EP0756486A1

EP0756486A1 - Pharmaceutical inhalation compositions containing a solid active ingredient

Info

Publication number: EP0756486A1
Application number: EP95913275A
Authority: EP
Inventors: Peter John-National Heart & Lung Institute WILLS; Peter John-National Heart & Lung Institute COLE
Original assignee: National Heart and Lung Institute
Current assignee: National Heart and Lung Institute
Priority date: 1994-04-22
Filing date: 1995-03-30
Publication date: 1997-02-05
Also published as: AU2080695A; GB9408053D0; WO1995028944A1

Abstract

Pharmaceutical preparations in a form suitable for inhalation comprising an active ingredient, usually a solid, chosen from: (i) a physiologically tolerable zwitterionic salt, or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid, or (iii) a mixture of two or more salts as defined in (i) and (ii) above are described. Use of those active ingredients, especially sodium chloride, in the manufacture of medicaments and in methods for the treatment and/or the prevention of mucus retention are also described.

Description

Pharmaceutical Inhalation compositions containing a solid active Ingredient.

The present invention relates to a pharmaceutical preparation for use in the treatment of disorders having mucus retention as a symptom. The invention is particularly concerned with, but not limited to, mucus retention in the lungs and airways.

There are several medical conditions in which respiratory mucus retention is a prominent symptom. In health, respiratory mucus is cleared unnoticed by the ciliary escalator, but in chronic bronchitis, bronchiectasis, and other conditions this mechanism fails to cleanse the lungs adequately, mucus is retained and usually becomes infected. A patient with mucus retention is generally troubled with a productive cough and has a tendency to infections in the lungs and respiratory tract, including pneumonia and other serious conditions.

Normal mucus is present as a microscopic layer which coats the membranes of the respiratory system and it is consequently extremely difficult to obtain samples of normal mucus for study without using very invasive techniques. It is generally recognised that a person having enough mucus for the collection of a sample of mucus to be possible, without the use of such invasive techniques, is not in good health. In most cases it is not known exactly why mucus in patients suffering from mucus retention fails to be cleared by ciliary action. The general assumption is that the mucus is in some undefined way too "sticky" or "thick", but because normal mucus cannot be examined that assumption is speculative.

One of the main aims in treating patients with mucus retention and conditions associated with such retention is to try to clear the lungs of infected and potentially infected secretions. Various medications and methods of treatment are available to aid expectoration. Physical therapy to mobilise mucus in the lungs has been used as have inhalations of steam or, sometimes, sodium chloride solutions. It is often not clear why treatments, such as the inhalation of steam or sodium chloride solutions, work but they are used because anecdotal evidence suggests that they are helpful.

Recently agents which liquify viscous mucus and sputum have been developed. One such agent is DNase (Pulmozyme) which has been developed by Genentech. It is a recombinant form of a natural human enzyme that degrades DNA, DNA often being one of the components of sputum that has accumulated in infected lungs. This liquifies sputum, making it easier to cough it up.

Other new drug treatments are being developed for particular conditions such as cystic fibrosis as a greater understanding of the genetic basis of the diseases is gained. Genetic therapies are also being developed.

Aerosolized hypertonic sodium chloride solution has been shown in one study (D. Pavia et al, American Review of Respiratory Disease Vol 117, 1978, pl99) to aid clearance of mucus from the lungs of chronic bronchitis sufferers. It is not known by what mechanism that effect occurs. Hypertonic saline, inhaled from an ultrasonic nebulizer, has also been used as a diagnostic aid to encourage the production of a sputum sample for laboratory examination in persons who do not normally expectorate (R.F. Miller et al, The Lancet, vol 335, pll2) Again, the mechanism of action has been a matter for speculation.

Inhalation of solutions from nebulizers requires relatively expensive equipment, is inconvenient and some patients find it unpleasant.

There still remains a need for simple, easily administered treatments that may be used by sufferers of mucus retention to improve the clearing of mucus from the respiratory system, if possible, treatments effective enough to stop mucus accumulation altogether.

The present invention provides a pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient is (i) a physiologically tolerable zwitterionic salt or

(ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above.

The present invention also provides a pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient comprises sodium chloride and one or more other active substances, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.

Examination of the sputum of bronchiectasis sufferers in an in vitro ciliated system showed it to be poorly transported. Prior incubation of the sputum with solid sodium chloride was found to cause a marked increase in the rate at which the sputum was transported. It is surprising that solid sodium chloride increases the transport of the sputum because the general belief is that one of the major problems with retained mucus is that it is too "thick" and that it is therefore necessary to make the mucus more watery in order to improve transport.

It has also been found that a variety of other salts are as efficacious as sodium chloride in transforming sputum from a gel that is slowly transported by cilia to one that is transported rapidly. Salts that are effective in improving mucus transportability include salts that are fully ionised in solution, for example, alkali, alkaline earth metal and ammonium salts of inorganic acids, and also salts that are only partly ionised in solution, for example, salts of organic acids, for example, carboxylic acids. Zwitterionic salts, for example, amino acids, for example, glycine, are also effective. It appears, however, that non-ionizable materials, for example, glucose, are not effective.

A salt to be used in a pharmaceutical preparation of the invention should generally be water-soluble. The chosen salts should be physiologically tolerable and it is preferable that any salt administered in solid form should, on dissolution in an aqueous solvent, give a solution having an approximately physiological pH.

Salts which may be used according to the present invention include but are not limited to (i) physiologically tolerable zwitterionic salts, for example, amino acids, for example, glycine and valine; (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids and mixtures of two or more salts as defined in (i) and (ii) above. If a salt comprises an organic component, as cation or anion, that component should generally have a low molecular weight such that it can diffuse readily into the mucus, for example, it should have a molecular weight of about 150 or less, for example, about 100 daltons or less. The amine component of an amine salt may be substituted, if desired.

An organic acid is especially a carboxylic acid, for example, having from 2 to 6 carbon atoms, and may be substituted. Examples are acetic, propionic and butyric acid.

A salt may be an alkali metal, alkaline earth metal or transition metal salt, for example, a sodium, potassium, calcium, magnesium or ammonium salt. A salt may be a chloride, sulphate, nitrate, phosphate, carbonate or bicarbonate salt, or a salt of a carboxylic acid having from two to six carbon atoms. The active ingredient in a pharmaceutical preparation of the invention may comprise a mixture of salts having (a) cationic components selected from sodium, potassium, calcium, magnesium and ammonium ions and (b) anionic components selected from chloride, nitrate, sulphate, carbonate and bicarbonate ions. Such a preparation may also comprise one or more amino acids. It is generally preferable to include sodium chloride in a pharmaceutical preparation of the invention. Sodium chloride may be the sole active ingredient or may be one of the active ingredients in a mixture of salts. It may be preferable to ensure that sodium chloride is the major component in a mixture of salts.

In a further preferred embodiment of the invention, a mixture of salts comprising ions found at the airway surface, for example, salts comprising sodium, calcium, magnesium, chloride, nitrate, sulphate and carbonate ions, is used as the active ingredient. The various ions are preferably used in the relative proportions as present at the airway surface.

A pharmaceutically active substance that may be incorporated in a pharmaceutical preparation of the present invention may be any substance useful in the treatment of any pathological condition of the lungs or airways, for example, an antibiotic or antiinflammatory agent.

Production of pharmaceutical preparations and medicaments suitable for administration by inhalation may be carried out by methods known in the art. For example by microcrystallisation methods, for example, freeze drying or spray drying, or by comminution, for example, using grinding, milling or ultrasonic techniques followed by sieving or other particle selection techniques known in the art. The particles may be coated or their surface characteristics modified.

Advantageously formulations and/or delivery methods deliver the solid in spheroidal particulate form as this reduces any irritation and damage caused by the particles. Additives may be included, for example, agents to stop adhesion or clumping of particles. Methods which may be employed include those described in GB1242211 for producing powders.

One method of preparing the pharmaceutical preparations and medicaments, or at least the active ingredient, which is preferred, is that of spray drying. Spray drying techniques allow the formation of fine powders of spherically shaped particles with mean sizes appropriate for pulmonary delivery. One advantage of spray drying is that it is a single stage process which can be completely controlled by a single operator. It is a well known process which has been used successfully in many industries, including the pharmaceutical industry.

The technique and factors affecting the resulting powders are discussed in relation to the preparation of powders of salbutamol sulphate, entitled "Production of spray dried salbutamol sulphate for use in dry powder aerosol formulation" in a paper in the International Journal of Pharmaceutics, Volume 108, 1994, pages 233 to 240. In this technique, the material to be prepared is first dissolved in a solvent, in the present case this will usually be water. The solution is then pumped to a spray dryer, for example, a Bύchi 190 mini spray dryer, and is generally heated before being sprayed into a chamber through which a drying air current flows. This leads to rapid drying; the resulting powder is then removed. Particle sizes should generally be in the micron range to ensure that they are able to travel deep into the lungs. Preferably the solid will be in a particulate form having an aerodynamic mass median particle size of <10μm, more preferably <5μm and most preferably of about 3μm or less. It is generally regarded that the ideal size for deposition of particles in the peripheral airways is 0.8 to 5μm. Ad- vantageously, the median particle size will fall within this range. Appropriately at least 70% and preferably 85 or 90 % of the particles comprising the active substance will be in the desired size range. Minimum particle size is less of a problem. Solid pharmaceutical preparations and medicaments for administration by inhalation may be administered by the use of dry powder inhalers, advantageously, breath activated dry powder inhalers since with these inhalers it is not necessary for the patient to synchronise activation of the inhaler and inhalation. Various types of dry powder inhalers are known, for example, the Spinhaler (trade name) , a dry powder aerosol device, (Fisons) and the Rotahaler (trade name) , which uses gelatin capsules of powder, (Glaxo) . Such devices generally incorporate means for controlling the unit dose dispensed. Inhalers that are known include but are not limited to those described in EP-A-488609, EP-A-495675, O92/10229, O92/10230, DE 4027390, DE 4027391 and EP 407028.

A solid pharmaceutical preparation of the present invention may be provided in a form suitable for use with a known inhaler, for example, in the form of hard gelatin capsules or a compressed disc.

Alternatively the formulation may comprises a propellant and be in the form of an aerosol. See, for example, EP-A-372 777 which describes medicinal aerosol formulations of solid medicaments. The salt may be dispersed as a powder or as drops of a suspension of the solid. Where the salt is dispersed as a powder the aerosol will usually comprise a liquid propellant gas having a boiling point of below room temperature, and if desired, carriers such as liquid or solid, non-ionic or anionic surface-active agents and/or diluents. The appropriate dose and frequency of treatment will be dependent on the symptoms and physical condition of the individual patient. Doses which provide in the range of 10 to 100 milligrams entering the lungs may be preferred. It will be appreciated that the use of dry powder inhalers and aerosols will allow patients to administer their own doses of medicament quickly, frequently and without the need for troublesome equipment and procedures as are experienced with nebulizers.

The invention further provides the use of sodium chloride in the manufacture of a medicament for administration of the sodium chloride in a solid form, for the treatment and/or the prevention of mucus retention, especially in the lungs and airways.

The sodium chloride may be used in combination with one or more other active substances, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances. The salts and mixtures thereof and other active substances are preferably as described above. In a mixture, it is generally preferred that sodium chloride is the major component. A medicament is, for example, a pharmaceutical preparation as described above.

The use of solid sodium chloride described above is generally for the treatment and/or prevention of mucus retention in the lungs and airways and in that case the medicament should be suitable for administration of the solid sodium chloride by inhalation.

The present invention also provides a pharmaceutical preparation which comprises an active ingredient in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient is (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above, with the proviso that the active ingredient is not sodium chloride alone.

The present invention further provides a pharmaceutical preparation which comprises an active ingredient and is in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient comprises sodium chloride and one or more other active substances. The other active substances are, for example, selected from (i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.

The present invention also provides the use of (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid (with the exception of sodium chloride alone) , or (iii) a mixture or two or more salts as defined in (i) and (ii) above, in the manufacture of a medicament for the treatment and/or prevention of mucus retention. The present invention further provides the use of sodium chloride and one or more other active substance in the manufacture of a medicament for the treatment and/or prevention of mucus retention. The salts and other active substances to be used are generally as described for the pharmaceutical preparations of the present invention described above.

According to these further embodiments of the invention, mixtures of salts, sodium chloride in admixture with other components, and individual salts other than sodium chloride alone may be presented for inhalation other than in solid form, for example, in the form of a solution or liquid suspension, for example, in a form suitable for administration by an atomizer or a nebulizer. Requirements for administration by such devices are well known. Such active ingredients may also be presented for inhalation in the form of an aerosol. The aerosol may disperse the salt or mixture of salts in the form of drops of a solution or a suspension, including a liquid/liquid suspension. Preparations in which the active ingredient is in solution may, if necessary, contain an additional solvent and/or a stabilizer. Compressed air, produced as required by means of a suitable compression and release device, may be used as the propellant.

If a solution for use in a nebulizer or atomizer is chosen then the solution is preferably a strong solution, preferably having total salt concentration of at least 600 milliosmoles/litre.

If the active ingredient is used in liquid form, for example, as a solution or suspension, the liquid is preferably of physiological pH, and may be buffered to maintain a physiological pH if necessary. Suitable buffers include phosphates. The use of a buffer enables salts to be used that do not themselves give rise to solutions having a physiological pH i.e. the range of salts for use in liquid preparations is greater than that for solid preparations. The present invention also provides a method for the treatment and/or prevention of mucus retention, which comprises administering, particularly by inhalation, a therapeutically effective dose of (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above.

In the case of sodium chloride when used alone the method of the present invention includes the administration of sodium chloride in solid form only. In the case of other salts and in the case of a mixture of sodium chloride and other substances, a solid preparation or a liquid preparation, may be administered. The various salts are preferably in the form of a pharmaceutical preparation of the invention. Diseases in which mucus retention occurs include bronchitis, cystic fibrosis, asthma, bronchiectasis and sinusitis all of which may be treated with medicaments and pharmaceutical preparations according to the present invention. Although the medicaments, pharmaceutical preparations, methods and uses according to the present invention are primarily concerned with the treatment and/or prevention of mucus retention in the lungs and airways it may also be possible to treat or prevent mucus retention in other locations, especially mucus retention on other ciliated epithelia, occurring in diseases such as cystic fibrosis with similar preparations. Such use is therefore part of the present invention.

The present invention may be used in the treatment of pre-existing mucus retention and it may also be used prophylactically to prevent mucus retention. Prophylaxis is particularly useful for cystic fibrosis, which can be diagnosed at an early stage when the lungs are apparently normal and before clinical symptoms of bronchiectasis occur. Prophylactic treatment according to the present invention should retard the development and the severity of bronchiectasis.

Although the primary use of the present invention is in the field of human medicine, it may also be desirable to treat other mammals for mucus retention and the present invention therefore also includes uses of the described medicaments and preparations for the treatment of mammals other than humans and further includes preparations and medicaments as described above that are suitable for the treatment of non-human mammals.

The present invention also includes the use of a physiologically tolerable substance that on dissolution in an aqueous solvent is fully or partially ionized, or a mixture of two or more such substances, in the manufacture of a medicament for the treatment and/or the prevention of mucus retention. The invention is particularly concerned with uses wherein the mucus retention affects the lungs and airways and the medicament is in a form suitable for administration by inhalation, and especially wherein the substance or mixture of substances is in solid form and the medicament is in a form suitable for administration of the substance or mixture of substances in solid form by inhalation. In such a case the substances used are preferably those that, on dissolution in an aqueous solvent, give a solution having a substantially physiological pH. The substance used or at least one of the substances used is preferably a salt.

The invention also includes the use of the salts described above (with the exception of sodium chloride alone) in the manufacture of other medicaments for the treatment and/or prophylaxis of mucus retention, for example, medicaments comprising the salts in solution or suspension for administration by inhalation. The contents of the specifications of the above- mentioned patent applications and patents and the contents of the above-mentioned literature references are hereby incorporated by reference.

The following non-limiting Examples illustrate the invention. The Examples relate to experiments carried out in vitro7 the teachings are directly applicable in vivo for example, to the treatment of humans and other animals, for example, as described in the specification.

EXAMPLES General Method

Tracheobronchial clearance is impaired in patients with bronchiectasis and experiments concerning the rheology of sputum were carried out using sputum from such patients. A mucus-depleted bovine trachea was used to measure the ciliary transportability of sputum samples.

Sputum samples were taken from patients and were then frozen and stored at -20^βC. When required the samples were thawed and either used in that form immediately or were incubated as described below or where mixed with test solutions. If mixed with a test solution then the sputum mixture was incubated.

The transportability of the sputum samples was measured by placing a portion of each sputum near the distal end of the tracheal explant and measuring the rate at which it moved proximally using a measuring-rod (ruler) and a watch. The control used was bovine tracheal mucus which had accumulated at the proximal cut end of the trachea during the process of mucus depletion. The control mucus was equilibrated in 300 milliosmolar phosphate buffered saline before use. The transportability index of a sputum sample is its transport rate expressed as a percentage of that of bovine tracheal mucus. Example 1 - Effect on transportability of sputum of solid sodium chloride

Sputum from 8 patients with bronchiectasis (not cystic fibrosis) was collected and frozen.

The samples were thawed and each sample was divided into two aliquots of approximately 1ml. One aliquot was weighed and sodium chloride crystals were added to increase the sodium chloride concentration by 0.6% w/w. The samples were incubated overnight at 4° C, which allowed full diffusion of the added salt. The transportability of each sample was measured on bovine trachea.

The results obtained are shown in the following Table 1:

TABLE 1

Mean Transportability index

Sputum sample Untreated [ Salinated

A 14 57

B 5 81 C 19 86

D 38 62

E 9 35

F 13 74

G 4 61 H 9 35 mean 14 61

The addition of solid sodium chloride clearly increases the ciliary transportability of sputum obtained from bronchiectasis patients (p=0.014, Wilcoxon signed rank test).

Example 2 - Effect on transportability of incubating sputum with various mineral salts and glucose

Sputum was obtained from one patient with idiopathic bronchiectasis, and samples of approximately 1 ml were incubated overnight at 4°C with 10 ml of a 600 milliosmoles/litre solution of a salt or of glucose, or with 10 ml of distilled water. The results obtained are shown in the following Table 2:

TABLE 2

Incubating solution Transportability index Sodium nitrate 63 Potassium chloride 70 Magnesium sulphate 96 Potassium sulphate 68 Glucose 14

Distilled water less than 4 Neat sputum 20

All the alkali and alkaline earth metal salts of mineral acids that were tested increased the transportability of bronchiectatic sputum. Glucose solution of the same tonicity were ineffective. Incubation of the sputum with water was found, in this experiment, to have a detrimental effect on transportability.

Example 3

Sputum from a patient with idiopathic bronchiectasis was divided into aliquots of approximately 1 ml, weighed, and one of each of the following substances was added in solid form to each aliquot. The amount of each substance added was that required to give a final concentration in the sputum of about 200 milliosmolar. The samples were then incubated at 4°C for 48 hours to allow full diffusion, and the transportability of each sample was then measured in duplicate on the bovine trachea as described in the General Method above. The results are presented in the following Table 3: TABLE 3

Substance added Mean transportability index

Untreated sputum control 19 Calcium chloride 84

Ammonium sulphate 65

Potassium dihydrogen phosphate 58

Ammonium chloride 75

Diammonium hydrogen phosphate 54 Dipotassium hydrogen phosphate 62

Sodium acetate 77

Glycine 73

Example 4 Sputum from 11 patients with chronic bronchitis was collected and frozen. The samples were prepared following the method described in Example 1 and and were tested in salinated (solid sodium chloride) and untreated form as described in Example 1.

The results obtained are shown in the following Table 4:

Table 4

Mean Transportability index

Sputum sample Untreated Salinated A 33 81

B 22 67

C 37 78

D 15 70

E 11 59 F 48 74

G 18 67

H 19 74

I 31 54

J 16 48 K 24 97 The addition of solid sodium chloride clearly increases the ciliary transportability of sputum obtained from patients with chronic bronchitis in every case examined (P<0.004, Wilcoxon signed rank test) .

Example 5

Sputum from 11 patients with cystic fibrosis was collected and frozen. The samples were prepared following the method described in Example 1 and and were tested in salinated (solid sodium chloride) and untreated form as described in Example 1.

The results obtained are shown in the following Table 5:

Table 5 Mean Transportability index Sputum sample Untreated Salinated

A 33 74

B 19 78

C 30 63 D 33 63

E 22 74

F 19 59

G 30 70

H 22 99 I 26 69

J 23 98

K 12 62

The addition of solid sodium chloride clearly increases the ciliary transportability of sputum obtained from patients with cystic fibrosis in every case examined (P<0.004, Wilcoxon signed rank test) .

The present invention is not to be limited in scope by the Examples given above which are intended to illustrate the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient is (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above.

2. A pharmaceutical preparation as claimed in claim 1, wherein a salt is an alkali metal, alkaline earth metal or transition metal salt.

3. A pharmaceutical preparation as claimed in claim 1, wherein a salt is a sodium, potassium, calcium, magnesium or ammonium salt.

4. A pharmaceutical preparation as claimed in any one of claims 1 to 3, wherein a salt is a chloride, sulphate, nitrate, phosphate, carbonate or bicarbonate salt, or is a salt of a carboxylic acid having from two to six carbon atoms.

5. A pharmaceutical preparation as claimed in claim 1, wherein a zwitterionic salt is an amino acid.

6. A pharmaceutical preparation as claimed in claim 1 wherein the active ingredient comprises a mixture of salts having (a) cationic components selected from sodium, potassium, calcium, magnesium and ammonium ions and (b) anionic components selected from chloride, nitrate, sulphate, carbonate and bicarbonate ions.

7. A pharmaceutical preparation as claimed in claim 6, which also comprises one or more amino acids.

8. A pharmaceutical preparation as claimed in any one of claims 1 to 7, wherein the active ingredient is sodium chloride or one of the active ingredients in a mixture of salts is sodium chloride.

9. A pharmaceutical preparation as claimed in claim 8, wherein the major component in a mixture of salts is sodium chloride.

10. A pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient is sodium chloride.

11. A pharmaceutical preparation which comprises a solid active ingredient and is in a form suitable for administration of the solid active ingredient by inhalation, characterised in that the solid active ingredient comprises sodium chloride and one or more other active substances.

12. A pharmaceutical preparation as claimed in claim 11, wherein the other active substances are selected from

(i) physiologically tolerable zwitterionic salts, (ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.

13. A pharmaceutical preparation as claimed in any one of claims 1 to 12, wherein the preparation is in a form suitable for administration by a dry powder inhaler.

14. A pharmaceutical preparation as claimed in claim any one of claims 1 to 12, wherein the preparation comprises a propellant and is in the form of an aerosol.

15. A pharmaceutical preparation as claimed in any one of claims 1 to 14, wherein the active ingredient(s) is or are in the form of particles having a mean particle size of less than 10 μm.

16. A pharmaceutical preparation which comprises an active ingredient in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient is (i) a physiologically tolerable zwitterionic salt or (ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above, with the proviso that the active ingredient is not sodium chloride alone.

17. A pharmaceutical preparation as claimed in claim 16, wherein the active ingredient is as defined in any one of claims 2 to 9, with the proviso that the active ingredient is not sodium chloride alone.

18. A pharmaceutical preparation which comprises an active ingredient and is in a form suitable for administration of the active ingredient by inhalation, characterised in that the active ingredient comprises sodium chloride and one or more other active substances.

19. A pharmaceutical preparation as claimed in claim 18, wherein the other active substances are selected from (i) physiologically tolerable zwitterionic salts,

(ii) physiologically tolerable metal, ammonium, amine and organic salts of inorganic and organic acids, and (iii) pharmaceutically active substances.

20. A pharmaceutical preparation as claimed in any one of claims 16 to 19, in the form of a solution or suspension.

21. A pharmaceutical preparation as claimed in claim 20, wherein the preparation is suitable for administration by an atomizer or a nebulizer.

22. A pharmaceutical preparation as claimed in any one of claims 16 to 21, in the form of a solution a total salt concentration of at least 600 milliosmoles/litre.

23. A pharmaceutical preparation as claimed in any one of claims 16 to 22, wherein the salt or mixture of salts is in the form an aqueous solution and that solution is buffered to maintain a physiological pH.

24. A pharmaceutical preparation as claimed in claim 23, wherein the buffer is a phosphate.

25. Use of solid sodium chloride in the manufacture of a medicament in a form suitable for administration of the sodium chloride in solid form, for the treatment and/or the prevention of mucus retention.

26. Use of (i) a physiologically tolerable zwitterionic salt or

(ii) a physiologically tolerable metal, ammonium, amine or organic salt of an inorganic or organic acid or (iii) a mixture or two or more salts as defined in (i) and (ii) above, with the proviso that the active ingredient is not sodium chloride alone, in the manufacture of a medicament for the treatment and/or the prevention of mucus retention.

27. Use as claimed in claim 26 or claim 27 wherein the mucus retention affects the lungs and airways and the medicament is in a form suitable for administration by inhalation.

28. A method for the treatment and/or prevention of mucus retention, which comprises administering, particularly by inhalation, a therapeutically effective dose of (i) a physiologically tolerable zwitterionic salt or

29. Use of a physiologically tolerable substance that on dissolution in an aqueous solvent is fully or partially ionized, or a mixture of two or more such substances, in the manufacture of a medicament for the treatment and/or the prevention of mucus retention.

30. Use as claimed in claim 29, wherein the mucus retention affects the lungs and airways and the medicament is in a form suitable for administration by inhalation.

31. Use as claimed in claim 30, wherein the substance or mixture of substances is in solid form and the medicament is in a form suitable for administration of the substance or mixture of substances in solid form by inhalation.

32. Use as claimed in any one of claims 29 to 31, wherein the substance or at least one of the substances is a salt.