WO1995013070A1

WO1995013070A1 - Nedocromil sodium for the treatment of upper respiratory tract infections

Info

Publication number: WO1995013070A1
Application number: PCT/GB1994/002454
Authority: WO
Inventors: Alan Martin Edwards
Original assignee: Fisons Plc
Priority date: 1993-11-10
Filing date: 1994-11-08
Publication date: 1995-05-18
Also published as: IL111538A0; GB9323132D0; ZA948741B; AU8112094A

Abstract

The present invention relates to the use of nedocromil sodium in the therapeutic treatment of the symptoms of upper respiratory tract infections (e.g. the common cold and influenza).

Description

Nedocromi l sodi um for the treatment of upper respi ratory tract i nfecti ons.

This invention relates to the use of nedocromil sodium in the therapeutic treatment of upper respiratory tract infections.

The term "upper respiratory tract infections" (URTIs) is used by those skilled in the art to describe those acute respiratory illnesses, including the common cold and influenza, which are caused by a variety of different viruses.

Such illnesses are characterised by their sudden onset, and highly infectious and self- limiting nature, with symptoms varying in severity depending upon the virus which is responsible.

Sympi ms of the common cold typically start with a mild malaise, fatigue, a dry or sore throat and nasal discomfort, usually reaching maximum severity on the second or third day. At this stage additional, more incapacitating symptoms such as nasal discharge and congestion, sneezing, hoarseness and a cough are observed. In more severe cases patients experience fever with *πciated headache and muscle pain, vocal impairment and loss of the senses of smell and taste.

Symptoms of influenza are usually more intense and include fever, which may be severe and persist for several days, general fatigue and weakness, and severe discomfort due to intense muscular aching and headache.

Although the symptoms of URTIs are typically not regarded as serious, they often result in lost time at work or school and in this respect impose a substantial cost on society. In addition, even mild URTIs have been known to lead to more serious conditions such as bronchitis; influenza is known to be fatal when acquired by vulnerable individuals.

Existing treatments which find utility in the symptomatic treatment of URTIs comprise active ingredients which target individual or closely related symptoms. Treatments indicated for overall relief of the symptoms of an URTI are thus merely combinations of these active ingredients.

Thus a treatment indicated for relief of all the symptoms of an URTI would typically comprise an analgesic (eg aspirin or paracetamol) to combat fever and relieve pain; a decongestant (eg ephedrine or pseudoephedrine) to reduce nasal congestion; an antitussive (eg codeine) or expectorant (eg ammonium chloride) to alleviate cough; and an antihistamine (eg diphenhydramine or triprolidine) for use as a sedative.

Treatments indicated for sore throats are usually administered separately and may comprise an anaesthetic agent (eg benzocaine) to relieve pain.

There is thus no treatment presently available, comprising a single active ingredient, which is effective against all the recognised symptoms associated with URTIs. All the aforementioned agents are known to exhibit adverse side effects. Moreover, it is the opinion of a substantial proportion of those skilled in the art that some of the treatments mentioned above have little to no positive therapeutic effect.

UK Patent No. 2022078 discloses a number of pyranoquinolinones including 9-ethyl- 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, the disodium salt of which, nedocromil sodium, is useful in the prophylactic treatment of, inter alia, asthma and allergic rhinitis.

The mode of action of nedocromil sodium in the prophylaxis of the above conditions is understood to proceed via the stabilisation of mast cell membranes. However, it is also known to combine this activity with a broad antiinflammatory action, affecting the inflammatory response at several sites, including eosinophils.

Nonetheless, nedocromil sodium is known to have no intrinsic antihistaminic action and possesses no bronchodilator activity. As a result it is known to be of little value in the therapeutic treatment of the symptoms of those conditions for which it is known to have preventative efficacy. For example, it is of no value in the treatment of acute asthma (see eg Martindale, The Extra Pharmacopoeia, 30th Edition, at page 1142) nor in the treatment of allergic rhinitis once the symptoms have appeared (ie on an "as needed" basis; see American Journal of Otolaryngology, 14, 379 (1993))

In addition to the prophylactic treatment of asthma and allergy, the compounds of UK Patent No. 2022078 were also indicated for use in the prevention of secretion of excess mucus and therefore in the prophylaxis of bronchitis, coughs and the nasal and bronchial obstructions associated with the common cold.

The prophylactic utility of nedocromil sodium in URTIs has been confirmed (Barrow et al, Clin. Exp. Allergy, 20, 45 (1990) and Smith et al, J. Psychopharmacology, 5, 251 (1991)). Challenge studies demonstrated that nedocromil sodium was partially effective prophylactically in reducing the development of some of the symptoms of colds artificially induced by rhinovirus (nasal secretion and psychomotor performance) and to a lesser extent coronavirus (psychomotor performance only), The effectiveness of the drug against development of other aforementioned symptoms of URTIs was not mentioned.

The authors concluded that one or more of the mediators affected by nedocromil sodium may play a minor role in the symptoms of URTIs, despite the fact that such mediators have not been detected in individuals infected with URTIs (see eg Acta Otolaryngol., 413 (Suppl.), 23 (1984) and Clinical Allergy (1988) 18, 119).

However, there is no indication in the prior art that nedocromil sodium is potentially useful in the therapeutic treatment of the symptoms of URTIs.

According to the invention there is provided the use of nedocromil sodium as active ingredient in the manufacture of a medicament for the therapeutic treatment of an URTI.

By "therapeutic treatment of an URTI" we mean treatment of the symptoms of an URTI following recognition of commencement thereof, as distinct from the prophylaxis of such a condition. Particular URTIs which may be mentioned include the common cold and influenza.

In particular nedocromil sodium when administered therapeutically may relieve fatigue, fever and nasal and bronchial congestion; reduce the volume of nasal s secretion and the incidence and severity of sneezing and cough; and relieve sore throats and vocal impairment experienced by patients suffering from URTIs.

Thus, according to another aspect of the invention there is provided a method of treating a human having an URTI which comprises administering a therapeutically o effective quantity of a medicament comprising nedocromil sodium to a patient suffering from such a condition.

The method of treatment according to the invention may find utility in the alleviation of symptoms of URTIs in hyperreactive patients and non-hyperreactive patients, s However, we prefer a method of treatment of a non-hyperreactive patient.

By "a non-hyperreactive patient" we mean a patient who does not exhibit abnormal sensitivity to spasmodic stimuli resulting in recurrent, variable or intermittent narrowing of intrapulmonary airways (eg a non-asthmatic patient). 0

Formulations comprising nedocromil sodium for the treatment of URTIs may be administered topically by a variety of routes, for example intra-nasally or by oral inhalation.

According to a further aspect of the invention there is provided a pharmaceutical formulation for the therapeutic treatment of an URTI, which contains a therapeutically effective quantity of nedocromil sodium.

Dealing first with oral inhalation, nedocromil sodium may be inhaled as a dry powder in formulations which may be pressurized and non-pressurized.

In non-pressurized powder formulations, the active ingredient may be presented in finely divided form, as described in European Patent Application 0 398 361. When the active ingredient is in finely divided form it may be used in admixture with a larger sized pharmaceutically acceptable inert carrier comprising particles, of eg up to lOOμm diameter. Suitable inert carriers include sugars, for example dextran, mannitol, preferably lactose and particularly crystalline lactose. Desirably, at least 95% by weight of the particles of the active ingredients have an effective particle size in the range 0.01 to lOμm.

The finely divided active ingredient may be made by grinding or milling and is preferably dried thoroughly before formulation.

The powder may also contain a flavouring agent, for example a polysaccharide flavouring agent as described in International Patent Application WO 93/17663. The powder may further comprise a sweetening agent, for example sugar, aspartame, cyclamates and preferably saccharin or salts thereof, eg saccharin sodium.

The powder may be administered from a capsule containing the active ingredient using an inhalation device. The capsule may contain from 5 to 40mg, for example 8 to 35mg and preferably 10 to 30mg of the active ingredient.

Inhalation devices from which the non-pressurized formulations may be administered include the Spinhaler^®. Powder formulations may also be inhaled from a pre-pierced capsule, eg as disclosed in International Patent Application WO 94/05560, using a device such as that disclosed in International Patent Application WO 94/19041.

Alternatively powder non-pressurized formulations may be inhaled directly from a disposable device such as that disclosed in European Patent N° 0 404 454.

The formulation may alternatively be pressurized and contain a compressed gas, eg nitrogen, or a liquefied gas propellant.

Suitable propellants include the chlorofluorocarbons sold under the Trade Mark "Freon", which are non-toxic and have a boiling point below 20°C at atmospheric pressure. Examples of these propellants are dichlorodifluoromethane, 1,2- dichlorotetrafluoroethane and trichloromonofluoromethane. It may be preferred however, in view of environmental concerns, to use one of the hydrofluoroalkane propellants, for example, 1,1,1,2-tetrafluoroethane, 1,1-difluoroethane or 2H- heptafluoropropane. Mixtures of the above mentioned propellants may suitably be employed.

The pressurized formulation may also contain a surface active agent. When the propellant is a chlorofluorocarbon, the surface active agent may be a liquid or solid non-ionic surface active agent (eg sorbitan trioleate) or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of the sodium salt, for example sodium dioctyl-sulphosuccinate. When the propellant is a hydrofluoroalkane, the surface active agent may be a polymer soluble in the liquid hydrofluoroalkane, for example those polymers containing amide containing units and carboxylic acid ester containing units as described in International Patent Application WO 93/05765.

The pressurised composition may also contain a flavouring agent, for example peppermint oil or menthol or combinations thereof, such as the commercially available product Dentomint™, and a sweetening agent, for example sugar, aspartame, cyclamates and preferably saccharin or salts thereof, eg saccharin sodium, as described in European Patent Application 0 365 119.

Metered doses from the pressurised composition may contain from 0.1 to 5mg, for example 0.25 to 4mg and preferably 0.5 to 3mg of nedocromil sodium.

Commercially available pressurised formulations of nedocromil sodium include TILADE^® (2mg dose). Commercially available pressurised formulations of nedocromil sodium which comprise a flavouring agent and a sweetening agent include TILADE^®-MINT (alternatively known as TILADE^® -M; 2mg dose).

Formulations suitable for administration by nasal inhalation include solutions, especially aqueous solutions. When nedocromil sodium is to be used in aqueous solution, it may be necessary to incorporate a tonicity modifying agent (for example sodium chloride or glycerol) to reduce irritation on administration of the active ingredient. In addition the solution may also contain an effective proportion of a pharmaceutically acceptable chelating or sequestering agent (for example sodium edetate or sodium carboxymethyl cellulose). The solution may also, if desired, contain an effective proportion of a pharmaceutically acceptable preservative or sterilising agent (eg quaternary ammonium salts, especially that known generically as Εenzalkonium chloride'). In addition the solution may also contain a buffering agent (eg sodium hydrogen phosphate or sodium phosphate).

The solution may contain from 0.1 to 6% w/v, preferably from 0.2 to 4% w v of nedocromil sodium. We particularly prefer solutions which contain from 0.5 to 3% w v of nedocromil sodium.

Typical single doses for nasal administration may contain from 0.1 to 6mg, for example 0.2 to 4mg and preferably 0.5 to 3mg of nedocromil sodium.

Nedocromil sodium may be formulated along with other active ingredients indicated for the treatment of URTIs, for example sympathomimetic agents commonly used as decongestants (eg ephedrine, oxymetazoline, phenylephrine and xylometazoline).

However, in view of the widely recognised side effects which are exhibited with conventional active ingredients indicated for the treatment of URTIs, we prefer formulations wherein nedocromil sodium is present as the sole active ingredient, ie formulations which consist essentially of nedocromil sodium.

By "formulations which consist essentially of nedocromil sodium" we mean formulations which are essentially free of other active ingredients such that the level of the latter is insufficient to have an effect on the relief of the symptoms of URTIs, for example less than 0.001% w/w, and that other components may also be present in the formulation, provided that the essential characteristics of the formulation are not materially affected by their presence. Although formulations adapted for nasal administration or oral inhalation may be used individually to treat all the recognised symptoms of URTIs, the preferred mode of administration will depend largely upon the symptoms to be treated.

Where the symptom to be treated comprises one or more of nasal congestion, nasal secretion, sneezing, fever and general weakness, we prefer administration to the nose.

Where the symptom to be treated comprises one or more of cough, sore throat, vocal impairment, fever and general weakness, we prefer administration via oral inhalation.

For complete treatment of all the symptoms of URTIs however, we prefer a method of treatment which comprises either separate, simultaneous or sequential adminstration of a formulation adapted for oral inhalation, and a formulation adapted for nasal inhalation.

Thus, according to a further aspect of the invention, there is provided a pharmaceutical product containing a first formulation of nedocromil sodium adapted for administration to the nose and a second formulation of nedocromil sodium adapted for oral inhalation, as a combined preparation for separate, simultaneous or sequential use in the therapeutic treatment of an URTI.

The dosage administered will naturally depend inter alia on the mode of adminstration, and also the severity of the URTI.

In general, we have found that in order to treat the symptoms of URTIs, nedocromil sodium should be administered at a frequency of, for example between a half hourly and twelve hourly basis, and particularly between a one hourly and four hourly basis.

Alternatively, nedocromil sodium may be administered more frequently (eg on a half hourly to three hourly basis) over the first few days (eg day one to day three) of the URTI and less frequently (eg three to twelve hourly basis) thereafter until complete relief of symptoms is achieved. The method of treatment according to the invention has the advantage that nedocromil sodium may be used to alleviate all the recognised symptoms of URTIs. Further nedocromil sodium is less toxic, is more efficacious, is longer acting, has a broader range of activity, is more potent, produces fewer side effects, or has other 5 more useful pharmacological properties, compared with active ingredients previously used in the treatment of URTIs.

The invention is illustrated by the following examples:

10 Example 1

Formulation for nasal adminstration

Nedocromil sodium nasal spray (1.3mg per dose; 1% solution)

Example 2 is Formulations for oral inhalation

(a) Capsules of nedocromil sodium dry powder blended with lactose (10 to 30mg dose);

(b) capsules of nedocromil sodium dry powder blended with lactose containing flavouring agent and sweetening agent (10 to 30mg dose);

20 (c) commercially available multi-dose inhaler containing nedocromil sodium and CFC's 12/114 (2mg dose; TILADE^®);

(d) commercially available multi-dose inhaler containing nedocromil sodium, CFC's 12/114, flavouring agent and sweetening agent (2mg dose; TILADE^® -MINT);

(e) nedocromil sodium dry powder blended with lactose (as Example 2(a); 10 to

25 30mg doses) contained in a pre-pierced capsule as described in International Patent Application WO 94/05560;

(f) r^{r "}ocromil sodium dry powder blended with lactose containing flavouring agent and ≤etening agent (as Example 2(b); 10 to 30mg doses) contained in a pre- pierced capsule as described in International Patent Application WO 94/05560;

30 (g) nedocromil sodium powder blended with lactose (as Example 2(a); 10 to 30mg doses) contained in a disposable device as disclosed in European Patent N° 0 404 454; or (h) nedocromil sodium powder blended with lactose containing flavouring agent and sweetening agent (as Example 2(b); 10 to 30mg doses) contained in a disposable device as disclosed in European Patent N° 0 404 454.

Example 3

Pharmaceutical Combination Product

The above formulations may be packaged together for separate, simultaneous or sequential use in the following manner:

(a) the nasal spray of Example 1 with the capsules of Example 2(a) administered via the commercially available Spinhaler^® device;

(b) the nasal spray of Example 1 with the capsules of Example 2(b) administered via the commercially available Spinhaler^® device;

(c) the nasal spray of Example 1 with the multi-dose inhaler of Example 2(c);

(d) the nasal spray of Example 1 with the multi-dose inhaler of Example 2(d); (e) the nasal spray of Example 1 with nedocromil sodium contained in the pre- pierced capsules of Example 2(e); nedocromil sodium is inhaled orally from the pre- pierced capsule using a device as disclosed in International Patent Application WO 94/19041;

(f) the nasal spray of Example 1 with nedocromil sodium contained in the pre- pierced capsules of Example 2(f); nedocromil sodium is inhaled orally from the pre- pierced capsule using a device as disclosed in International Patent Application WO 94/19041;

(g) the nasal spray of Example 1 with nedocromil sodium contained in the disposable device of Example 2(g) from which drug is directly inhaled; or (h) the nasal spray of Example 1 with nedocromil sodium contained in the dispoable device of Example 2(h) from which drug is directly inhaled.

Claims

1. Use of nedocromil sodium as active ingredient in the manufacture of a medicament for the therapeutic treatment of an upper respiratory tract infection.

2. Use as claimed in claim 1, characterised in that nedocromil sodium is the sole active ingredient.

3. Use as claimed in either of claim 1 or claim 2, characterised in that the upper respiratory tract infection is the common cold.

4. Use as claimed in either of claim 1 or claim 2, characterised in that the upper respiratory tract infection is influenza.

5. Use as claimed in any of claims 1 to 4, characterised in that the treatment is of a non-hyperreactive patient.

6. Use as claimed in any of claims 1 to 5, characterised in that the medicament is adapted for administration to the nose.

7. Use as claimed in any of claims 1 to 5, characterised in that the medicament is adapted for oral inhalation.

8. Use as claimed in any of claims 1 to 5, characterised in that the medicament comprises a first formulation of nedocromil sodium adapted for administration to the nose and a second formulation of nedocromil sodium adapted for oral inhalation.

9. A pharmaceutical product containing a first formulation of nedocromil sodium adapted for administration to the nose and a second formulation of nedocromil sodium adapted for oral inhalation, as a combined preparation for separate, simultaneous or sequential use in the therapeutic treatment of an upper respiratory tract infection.

10. A pharmaceutical product as claimed in claim 9, characterised in that the formulations contain nedocromil sodium as the sole active ingredient.

11. A pharmaceutical product as claimed in either of claim 9 or claim 10, characterised in that the treatment is of a non-hyperreactive patient.

12. A method of treating a human having an upper respiratory tract infection which comprises administering a therapeutically effective quantity of a medicament comprising nedocromil sodium to a patient suffering from such a condition.

13. A method of treatment as claimed in claim 12, which comprises separate, simultaneous or sequential administration of a first formulation of nedocromil sodium adapted for administration to the nose and a second formulation of nedocromil sodium adapted for oral inhalation.

14. Use of nedocromil sodium for the therapeutic treatment of an upper respiratory tract infection, which comprises administering a medicament including nedocromil sodium to a patient suffering from such a condition.

15. A pharmaceutical formulation for the therapeutic treatment of an upper respiratory tract infection, which contains a therapeutically effective quantity of nedocromil sodium.