Pharmaceutical composition containing alkylsulfonic - agonist at 5ht₁for rectal introduction

 

(57) Abstract:

The composition is intended for the treatment of migraine and histamine headaches. It contains an effective amount of 3-[2-(dimethylamino) ethyl]-N-methyl-1H-indol-5-methanesulphonamide or N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-acanalonia in free base form or pharmaceutically acceptable MES and solid fatty base with a hydroxyl number greater than 15. The composition is made in solid dosage form for rectal application. The composition has an improved absorption of the drug by the body and a rapid onset of its effects. 8 C.p. f-crystals, 2 ill., table 2.

The present invention relates to pharmaceutical compositions containing as active ingredient a compound which is a selective agonist activity of 5-HT₁-like receptors, in particular compositions for rectal administration.

5-HT₁-like receptors are, for example, in subcutaneous Vienna leg of the dog, and agonists of 5-HT₁-like receptor, which is associated with the present invention, reduce subcutaneous veins of the legs of the dog. Therefore, such compounds can be identified because of the reduction is, 6, 215 - 224 (1980). Compounds that are selective agonists of 5-HT₁-like receptor, as was found to be selectively reduces the carotid arterial vascular bed shot the dog.

A variety of compounds that selectively reduce the allocated bandwidth of the subcutaneous veins of the legs of the dog described in the literature. These compounds include derivatives of indole disclosed in patent applications in the UK N 2082175, 2081717, 2083463, 2124210, 2150932, 2162522, 2168347, 2168973, 2185020, 2186874, 2191488, 2208646, published European patent applications NN 147107, 237678, 242939, 244085, 225726, 254433, 303506, 313397, 354777, 382570, 464558, 506363, 506369, 450238, 451022, 451008, 478954, 494774, 497512, 501568 and published international patent applications NN WO 92/11013, WO 92/11014, WO 92/06973, WO 93/00086, WO 92/13856, WO 93/00094, WO 91/18897, and WO 93/00333.

Compounds disclosed in the descriptions (hereinafter, described as compound A), are useful in the treatment of migraine and histamine headaches.

Oral introduction is usually the preferred way to administer medicines, as this path is a particularly convenient and acceptable to the patient. Unfortunately, the oral composition may be associated with certain disadvantages, in particular, in the treatment of conditions, still the bridges: emptying, what can cause slow and poor absorption of drugs after oral administration.

It is very desirable, especially in the treatment of acute conditions such as migraine, to pharmaceutical compositions had a rapid and consistent onset of impacts associated with the maintenance activity, and good biocompatibility. Fast absorption can be achieved by parenteral injection, but this is unacceptable for some patients, especially if the drug is taken without direct medical prescriptions, i.e., self-treatment (simplemom).

The present invention provides a pharmaceutical composition for rectal administration, which includes connection, acting as agonists 5HT₁-like receptor, in the form of its free development or its physiologically acceptable MES as an active ingredient together with one or more pharmaceutical carriers or excipients.

In a preferred embodiment of the invention we provide a pharmaceutical composition for rectal administration, which includes one or more compounds in A form of its free development or its pharmaceutically acceptable MES is IU, acceptable for use in medicine, in particular for the treatment of humans.

Particularly preferred compounds for use in compositions of the present invention are 3-(2-(dimethylamino)ethyl)- N-methyl-1H-indol-5-methanesulfonamide and N-methyl-3-(1-methyl-4 - piperidinyl)-1H-indol-5-econsultant, especially 3-(2-dimethylamino)ethyl-N-methyl-1H-indol-5-methanesulfonamide.

3-2-(dimethylamino)ethyl)-N-methyl-1H-indol-5-methanesulfonamide formula 1

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and its physiologically acceptable salt and solvate are disclosed in UK patent 2162522. The compound of formula 1 is described as useful in the treatment and/or warnings of pain resulting from the expansion of the cranial vasculature, in particular migraine.

Numerous clinical trials have demonstrated the effectiveness of the compounds of formula 1 for migraine sufferers. Before the medicine was always introduced in the form of a salt, for example, succinate (1:1), orally or vnutripuzarno or parenteral injection.

Alternative routes of administration of the compounds of formula 1 as proposed in patent GB 2162522, including rectal administration. Patent GB 2162522, in particular, reveals a number of pharmaceutical compositions comprising 3-(2-(dimethyl what the Oia for rectal injection in the form of a suppository.

The present invention provides a very useful pharmaceutical composition is not disclosed in particular in patent GB 2152522 which is suitable for rectal injection of compounds of formula (1).

Thus, in particular, a preferred aspect of the invention is a pharmaceutical composition for rectal administration, which includes 3-(2-(dimethylamino)ethyl)-N-methyl-1H - indol-3-methanesulfonamide or its pharmaceutically acceptable MES as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients.

In contrast to previously known compositions 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 the use of the compounds of formula 1 in the form of its free base rather than the form of its succinate salts possess unexpected advantages, if the active ingredient is introduced rectally.

Largely it is desirable in the treatment of acute conditions such as migraine, to pharmaceutical compositions had good biocompatibility and rapid onset vozdeistvuyuschih parameters.

When compared with suppozitornyj compositions containing 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indol-5-methanesulfonamido salt (succinate salt 1: 1), the compositions according to the present invention, the unexpected result is a more rapid and complete absorption of the active ingredient.

Compositions according to the invention can be in the form of a retention enema or solid dosage forms such as suppositories, or soft gelatin capsules. Preferably, the compositions are in the form of solid dosage forms suitable configuration, such as conical, cylindrical or in the form of torpedoes, for rectal administration. Solid dosage forms or melt at body temperature, or dissolved or dispersed in the cavity mucous secretion.

Conventional media that can be used in the compositions according to the invention include cocoa butter, hard fat, glycoregulation Foundation, macrogol (glycols) and their mixtures. Preferred compositions include solid fatty base such as esterified hydrogenated or fractionated vegetable oils and synthetic mixture of triglycerides obtained under the name t is but, di - and triglycerides of saturated C_9-18fatty acid. Preferably the substrate has a high hydroxyl number (USP Chemical Test), for example a hydroxyl number greater than 10, preferably more than 15, particularly in the area of 20 to 100, for example 40 to 50.

Solid dosage forms such as suppositories, can be obtained in the usual way, for example by mixing until a homogenous mixture of the active ingredient with the carrier, preferably the molten media. Preferably the active ingredient is subjected to fine grinding prior to introduction of the molten base, for example such that at least 90% of the active ingredient (the number of particles measured using Malvern laser partic le size) was in the form of particles having a particle size of 1 μm or less, preferably a diameter of 5 μm or less, for example about 2 μm.

The molten composition may then be poured into the appropriate forms, for example form of polyvinyl chloride, polyethylene or aluminum forms. Optional suppositories can be covered before packaging, for example, etilovym alcohol, macrogol or polyvinyl alcohol and Polysorbate to increase the decay time or lubrication, or to reduce adhesion during storage is ingredient may be 0.1 - 20 wt.% compositions, preferably 0.5 to 10 wt.% song.

The amount of active ingredient, for example 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indol-5-methanesulfonamide used in the compositions of the invention will preferably be in the region of about 1 to 200 mg, more preferably about 5 to 100 mg, preferably 5 to 30 mg.

Another aspect of the invention provides a method of treating mammals, including humans, suffering from or susceptible to conditions associated with headache, such as histamine headache, chronic proximally hemicrania, headache associated with vascular disorders, headache associated with the drug or a syndrome of cancellation (such as a drug), headache associated with pressure and, in particular migraine, which includes rectal administration of pharmaceutical compositions containing a compound that acts as an agonist at 5HT₁-like receptor, for example 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indol-5 - methanesulphonamide or its pharmaceutically acceptable MES as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients. It should be noted that the reference point, the number of compounds that act as agonists 5HT₁-like receptor used in the compositions of the invention will depend on the individual compounds used. In addition, the precise therapeutic dose of the active ingredient will depend on the age and condition of the patient and the nature of the condition being treated and will ultimately depend on the decision of the attending doctor.

However, the usual effective dose for the treatment of conditions associated with headache, for example acute treatment of migraine will be in the range of 1 to 500, preferably 2 to 200 mg, most preferably 5 to 100 mg, for example 10 or 25 mg of active ingredient per dose, which may be inserted one or two doses, for example, 1 to 4 times a day.

The invention is further illustrated by the following examples but is not limited to them.

Example 1.

Suppository for rectal injection

3-(2-(Dimethylamino(ethyl)-N-methyl-1H-indol-5-methanesulfonamide (micronized free basis) - 25 mg

Solid form (Adeps Solidus Ph. Eur) (sold under the brand name Witepsol W32). Hydroxyl number of 30 - and 40-Up to 2 kg

Preparing a suspension of the active ingredient in the molten PR> Prepare suppositories containing 5, of 12.5, 50, or 100 mg of 3-(2-(dimethylamino)ethyl)-N-methyl-1H-indol-5-methanesulfonamide (micronized free base) as described for suppositories of example 1.

Examples 6 to 10.

Prepare suppositories containing 1, 2,5, 5, 10, or 25 mg of N-methyl-2-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant (micronized free base) as described for suppositories of example 1.

Appendix A.

Pharmacokinetic study - rectal injection of sumatriptan.

The study involved sixteen healthy male volunteers aged 18 - 28 years old and weighs 57 - 82 kg. Each of the volunteers the night before dose received glycerin suppository (4 g) for emptying of the bowel. The study was conducted double-blind method, using random sampling and cross-sectional studies, in which eight volunteers-men was appointed one of eight different suppozitornyj compositions containing 25, 50, 100 or 200 mg micronized Foundation sumatriptan:^#or 25, 50, 100 or 200 mg micronized succinate sumatriptan⁺. Between each dose were conducted washout period glutelin is,25 - 0,33 - 0,5 - 0,75 - 1 - 1,25 - 1,5 - 2 - 2,5 - 3 - 4 - 6 - 8 - 10 - 12 hours after a dose. The concentration of sumatriptan in plasma were determined using high performance liquid chromatography (HPLC) with electrochemical detection.

Results.

The peak concentration (C_maxand the time required to reach this peak concentration (T_max), was determined directly from the data. In the curve of the dependence of the plasma concentration/time plot from 0 to infinity (AC) was calculated using the method of tangents. The results are shown in the drawing and collated in the table. 1 below.

Summary.

The data obtained indicate that suppozitornyj compositions containing succinate or free base sumatriptan have accelerated action (T_maxabout 1.0 hours for doses of 25 and 50 mg) and smooth absorption (AC) from 25 to 200 mg However, showed a strong difference between the values of C_maxand AC for the two compositions. In General suppozitornyj compositions containing sumatriptan in the form of a free base, had a 57% higher average AC than the corresponding compositions succinate sumatriptan.

Appendix B.

is there males Burgundy rabbits weighing 2.5 to 3.5 kg were not fed for 16 hours before the start of the experiment, but access to water is not limited. Suppozitornyj composition contained 10 mg of base sumatriptan (micronized) in 190 mg of solid fatty base (sold under the trademarks "Witepsol H15", "Witepsol H19" or "Witepsol W32". Each suppository was inserted into the rectum and prevent ejection during the first minutes of observations. In the marginal ear vein was inserted the catheter, after which he entered the heparin. After a certain period of time, 0,25 - 0,5 - 1 - 1,5 - 2 - 4 - 8 hours selected from 1 to 2 ml of blood. The concentration of sumatriptan in plasma were determined using high performance liquid chromatography (HPLC) with electrochemical detection.

Results.

For each composition was determined the dependence of the concentration of sumatriptan in plasma from time to time, and was calculated following farmakokineticeskih parameters:

- maximum plasma concentration (arithmetic mean).

- C_max(average value).

land plot on the curve plasma concentration from time to time up to 8 hours (average).

Biological availability in % vs. IV:

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The results are given in table. 2, below.

Composition B: 10 mg micronized Foundation sumatriptan. 190 mg Adeps Solidus (produced under the trademark "Witepsol H19).

Composition: 10 mg micronized Foundation sumatriptan. 190 mg Adeps Solidus (produced under the trademark "Witepsol H15).

Summary.

The data obtained indicate that suppozitornyj compositions containing the basis of sumatriptan and the media in the form of a solid fatty base, having a hydroxyl number of from 20 to 50, have higher rates of C_maxand % bioavailability than suppozitornyj compositions containing the basis of sumatriptan, and as a carrier of solid fatty base with a hydroxyl number of 15 or less.

1. Pharmaceutical composition for rectal administration, made in solid dosage form comprising as active ingredient a compound capable of acting as agonists NT₁- like receptor, and a pharmaceutically acceptable carrier, characterized in that as an agonist NT₁- like receptor it contains an effective amount of 3-[2-(dimethylamino)ethyl] -N-methyl-1H-indol-5-methanesulphonamide or N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant rye base with a hydroxyl number of > 15.

2. The composition according to p. 1, characterized in that the active ingredient is 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indol-5-methanesulphonamide or its pharmaceutically acceptable MES.

3. The composition according to p. 1, characterized in that the active ingredient is N - methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant or its pharmaceutically acceptable MES.

4. Composition according to any one of paragraphs.1 to 3, characterized in that it is made in the form of a suppository.

5. Composition according to any one of paragraphs.1 to 4, characterized in that the solid fatty base has a hydroxyl number of from 20 to 100.

6. Composition according to any one of paragraphs.1 to 5, characterized in that it comprises 0.1 to 20.0 wt.% the active ingredient.

7. Composition according to any one of paragraphs.1 - 6, characterized in that it contains 1 to 200 mg of active ingredient.

8. The composition according to p. 7, characterized in that it contains 5 to 30 mg of active ingredient.

9. Composition according to any one of paragraphs.1 to 8, characterized in that the active ingredient is microtelecom.