AT396870B - Process for the production of a pharmaceutical formulation for the nasal administration of serotonin antagonists - Google Patents

Abstract

Process for the production of a pharmaceutical form for nasal administration containing a therapeutically effective amount of carboxylic esters or carboxamides of the formula.

Description

AT 396 870 B

The invention relates to a process for the preparation of a galenic form for nasal administration which comprises a therapeutically effective amount of a compound of the formula (I)

A-B-C-D contains, wherein A is a group of formula

(Π) means in which the free bond can be located on each of the rings connected to one another, Z for -CH2-, -NR3-, -0- or -S-,

R1 and R2 independently of one another for hydrogen, halogen, (Ci-4) alkyl, (Ci4) alkoxy, hydroxy, amino, (Ci-4) alkylamino, di (Ci_4) alkylamino, mercapto or (Ci_4) alkylthio and R3 for hydrogen or (Ci.4) Stand alkyl and B -CO-, C -NH-, or -O- and D a group of the formula

(VI) mean where n is 2, 3 or 4 and

Rg means hydrogen or (Ci_7) alkyl, in the form of the free base or an acid addition salt or a quaternary ammonium salt thereof.

The process according to the invention is characterized in that compounds of the formula (I) or their acid addition salts or quaternary ammonium salts are mixed with pharmaceutically acceptable diluents and / or other carriers suitable for use on the nasal mucosa and the mixture thus obtained is mixed into a galenic form for nasal administration.

The compounds of formula I can be in the form of acid addition salts or their quaternary ammonium salts.

The compounds of formula (I) are already known, for example, from Belgian patent no. 897117, which describes a 5HT3 antagonism for these compounds. The compounds are said to have potent activity against migraines and as antiarrhythmics. EP-A 189 002 states that the compounds are effective in eliminating serotonin-related gastrointestinal disorders and in accelerating gastric emptying.

It has now been found that, when administered nasally, the compounds of the formula (I) have a favorable action against rhinitis and pulmonary embolism and, moreover, to improve the nasal absorption and thus to improve the bioavailability of other active substances, for. B. contribute from peptides.

The preferred compounds according to the present invention include:

Indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo [3 2. l] -oct-3-yl ester (hereinafter compound E)

Benzo [b] thiophene-3-yl-carboxylic acid-endo-9-methyl-9-aza-bicyclo [3.3.1] non-yl ester (hereinafter compound F) 5-fiorio-l-methyl-indol-3- yl-carboxylic acid endo-9-methyl-9-aza-bicyclo [3.3.1] non-3-yl ester (hereinafter Ver- -2-

AT 396 870 B bond G)

The nasal route d. i. Via the nasal mucosa is a simple and quick delivery method that can be easily carried out by the patient himself, e.g. B. by administration of a liquid nasal dosage form, for example a nasal spray or drip solution with the aid of a nasal applicator, or by inserting a gelatin-like sponge soaked with the active ingredient, and further blowing the galenic form as a powder into the nostrils.

In the preparation of a liquid galenical molded compound for nasal administration according to the invention, the compounds of the formulas or their acid addition salts or their quaternary ammonium salts 10 should be present in a proportion of 1 to 30%, preferably 5 to 20%, in particular 10 to 15% (w / v) be.

In particular in the manufacture of liquid galenic forms for nasal administration, the risk of contamination with pathogenic or other undesirable microorganisms must always be considered. Procurement of a suitable, fully compatible preservative to avoid contamination 15 z. B. with pathogenic or other undesirable microorganisms is a problem in the manufacture of galenic forms for nasal administration. It is particularly critical for those galenic forms in which the risk of contamination is particularly high. The preservative should not only be able to initial contamination, e.g. B. during the formulation and filling of the composition into the container, but also further possible contamination during use, 20 especially when multiple administration with a single container / applicator is required. Problems arise particularly where, for. B. A nasal applicator, which is often the case, is kept for months after use before being used again. During this phase the selected preservative can be inactivated, e.g. B. by adsorption on the inner walls of the applicator, by heat degradation, or when the preservative is somewhat volatile, by escaping from the applicator. Furthermore, there is a risk that during the actual use phase (in the case of multiple administration with a single applicator this phase can extend over several days or weeks), the applicator will leak or in some other way undesired microorganisms or other germs from the atmosphere or from the Penetrate nostrils into the applicator. Furthermore, the composition may be at higher temperatures, e.g. B. during transport or storage. 30 In addition to the difficulties mentioned above, there is also the problem that a liquid nasal

Form of administration should also be well tolerated, especially at the direct application site.

The liquid nasal dosage form should e.g. B. do not irritate the nasal mucosa (e.g. do not cause significant irritation) nor cause a significant decrease in ciliary movement frequency. Surprisingly, it has now been found that liquid administration forms suitable for nasal administration can be obtained which contain the compounds of the formula I or acid addition salts or quaternary ammonium salts and meet the high stability and tolerance standards for nasal administration and are suitable for use in nasal spray applicators are, whereby the administration can be carried out in several doses (batches), d. H. in applicators, which are capable of a number of single doses over z. B. to give a period of several days or weeks, if benzalkonium chloride is used as a 40 preservative in the carriers. Surprisingly, it was also found that the

Use of benzalkonium chloride, even at the low concentrations required for preservation, can favorably influence the nasal absorption of the compounds of the formula I used according to the invention or their acid addition salts or their quaternary ammonium salts and the initial bioavailability of these compounds can be increased when administered nasally. 45 The proportion of benzalkonium chloride in the compositions produced according to the invention is preferably about 0.002 to about 0.02, particularly about 0.01% (weight / volume) of the total composition.

According to the administration forms z. B. as drops or as a spray for use on the nasal mucosa. However, as described below, they are preferably used as a spray, i.e. H. formulated as finely divided droplets. Another way of bringing the liquid nasal dosage form into contact with the nasal mucosa is to soak a gelatin-like sponge (e.g. SPONGOSTAN from Novo Industri A / S Bagsvaerd, Denmark) and then into the sponge Introduces nostrils.

Water (pharmaceutical grade) is expediently used as the liquid diluent or carrier. An aqueous salt solution is particularly preferred. According to the invention, the liquid nasal administration forms are formulated in such a way that they allow administration via the nasal route. For this purpose they can e.g. B. also minimal amount of other desired ingredients od »excipients, eg. B. additional preservatives, od »z. B. ciliary stimulants such as caffeine. -3-

AT 396 870 B

The liquid nasal administration forms produced according to the invention preferably have a pH of 5.5 to 6.

The liquid nasal dosage forms should also have suitable isotonicity and viscosity. They preferably have an osmotic pressure of approximately 260 to approximately 380 mOsm / liter. The desired viscosity of the compositions produced according to the invention depends on the particular administration form, e.g. B. whether nasal drops or a nasal spray are administered. For nasal drops a viscosity of approx. 2 to approx. 40 x 10 " 3 Pa.S. suitable. For nasal sprays, the viscosity is less than 2 x 10 * 3 Pa.S. Suitable The liquid nasal administration forms can of course also contain further constituents, in particular customary pharmaceutically applicable surface-active agents. In this context and as a further aspect of the present invention, it has been found that the use of surface-active compounds in the nasal administration of the compounds increases their absorption via the nasal mucosa and improves the initial bioavailability. In this case, non-ionic surface-active agents, for example polyoxyalkylene ethers of higher alcohols, e.g. . B. the general formula XXXVI,

(XXXVI) wherein R0 is the residue of a higher alcohol, especially a higher alkanol such as. B. lauryl or cetylalkdiol, or an alkylphenol, or a sterol, especially lanosterol, dihydrocholesterol or cholesterol, and mixtures of two or more such ethers are preferred. Preferred polyoxyalkylene ethers which can be used for the present invention are polyoxyethylene and polyoxypropylene ethers (ie in which n 'in the above formula 2 or 3), especially lauryl, cetyl and cholesteryl polyoxyethylene and polyoxypropylene ether, and mixtures of two or more such ethers.

Particularly suitable polyethers for use according to the invention are those in which the mean value of the repeating units in the polyoxyalkylene part (x in the formula above) is between 4 and 75, particularly between 8 and 30 and very particularly between 16 and 26 Methods are obtained a large selection of such products is commercially available and is z. B. from the company Amerchol under the name Solulan (R), from the companies KAO Soap under the name Emalex (R), ICI under the name BRU (R), Adas under the name Laureth (R) and Croda under the name Cetomacrogol (R) sold

Examples of polyoxyalkylene ethers suitable for use in accordance with the invention, e.g. B. (POE = polyoxyethylene ether, POP = polyoxypropyl ether, x = mean value of the repeating units in the POE / POP part) are listed below: 1. Cholesterol latex 1.1 Solulan (R) C-24 - POE, x = 24 2. ether yon Lanolin alcohols: 2.1 Solulan (R) 16 - POE, x = 16 22 Solulan (R) 25 - POE, x = 25 2.3 Solulan (R) 75 - POE, x = 75 2.4 Solulan (R) PB-10 - PPE, x = 10 2.5 solulan (R) 98 - POE, x = 10 - partially acetylated 2.6 solulan (R) 97 - POE, x = 9 - fully acetylated 3. Laurvläthen 3.1 Emalex (R) 709 / Laureth (R) 9 - POE, x = 9 32 Laureth (R) 4 / Brij (R) 30 - POE, x = 4 3.3 Laureth (R) 23 / Brij (R) 35 - POE, x = 23 4. 4.1 Cetomacrogol (R) - POE, x = 20 to 24

Lanolin alcohols are also known as wool fatty alcohols and are a mixture of cholesterol, dihydrocholesterol and lanosterol.

Preferred polyethers for use in accordance with the invention are cholesteryl polyoxyethylene ethers, i.e. H. -4-

AT 396 870 B

Polyethers of the formula XXXVI, in which n '= 2 and R0 is a cholesteryl radical, especially those polyethers in which the number of repeating units in the polyoxyethylene part is 16 to 26, in particular approximately 24.

Preferably such polyethers are free from contaminants, especially other polyoxyalkylene ethers. They preferably contain at least 75%, particularly preferably at least 85% and very particularly preferably at least 90% (weight) of the pure cholesteryl polyoxyethyl ether.

If a surfactant, e.g. B. a polyoxyalkylene ether is used, the amount present in the compositions produced according to the invention will depend on the surface active agent used, on the form of administration (for example drops or spray) and on the desired effect.

Generally the amount of surfactant used will be between about 2.0 and about 200 (preferably up to about 100, especially up to about 20), especially between about 5 and about 30 (preferably up to about 15) and especially about 10 mg / ml. For nasal administration, the liquid nasal administration forms are preferably brought into an applicator which is provided with a device which enables the application (composition to the nasal mucosa, for example into a nasal spray applicator)

Such applicators are known per se and include those which are suitable for the administration of liquid preparations as drops or spray on the nasal mucosa. Since the dosage of the compounds of the formula <J) or their acid addition salts or their quaternary ammonium salts used according to the invention should be as precise as possible, the use of spray applicators in which precise regulation of the amount administered is possible is generally preferred . Suitable administration devices are e.g. B. atomizers such as pump atomizers or spray cans. In the latter case, the applicator will contain a composition made according to the invention, as well as a propellant, which is suitable for use in a nasal spray applicator. The atomizer is provided with a suitable spray device which enables the composition to be applied to the nasal mucosa. Such devices are generally known

The container, e.g. B. a nasal spray applicator, an amount of the composition for a single nasal dose or for the administration of multiple doses z. B. sufficient over a period of several days or weeks. The amount of the individual doses will preferably correspond to the doses mentioned above.

Applicators as defined above are preferably spray applicators for nasal use. They preferably allow the composition contained to be administered in individual doses of from about 0.05 to about 0.15 ml, e.g. B. about 0.1 ml.

The stability of the composition produced according to the invention can be determined in the usual way.

Compositions produced according to the invention which contain benzalkonium chloride are stable against contamination by germs, e.g. B. according to standard tests as described by S. Urban et al. in Zbl. Bakt Hyg. I Abt Orig. B. 1972, 478-484 (1981) and S. Urban, Acta Pharm. Technol. 22, 247-253 (1976). For example, the cell number of the standard bacteria, namely E. coli ATCC 8739, Pseud. Aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi cand. abicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen. steckii ATCC 10499, reduced to 0.1% or less within 24 hours after inoculation of the composition, as evidenced by standard tests.

In a stability test, the nasal spray composition of Example 1 below was kept in a glass container for 3 months at 30 ° C. under a nitrogen atmosphere. Pseudo aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept pyogenes ATCC 8668 and the Fungi Cand. Albicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergilles niger ATCC 16404 and Pen. stechii ATCC 10499 were added up to a cell count of approximately 2 x 10 ^ organisms in the inoculated liquid. The germ count had decreased to less than 0.1% within 2 hours. No germs could be detected within 4 weeks.

In addition, the compositions are well tolerated, as can be seen from standard tests, e.g. B. Less than 50% inhibition of ciliary movement frequency is observed 20 minutes after administration, according to the microphoto-oscillographic method of L. Chevance et al., Acta Otolaiyng. 7Q, 26-28 (1970).

The liquid nasal administration form - preferably produced according to the invention - has advantageous properties, in particular it enables the active ingredient to be absorbed rapidly in the body after administration. So already after about 5 to 10 minutes after nasal administration, 200 ng of the compound indol-3-yl-caibonic acid-endo-8-methyl-8-aza-bicyclo [3,2,1] oct-3-yl ester (CompoundE) in lml plasma.

When administered orally, this concentration of active substance in the plasma is only reached after about 30 to 40 minutes. The general bioavailability of the compounds of the formula or their acid addition salts or their quaternary ammonium salts over a period of 6 hours is of the same order of magnitude after nasal administration as after oral administration.

The same favorable results are obtained if compounds summarized under the formula (0) or their acid addition salts or quaternary ammonium salts are administered in a galenic form which is in the form -5-

AT 396 870 B of a powder and is inserted into the nostrils by blowing.

When administered by the nasal route, a beneficial effect of active substances against rhinitis used in accordance with the invention is achieved. This manifests itself in a reduction in the nasal fluid section. It is advantageous that the application of the substances does not affect the ciliary movement of the nasal mucosa.

Necessary doses: 0.01 mg to 1 mg / pulse applied once or several times a day

The effect of compound E on pulmonary embolism can be determined as described below:

Reflex examinations are performed on spontaneously breathing rabbits who have been anesthetized with a continuous infusion of sodium pentobarbital. Both vagi remain intact, systemic arterial blood pressure, heartbeat, air volume, respiratory rate and platelet count are recorded

Control of the emollient reflex

By injection of 1 mg Sephadex G 25 (Pharmacia AB, Uppsala) beads suspended in 0.2 ml dextran (6%) at 1 minute intervals in 6 control rabbits, embolization reflexes are induced. The improvement in a) mortality and b) in the Caidiovascular and respiratory reflex reactions to the pulmonary pulmonary embolism which was achieved with pretreatment with the compound E are analyzed. The results show a clear preventive effect of compound E on pulmonary embolism.

The compounds of formula I surprisingly increase the absorption of other active substances, in particular of peptide structure, e.g. B. Salmcalcitonin, if administered together nasally.

For example, when compound E (15 mg) and salmon calcitonin (100 IU) are used in combination, half of which is inserted into each nostril, the salmon calcitonin bioavailability (AUC up to 2 hours) increases from 0.08 IU / rhesus monkey ml / h in plasma to 1.632 IU / ml / h.

In nasal administration, the dose of the compounds of the formula I should be from 0.13 to 0.4 mg per kg of body mass d. i. approximately 100 mg to 300 mg or 10 to 30 bursts of nasal spray per patient.

When administered together with another active ingredient, the amount administered of a compound used according to the invention depends on the other active ingredient and the type of treatment. Usually half to 1/10 of the dose of the other active ingredient is used.

The following »! Examples illustrate the invention.

Example 1:

Production of a nasal composition for the treatment of rhinitis, pulmonary embolism or to improve the nasal absorption of other active substances

Ingredients amount of

Components

Indol-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo [3,2,1] oct-3-yl-ester.HCl 100 g benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution ) 0.6 mg distilled water 0.4 ml

The solution obtained is filtered (for example through a 0.2 pm filter) and poured into a nasal spray can or soaked in a gelatin-like sponge (SPONGOSTAN from Novo Industri a / s Bagsvaerd, Denmark)

AT 396 870 B

Example 2:

Production of a nasal composition for the treatment of rhinitis, pulmonary embolism or to improve the nasal absorption of other active substances

Ingredients amount of

Ingredients l-methyl-N-endo-9-methyl-9-azabicyclo- [33> l] indol-3-yl-carhoxamide 50 mg benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution) 0.83 mg distilled Water 0.17 ml

The solution obtained is filtered (for example through a 0.2 pm filter) and poured into a nasal spray can or soaked in a gelatin-like sponge (SPONGOSTAN from Novo Industri a / s Bagsvaerd, Denmark)

All active ingredients I listed below can be used to prepare compositions analogously to Examples 1 and 2. (Qnertables follow) -7-

AT 396 870 B 00 PH t * · S te ^ ffiBKtqÄasaKKaBKBBBBtriaÄBffiSÄV ÜKÜÜÜÜÜÜÜÜÜÜUUUÜUUÜÜÜUUÜÜUeBB t-4 &gt; II Ω c (nmNNNMWNNNNNNNNNNNtomtOWWt ^ WClNW conf 4 &gt; © &lt; Ü ©GG 04) 06} ©GGG 4 &gt; © GG 4 &gt; 4) © GG 4 &gt; © GG 00 ü S txJKKKW ffiffiffiK zooooooooooozzzzzxozzozzooooo carboxyl group in position N m tn co «5 SK» S ffi KB SB 5 Ä BS ® W «B KKKWas« ZZZZZZZZZZZZZZZZZZmOOuZZZZZZ I 5 II M «Pt m 8 cn ΰΒ„ S BBiNcsmBKBBBÄKKBoiBBBBKBBBKBffiBBB 1—1 κ-t ii _ &lt; & CO CO Ä w a u 8 8 a u [x, S ^ KWWKW'n4 &gt; 0KW ^ WSWWv! IWWWWKWSWWKin connection No.

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AT 396 870 B

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ü o V— / o &lt; e V3 243-244 (hydrochloride) 290 (decomp.) (hydrochloride) 284-286 (decomp.) (hydrochloride) CO CO CO 00 SB «Pi u u u NN &gt; II Μ M IN ocooo CO CO CO o WWW w S 2 2 U ooo o oo s &gt;% 3 XS CO CO CO Π NJ Έ C / 3 ci - ü .s US ÖS ÖS NI zzz 6 U 1 W ffi w II OJ PQ PS CO NN ffi eo NN FM ^ iN OOü &lt; PS VÖ νό &gt; A ö z 00 G 3 T3 e Tf &gt; o VÖ 3 · ^ ^ u &gt; in CM o CO

Claims (2)

AT 396 870 B PATENT CLAIMS 1. Process for the preparation of a - preferably liquid - galenic formulation for nasal administration of serotonin antagonists with the addition of carriers customary for this purpose and optionally further additives, characterized in that carboxylic acid esters or amides of the formula ABCD ( I), in which A is a group of the formula means where the free bond may be on each of the interconnected rings, Z is -CH2-, -NR3, -O- or -S-; Rl and R2 independently of one another for hydrogen, halogen, (C14) alkyl, (Ci-4) alkoxy, hydroxy, amino, (Ci-4) alkylamino, di (C14) alkylamino, mercapto or (Ci4) alkylthio and R3 represent hydrogen or (C i4) alkyl; B -CO-; C -NH- or -O- and D is a group of the formula A N-Rc (VI), in which n is 2,3 or 4 and Rg is hydrogen or (Ci-7) alkyl, in the form of the free base or an acid addition salt or a quaternary ammonium salt thereof. 2. The method according to claim 1, characterized in that the indoton-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo [3,2, ljoctyl ester is used as the serotonin antagonist. -10-