal injection in the form of a suppository containing one or more pharmaceutically acceptable carriers, characterized in that it contains as active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one in the form of its free base or pharmaceutically acceptable MES, and as the pharmaceutically acceptable carrier is cordaronebuy basis having a hydroxyl number in the range of 60-70.

2. Composition under item 1, characterized in that the I, that it contains from 0.1 to 100 mg of the indicated active ingredient.

4. The method of preparation of a pharmaceutical composition for rectal injection in the form of a suppository containing one or more pharmaceutically acceptable carriers, wherein as the active ingredient 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl] -4H-carbazole-4-one in the form of its free base or pharmaceutically acceptable MES, as a pharmaceutically acceptable carrier - cordaronebuy basis having a hydroxyl number in the range of 60-70, and the specified active ingredient is thoroughly mixed with the specified media.

5. A method of treating a mammal suffering from or susceptible to a condition, caused by the action of 5-hydroxytryptamine on 5-HT3receptors, characterized in that rectally administered pharmaceutical composition in the form of a suppository according to any one of paragraphs.1-3.

6. The method according to p. 5, wherein the specified condition is nausea and vomiting.

 

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