EP1549288A1

EP1549288A1 - Nasallly applicable pharmaceutical preparation and the production thereof

Info

Publication number: EP1549288A1
Application number: EP03747695A
Authority: EP
Inventors: Ernst Hesse; Gerhard Hantich; Wolfgang H. Nitschmann; Helmut Scheidl
Original assignee: Gebro Pharma GmbH
Current assignee: Gebro Pharma GmbH
Priority date: 2002-10-10
Filing date: 2003-10-09
Publication date: 2005-07-06
Also published as: AU2003266811A1; US20060127317A1; ATA15402002A; PL375762A1; NO20052251L; WO2004032896A1; CA2501760A1; AT413078B; JP2006503868A

Abstract

The invention relates to a novel nasally applicable pharmaceutical preparation based on an aqueous solution, emulsion or the like containing at least one mucous-membrane-resorbing and/or locally active pharmaceutical active ingredient, at least one preserving agent formed from benzalkonium chloride exclusively or in conjunction with other preserving agents, at least one buffer with a pH value of 4-6 and at least one osmotic agent and/or at least one wetting agent, characterized in that said preparation exhibits substantially improved ciliary compatibility, and in that it contains therein a buffer based on malic acid instead of a buffer based on citrate(s), phosphate(s) and acetate (s) which were previously used in the pharmaceutical preparation and which are fully or partially replaced thereby while at the same time maintaining the composition ratios, concentration ratios and amount ratios of active ingredient(s), preserving agent(s), osmotic agent(s) and wetting agent(s). The invention also relates to a method for the production of said preparation and the use of a malic acid buffer in said preparation.

Description

1 Nasal pharmaceutical preparation and its preparation

The present invention relates to liquid, preserved pharmaceutical preparations for the application of various active substances to or in or over the nose of a patient in the form of a solution, their preparation and the use of a special buffer system for and in the preparations mentioned.

There are a large number of drugs that can be applied in particular in the form of solutions and / or emulsions in a patient's nose, whether in the form of nasal drops or lately increasingly, especially in the form of i ^ι n ^u nasal sprays. These nasal pharmaceutical preparations can either be used for the treatment or prevention of diseases on the nose itself or should lead to the absorption of active substances in the bloodstream so that they develop their effects elsewhere in the body.

As representatives of the first-mentioned group of nasally applicable

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Medicines are primarily agents or active substances against runny nose, such as allergy agents, e.g. Cromoglicic acid, or sympathomimetics, e.g. Xylometazoline, tetrazoline,

Oxymetazoline, Naphazolin, Phenylephrin, to name.

An example of the second group of such drugs are peptide Q preparations, e.g. those with desmopressin as an active ingredient, which is an effective

Means for the treatment of diabetes insipidus.

Most such nasal sprays or medications

Nose drops contain at least one active ingredient

- Substances for setting a certain osmotic pressure (e.g. NaCl) and / or 5 wetting or surface-active substances (e.g. Cremophore), further

- auxiliaries for stabilizing the active ingredient or for maintaining a certain physiologically acceptable pH in the nose. To this day, almost exclusively phosphate or phosphate / citrate or citrate buffers and, under certain circumstances, acetate buffers are used. Furthermore, they contain in 0 most cases

- Benzalkonium chloride as a preservative.

Benzalkonium chloride, abbreviated BAC, has been used in many ways since its introduction in 1935 as an effective antiseptic or preservative. The scientific literature reports that it is on the skin and on the 5th

Mucous membranes are well tolerated because they are hardly irritating (H. P. T. Ammon,

Drug Side Effects and Interactions, Chapter 69: 1211; 1991, Mutschier E.,

Drug Effects, Textbook of Pharmacology and Toxicology, Chapter 9: 642; 1997).

Therefore, benzalkonium chloride is widely used in mouth and throat disinfectants as well as wound and vaginal irrigation. Due to its good antimicrobial effectiveness and good tolerability, it is the most frequently used preservative that is used in nasal sprays and eye drops in conjunction with a large number of active pharmaceutical ingredients.

In numerous works, however, it was also pointed out that the preservative benzalkonium chloride considerably restricted, sometimes even irreversibly, the activity of the ciliated epithelium, i.e. the ciliary apparatus of the nasal mucosa, which is extremely important for maintaining the physiological function of the nose (Klöcker and Rudolph , PZ 145 (21) 40-42, 2000; Hofmann, et al. ENT 1998; 46 (2): 146-151; Neugebauer et al., Annual meeting of the German Society for Otorhinolaryngology, Head and neck surgery, 1998.

For this reason, some authorities in the European Union even propose or demand a massive restriction on the use of this preservative (German Federal Institute for Drugs, Step-by-Step Procedure II, Federal Gazette No. 120, July 3, 2002), although in addition to those that directly affect the respiratory system Runny nose and allergy diseases today, numerous, often even lifelong chronic diseases can be treated with nasal sprays preserved with benzalkonium chloride.

The only way out of this problem resulting from the negative effects of the BAC on the ciliary apparatus is that conservatives demand completely free pharmaceutical preparations. However, these are associated with considerable economic outlay: Special nasal spray systems must be used, among others: All packaging and sprayer parts that come into contact with the nasal spray solution must be subjected to extensive sterilization with highly toxic chemicals and / or radioactive rays, which is not exactly what is desired.

In the course of in-depth investigations with the purpose of finding a viable way out, it has surprisingly been found that by using a very specific, specific - as such known - buffer system, at least a large part of those damaging the cilia and their activity Effect of the BAC, which is valued and proven in its other properties as a conservant, can be canceled.

The present invention thus relates to a new nasally applicable pharmaceutical preparation based on an aqueous, at least one per se known mucous membrane-absorbable and / or locally acting pharmaceutical active ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one buffer keeping the pH value at 4 to 6 or at about 5 and furthermore at least one osmotic and / or at least one wetting agent containing solution, emulsion or the like, which is characterized in that the preparation has a significantly improved compatibility with cilia in that in the same or in the underlying solution, emulsion or the like. while maintaining the respective composition, concentration and quantity ratios of active ingredients), preservative (s), osmotic agent (a) and wetting agent (s) instead of a buffer based on citrate (s) previously used in the pharmaceutical preparation , Phosphate (s) and / or acetate (s) - partially or completely replacing the same - a buffer based on malic acid is contained.

With the present invention, the case per se in the field of pharmaceutical preparations is not so frequent that the essence of the same does not consist in a new active ingredient and its use in a pharmaceutical, but rather in the apparently much less spectacular area of a routine that has long since become routine Accompanying substance that has become established and has long proven itself in practice, such as the buffer system contained in a pharmaceutical preparation and decisive for its effectiveness and durability, or in an unexpectedly positive change away from proven and widely used buffer systems for liquid pharmaceutical preparations to another buffer that is used much less frequently in medicinal products.

It is very important to emphasize that the advantage of the present invention is that the change from the previous buffer system to the malic acid buffer to be used now without changing the quantity, concentration

Composition ratios of the other components including the active ingredients in the various tried and tested pharmaceutical preparations can take place, while costly changes and administrative procedures can be saved.

With regard to the already known use of malic acid buffers in compositions for pharmaceutical and possibly also diagnostic purposes, reference is made, for example, to WO 98/47490 relating to the lyophilisates of biomolecules, in which, in addition to a larger number of different buffers based on organic acids, malic acid is also mentioned is, the buffers mentioned there serve to adjust the pH, but the main task of which is the formation of Use to prevent disruptive arginine-phosphate or citrate-protein aggregates that occur in known phosphate or citrate buffers.

Furthermore, with regard to the use of a malic acid buffer in an orally sublingually or nasally applicable pharmaceutical preparation containing the active ingredient desmopressin, mention should be made of AT 409 081 B1, according to which by using the malic acid buffer, be it now together with significantly reduced Amounts of benzalkonium chloride as a preservative, whether to the exclusion of the same, a substantial improvement in stability or pharmaceutical preparation can be achieved. Neither of the two mentioned publications even touches in the slightest the problem solved by the present invention of the damage to the ciliary apparatus of the nasal mucosa caused mainly by the proven conservant benzalkonium chloride, which is particularly relevant to a great extent if a nasally administrable pharmaceutical preparation is administered for a long time must become.

In the sense of reducing the cilia-damaging effect of this preservative and in particular also a rapid and extensive regeneration of the cilia activity after application of the medicament with the various medicinal active substances containing the same, as already emphasized above, racemic is the simplest and quite effective embodiment Malic acid as a pH stabilizer and the ciliary-damaging effects are largely suppressing agents. However, enantiomerically pure malic acid can also be used instead of racemic malic acid.

Particularly proven concentration ranges of the malic acid buffer in the new pharmaceutical preparation are given in A n s r u c h 2.

As shown in A n s r u c h 3, malic acid buffers, in which sodium hydroxide solution is used to form the counter ion in the buffer system, have proven effective.

The A n s p r u c h 4 names NaCI as a particularly proven osmosis-active ingredient in connection with the cily-friendly effect of the new pharmaceutical preparations.

In A n s r u c h 5 some are not exhaustive

Active ingredient groups or special important active ingredients mentioned, which can be used in the preparations according to the invention with the malic acid buffer.

Another essential object of the present invention is the method for producing the new nasally administrable pharmaceutical preparation, the details of which are given in claim 6, the essential <l Characteristic of this production process is the targeted replacement of the previously used - and in the course of the investigations of the present invention as - in the presence of benzalkonium chloride - buffer systems which prove to be very dangerous for the cilia activity by a malic acid buffer. 5 The features of claims 7 and 8, which are subordinate to production claim 6 and referenced to it, are analogous to the features of claims 2 to 6 already explained above.

Another essential objective of the invention is to -As described above - surprisingly discovered and previously nowhere about only ^{ι υ} suggestively mentioned use of based on malic acid as an essential component buffer system instead of usual buffers for the preparation of cilienverträglichen, nasally administrable pharmaceutical preparations, the details are not cited here and are disclosed in claim 9. 5

What the subordinate to the use claim 9 and related to him, also to the use of a malic acid buffer in the in question

Pharmaceutical preparations-related products 10 and 11 are concerned, their characteristics are analogous to those of claims 2 to 4 and 7 and 8 0 explained in more detail above.

Finally, reference should also be made to the further subject matter of the invention relating to the use of the malic acid buffer system in the new pharmaceutical preparations, the full scope of which can be found in A n s p r u c h 12. 5 The invention is explained in more detail using the following examples:

General example:

In a standard test to check the ciliary function, a classic nasal preparation with a phosphate / citrate buffer and 0 benzalkonium chloride as a preservative was compared with a preparation according to the invention with malic acid as a buffer and benzalkonium chloride as a preservative:

In the tests on which the comparison is based, pieces of tissue made from cilia-covered epithelium of the trachea of chicken embryos are used, the details of the test being based on SG Romejn et al, Int. J. of Pharmac. 135 (1996) 137-145 and 5 van De Donk et al., Rhinology, 20 (1982) 81-87. Active ingredient solution 1:

0.335 mg / ml malic acid; 0.168 mg / ml NaOH; 9.115 mg / ml sodium chloride; 0.1 mg / ml benzalkonium chloride; pH: 5.07.

Active ingredient solution 2:

1.7 mg / ml citric acid; 3 mg disodium phosphate dihydrate; 7.5 mg / ml sodium chloride; 0.1 mg / ml benzalkonium chloride; pH: 5.04.

After 15 minutes of exposure, the beat frequency of the cilia is reduced significantly less by solution 1 with malic acid buffer than by solution 2 with the usual buffer. Then the self-cleaning of the nasal mucosa is simulated by washing out the respective solutions and adding Ringer's solution over 45 minutes. Afterwards, a clear recovery of the cilia beat frequency is achieved in solution 1 with the malic acid buffer, increased from 48 to 74%.

Example 1 :

4900 g of distilled water are placed in a 5 liter beaker. submitted and therein 45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 1.675 g of malic acid and 5 g of xylometazoline hydrochloride are dissolved with stirring. The pH is adjusted to 5.5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained is further processed into nasal drops or a nasal spray.

Example 2: In a 5 liter beaker, 4900 g of aqua dest. submitted and in it

45.58 g sodium chloride, 0.5 g benzalkonium chloride, 1.675 g malic acid and 2.5 g xylometazoline hydrochloride dissolved with stirring. The pH is adjusted to 5.5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained becomes Nasal drops or processed into a nasal spray.

Example 3:

4900 g of distilled water are placed in a 5 liter beaker. submitted and therein 45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 1, 675 g of malic acid and 12.5 g

Phenylephrine hydrochloride dissolved with stirring. The pH is adjusted to 5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained becomes

Nasal drops or processed into a nasal spray.

Example 4:

4900 g of distilled water are placed in a 5 liter beaker. submitted and therein 45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 0.67 g of malic acid and 6.25 g of phenylephrine hydrochloride are dissolved with stirring. The pH is adjusted to 5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained is further processed into nasal drops or a nasal spray.

Summary of the results obtained with the preparations according to Examples 1 to 4 with regard to the substantial improvement in the cilia

Compatibility:

The composition of the reference solutions for Examples 1 to 4 is shown in Table 1 below:

Table 1 :

The comparative results with regard to cilia tolerance are summarized in Table 2.

Table 2:

After 15 minutes of exposure, the beat frequency of the cilia is reduced significantly less by the sample solutions with malic acid buffer than by the reference solutions. Then the self-cleaning of the nasal mucosa is simulated by washing out the test solutions and adding a Ringer's solution over 45 min. As a result, in the example solutions with malic acid buffers, a significantly better recovery of the ciliac impact is achieved, which reaches up to over% of the initial impact (of 100%). This is a very good value, especially since even if the cilia are incubated in physiological saline after 45 min, only 55% of the cilia initial beat frequency is obtained.

Example 5:

To produce a nasal spray with benzalkonium chloride as a preservative for the treatment of diuretic disorders and bleeding disorders, 990 g of aqua ad. inj. submitted and dissolved therein 9.115 g sodium chloride, 0.1 g desmopressin acetate, 0.1 g benzalkonium chloride and 0.335 g malic acid. The pH is adjusted to 5 with 4.2 ml of 1N NaOH, then made up to 1 l, the solution is filtered through a Millipak filter and filled into brown glass bottles which are closed with pump attachments. The solution is manufactured and filled in pharmaceutical production rooms under low-germ conditions.

In orientational tests with the active ingredient solution of Example 5, results quite similar to the results given in Table 2 above were obtained with regard to significantly less reduced cilia activity and improved regeneration of the cilia.

In further, also orienting tests, similar results could be achieved with the active ingredients calcitonin (from salmon) for the treatment of osteoporosis and cromoglicic acid for the treatment of allergic rhinitis.

Claims

1Patentansprüche:

1. Nasally administrable pharmaceutical preparation based on an aqueous, at least one known mucous membrane-absorbable and / or locally acting pharmaceutical active ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one of the pH values from 4 to 6 or about 5 holding buffer and further at least one osmotic and / or at least one

1 ° wetting agent, containing solution, emulsion or the like. characterized in that the preparation has a significantly improved cilia tolerance in that in the same or in the underlying solution, emulsion or the like. while maintaining the for the pharmaceutical preparation each

15 intended composition, concentration and quantity ratios of active ingredients), preservative (s), osmotic agent (a) and wetting agent (s) instead of a buffer based on citrate (s), phosphate (s) and / / previously used in the pharmaceutical preparation. or acetate (s) - the same (the same) partially or

" _N completely replacing - it contains a buffer based on malic acid.

2. Preparation according to claim 1, characterized in that the malic acid buffer is present in the same in a concentration in the range of 1 to 5 mM / l, in each case based on the entire pharmaceutical preparation.

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3. Preparation according to claim 1 or 2, characterized in that the malic acid buffer is formed with sodium as the counter ion.

4. Preparation according to one of claims 1 to 3, characterized in that it contains sodium chloride as an osmotic agent.

5. Preparation according to one of claims 1 to 4, characterized in that it

- at least one allergy agent, e.g. Levocabastine, or azelastine

³⁵ r C, romoglicinsa -ure,

at least one sympathomimetic or sniffing agent, such as xylometazoline, tetrazoline, indanazoline, phenylephrine, naphazoline, tramazoline, oxymetazoline, - At least one corticoid, such as beclometasone or triamcinolone, and / or

- at least one peptide or hormone, e.g. Contains calcitonin, desmopressin, gonadorelin, buserelin, nafarelin or oxytocin as the active ingredient (s).

6. Process for the preparation of a nasally administrable pharmaceutical preparation based on an at least partially aqueous, at least one known mucous membrane-absorbable and / or locally active pharmaceutical agent, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one pH -Value to 4 to 6 or to about 5, holding buffer, and furthermore at least one solution containing an osmotic and / or at least one wetting agent, emulsion or the like, according to one of claims 1 to 5, characterized in that for the preservation such a preparation with significantly improved compatibility with cilia

- When preparing the solution, emulsion or the like on which the preparation is based. while maintaining the composition, concentration and quantity ratios of active ingredients intended for the pharmaceutical preparation), preservative (s), in particular benzalkonium chloride, and osmotic agent (a) and / or wetting agent (s), instead of a buffer previously used in the preparation Base of citrate (s), phosphate (s) and / or acetate (s), - partially or completely replacing the same (s) - a buffer based on malic acid is used.

7. The method according to claim 6, characterized in that

- A malic acid buffer is used, which is formed with sodium as a counter ion, and / or

- The malic acid buffer is used in a concentration in the range of 1 to 5 mM / l, in each case based on the entire pharmaceutical preparation, and / or

- Sodium chloride is used as an osmotic agent.

8. The method according to claim 6 or 7, characterized in that the pharmaceutical preparation using

- at least one allergy agent, e.g. Levocabastine, azelastine or cromoglicic acid,

- At least one sympathomimetic or snuff, such as Xylometazoline, tetrazoline, indanazoline, phenylephrine, naphazoline, tramazoline or

oxymetazoline,

- at least one corticoid, e.g. Beclomethasone or triamcinolone, and / or

- at least one peptide or hormone, e.g. Calcitonin, desmopressin, gonadorelin, buserelin, nafarelin or oxytocin is produced as the active ingredient (s).

9. Use of a buffer based on malic acid for the production of a nasally applicable pharmaceutical preparation - which has a significantly improved cilia tolerance - based on an at least partially aqueous, at least one known mucous membrane-absorbable and / or locally acting pharmaceutical active ingredient, at least one preservative , which is formed by benzalkonium chloride alone or together with additional preservatives, at least one holding the pH to 4 to 6 or to about 5 buffers and furthermore at least one osmotic and / or at least one wetting agent-containing solution, emulsion or the like. , with the proviso that the buffer based on malic acid - while otherwise maintaining the composition, concentration and quantity ratios intended for the respective pharmaceutical preparation - instead of a buffer previously used in the pharmaceutical preparation based on vo n citrate (s), phosphate (s) and / or acetate (s)

- the same (the same) partially or completely replacing - is used.

10. Use of a malic acid buffer with the stipulation or with the stipulations - that it is formed with sodium as a counter ion and / or

- That it is used in a concentration in the range of 1 to 5 mM / l, based on the total amount of the pharmaceutical preparation, and / or

- That it is used together with sodium chloride as an osmotic agent, for the purpose specified in claim 9.

11. Use a malic acid buffer provided that it is used together with

- at least one allergy agent, e.g. Levocabastine, azelastine, cromoglicic acid,

- At least one sympathomimetic or snuff, such as Xylometazoline, tetrazoline, indanazoline, phenylephrine, naphazoline, tramazoline, oxymetazoline,

- At least one corticoid, such as beclometasone or triamcinolone, and / or ₁ - at least one peptide or hormone, such as calcitonin, desmopressin,

Gonadorelin, buserelin, nafarelin or oxytocin is used for the purpose specified in claim 9, possibly taking into account at least one of the requirements of claim 10.

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12. Use of a buffer based on malic acid in an at least partially aqueous, at least one known mucous membrane-resorbable and / or locally active pharmaceutical ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one pH -Value to 4 to 6 or to about 5 holding buffers, and preferably also containing at least one osmotic and / or at least one wetting agent, the base for a nasally administrable pharmaceutical preparation solution, emulsion or the like. as a replacement for those known in the past, intended for such preparations

15 solutions, emulsions or the like. contained buffers based on citrate (s), phosphate (s) and / or acetate (s) for the purpose of preparing such a nasally applicable pharmaceutical preparation with significantly improved cilia tolerance.

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