WO2003086429A1

WO2003086429A1 - A pharmaceutical formulation for endonasal administration and its use in the treatment of rhinitic symptoms

Info

Publication number: WO2003086429A1
Application number: PCT/EP2003/003832
Authority: WO
Inventors: José Sebastian FRANZONE; Claudio Omini; Giuseppe Zuccari
Original assignee: Medestea Research & Production S.R.L.
Priority date: 2002-04-16
Filing date: 2003-04-14
Publication date: 2003-10-23
Also published as: AU2003229656A1; ITTO20020331A1; ITTO20020331A0

Abstract

A pharmaceutical formulation is described suitable for endonasal administration, comprising active principles present in extracts of Camellia sinensis in association with active principles in extracts of Melaleuca alternifolia, useful in the treatment of rhinitic symptoms.

Description

A pharmaceutical formulation for endonasal administration and its use in the treatment of rhinitic symptoms

The use of substances of natural origin for the treatment of various diseases has received particular public attention in recent years both in the economically advanced countries and in the developing countries . The increase in the cultural level of the population, the desire to improve their quality of life, the need to avoid or reduce the side effects of traditional pharmaceuticals are all factors which have contributed to this development towards a medicine based essentially on the use of natural products. These necessities are particularly felt when the illnesses are not particularly serious even if may be chronic, as can be seasonal respiratory affections or syndromes very often having a psychosomatic character such as violent headaches, some digestive disturbances, excessive stress and illness tied to pollution which together deteriorate the quality of life.

There are numerous products of natural origin which have been counted as great successes among the population which evidently has gained benefit from their use. All this has stimulated the scientific community both to search for evident clinical efficacy of such products and to identify the active principles which support this efficacy.

To this end the use of plant extracts commonly called tea such as the extract of Melaleuca alternifolia (tea tree oil; TTO) or the tea (Camellia sinensis, Thea sinensis, green tea, black tea, TV) has a valid scientific rationale confirmed by a rich literature on its effects. TTO has a proven anti bacterial activity (1, 2) , anti fungal activity (3) and a particularly interesting anti-viral activity (4) . It is therefore well known in the art that its administration might be useful in bacterial and viral infections.

On the other hand the beneficial effects of the extracts of tea have been known for centuries, so much so that it represents a cornerstone of the oldest traditional medicines such as those of the Chinese or Japanese. The research in recent decades has made possible to identify the active principles (catechins) and the mechanisms by which tea exerts its therapeutic action. In particular, it is recognised that tea has a very notable anti-oxidant activity (5, 6, 7) and anti-radical activity (8) which justify a conspicuous anti- inflammatory action.

The present invention is based on the working hypothesis that many diseases characterised by the presence of bacterial and viral infective agents, and by inflammatory processes which cause hyperaemia causing tissue congestion, can be beneficially treated by the combined use of TTO and TV. Among these pathologies the syndromes which normally strike the nasal cavities (rhinitis, sinusitis, rhinosinusitis etc) are particularly characterised by tissue hyperaemia and consequent selective or partial obstruction of the cavities. Rhinitis for example is a* very common illness condition caused essentially by an inflammatory process of the nasal ucosa associated with rhinorroea, that is abundant nasal secretions, sneezing and nasal blockage. All, or the vast majority of the population, have, at least once, suffered acute classic rhinitis and therefore have a perception of the considerable discomfort , and inconvenience which it causes. However this pathology, whilst not being seriously disabling as other more serious illnesses, causes an undoubted reduction in the quality of life. Overall rhinitis is sub divided into various forms such as :

- acute rhinitis, which as has been indicated above, does not normally require specific pharmacological treatment as the symptoms, although particularly annoying, have a temporal duration of a few days only; the use of antibiotic drugs is generally not advised as the pathogenic organisms are normally viral agents; likewise the prolonged use of pharmaceutical vasoconstrictor drops is not advised as the initial relief of the nasal blockage is generally followed by the rebound of the nasal blockage, which in the most serious cases takes the form of rhinitis medicamentosa which may become a chronic rhinitis;

- chronic rhinitis is also usually determined by an infection of specific organisms and is characterised by progressive weakening of the nasal mucosa and secretions of viscous mucus; allergic rhinitis is also a well recognised pathological form, which is generally seasonal in occurrence and coincides with an allergic reaction to air-borne pollen. The patient has ocular reddening, frequent sneezing and abundant aqueous nasal secretions with nasal blockage. Although the symptoms of allergic rhinitis can be superimposed over those of acute rhinitis, nevertheless the pathogenesis is completely different and the drugs usable in allergic rhinitis are the classic anti-reactive agents which include antihistamines, corticosteroids and chromones.

In general the rhinitic subject tends to take nasal vasoconstrictors to reduce the symptoms even if he knows well that the action of such drugs is transitory and normally results in the subsequent of the symptoms return. Indeed the vasoconstriction of the nasal vessels temporarily reduces the secretions, but at the end of the pharmacological effect, the nasal secretions return in a more abundant way. It would therefore be useful to have medicaments which can reduce the rhinitic symptoms without causing the rebound effects .

An object of the present invention is that of making available a simple and effective therapeutic means of natural origin for use in the treatment and prevention of rhinitic symptoms which does not lead to the side effects of traditional medicines such as, for example, clinical rhinitis.

According to this object a subject of the invention is a pharmaceutical composition as defined in the following claims, and its use for the prevention and treatment of rhinitic symptoms.

The present invention provides a coposition for nasal administration for the cure and prevention of rhinitic symptoms of the mammals in the need of. which comprises an effective amount of natural origin compounds, which does not lead to the side effects of the classical decongestant drugs such as, for example, rebound nasal blockage.

Within the aim of the invention different pharmaceutical compositions have been prepared containing the combination of TTO and TV in aqueous solution, suitable for endonasal administration by means of suitable devices .

Considerable claimed advantages of the present invention relate to prevention of rhinitic symptoms by said pharmaceutical compositions, counteracting the pro- inflammatory agent adherence to the nasal mucosa, the most frequent cause of acute rhinitis. Among these pro- inflammatory agents it should be underlined the damage due to environmental pollution caused by the combustion of products derived from petroleum such as the exhaust gas of motor vehicles or as the emissions of domestic heating boilers. Moreover among other possible agents known for their nasal mucosa irritant capacity, cigarette smoke, whether active or passive, not only causes an increased incidence of cancerous pathology but it also induces pulmonary hyperreactivity linked to the inflammatory process of the airways (10, 11) .

Indeed of the active ingredients present in the TTO and TV extracts cause a synergistic interaction, between the anti bacterial and anti viral action of TTO, able to prevent and knockdown the bacterial and viral infections directly responsible for the rhinitic pathology, associated with a recognised anti-inflammatory and anti-radical activity of TV. Moreover it is well known that the processes of oxidation and generation of free radicals contribute to the inflammatory phenomenon. In this regard, in one male subject with acute rhinitis the administration of a solution of TTO and TV in concentrations of 0.1% and 0.005% respectively caused an evident reduction in the rhinitic symptoms and the subject reported a surprisingly conspicuous reduction in the nasal blockade after only 3-4 inhalations of the composition.

Likewise, surprisingly the administration of the same composition to a subject suffering of allergic rhinitis (acarus) during an active phase caused a conspicuous reduction of symptoms even if the frequency of administration was increased to 6-10 inhalations. In parallel, in the same subject, the preventive administration for 7 days 3-4 times per day of the composition significantly reduced the symptoms experienced by the exposure of the subject to house dust . These results were entirely surprising and unexpected, in fact, if in the case of the subject with acute rhinitis, in a long term basis, the well known anti viral and anti bacterial activity associated with the anti inflammatory and anti radical activity could provide a possible theoretical explanation. However, the rapidity in onset of the symptomatic efficacy, in particularly the nasal blockade and rhinorroea remains entirely surprising since, from what has been reported in the literature, no vasoconstrictive action was recognised for the active principles present in TTO and TV.

Similarly, the capacity of the combination of TTO and TV to reduce the symptoms in the subject with allergic rhinitis is equally surprising and unexpected in that, as already stated, the pathogenetic mechanisms underlying the two types of rhinitis cannot be certainly correlated with one another. On the other hand, as already stated, neither it is known nor scientifically supported to be a decongestant activity associated with a vasoactive capacity of the two teas under examination, and even less an anti-allergic efficacy thereof. In this respect the appearance of potential allergic reactions with TTO has been indicated at least on the skin (9) •

Moreover further clinical studies have confirmed the anti- rhinitis activity of the combination of TTO and TV. Indeed, a composition as reported in example 7 has been administered to 59 patients with acute or chronic rhinitis as reported in table 1 and table 2. Table 1

Table 2

PATOLOGIES

& NUMBERS ADULTS PAEDIATRICS

SYMPTOMS

Acute rhinitis 28 (47%) 16 (57%) 12 (43%)

Chronic rhinitis 31 (53%) 24 (77%) 7 (23%)

Dryness 48 (81%) 31 (65%) 17 (35%)

Nasal discharge 58 (99%) 39 (67%) 19 (33%)

Nasal blockade 57 (97%) 39 (68%) 18 (32%)

Fever 14 (24%) 11 (78%) 2 (22%)

Headaches 25 (42%) 21 (83%) 4 (16%)

The formulation has been administered by inhalation into both nasal nostrils in the amount of 200 μl (2 puffs) each nostril, 4 time a day for 7 days. The symptoms were recorded before and after the first dose and at the end of the treatment (7 days) .

Table 3 shows the results obtained after the first treatment, and expressed as hours without symptoms. Table 3

It is important to underline that, as already observed in the preliminary study, also in this controlled clinical study, surprisingly, the therapeutic efficacy of the formulation was evident even after a single dose, highly suggesting an unknown mechanism for the combined treatment of TTO and TV.

After 7 days of treatment a considerable clinical efficacy of the formulation was observed with a marked decrease in the intensity of the symptoms of rhinitis .

Table 4 shows the results obtained and expressed as mean + SD of the appropriate scores.

Table 4

The overall assessment of all scores indicated an average of 60% decrease in the symptoms after 7 days of treatment with no difference between the two group (adults 63% and paediatrics 57%) .

Another important point of the present invention relates to a pharmaceutically acceptable formulation to optimize the therapeutic efficacy of the association of TTO and TV. In this regard there have been tested several formulations in order to obtain an adequate solution of the active principles which could be nebulised with common nebulising pumps, with or without additional propellant gas and which at the same time would respect the necessity to utilise functionally adequate eccipients .

In this regard the low solubility of TTO in aqueous solution has required eccipients or mixtures of eccipients with surfactant capacity in order to optimise the emulsion of the TTO in aqueous solvents . Current and classical examples of eccipients or mixtures of eccipients suitable for the purpose are polysorbates, propylene glycol, poly vinyl pyrrolidone, polyethylene glycols, polyethylene glycolstearates, sorbitan monolaurate, lauryl ether sulphate as sodium- or monoethanolamine- salts, glycerol, ethyl alcohol or isopropyl alcohol, in the presence or not of C10-C18 triglycerides alcohol. If desired perfumes and essences can be added (including natural aromatics and essential oils) and if necessary eccipients with a preservative function can be added.

For the preparation of the said formulations suitable reference can be made to classical texts in the art of pharmaceutical formulations such as, for example, "Remingtons Pharmaceutical Sciences" handbook, Mack Publishing Company, USA. For greater clarity we give hereinafter several examples of formulations used, which however are to be considered solely as explanatory and non-limitative of the scope of the present invention.

In the examples - as in the claims - which follow, the contents of active agents are referred to commercial extracts of, respectively, dry extracts of green tea and oily extract of tee tree oil which have the following:

Example 1

A formulation of nasal spray having the following composition per lOOg was thus prepared:

Green tea 0.01%

Tea Tree Oil 0.1%

PEG-40 hydrogenated castor oil 1%

Isopropyl alcohol 0.1%

Glycerol 1%

Esters of p-hydroxy benzoic acid 0.2%

Essential oil of eucalyptus 0.2%

Saline (NaCl 0.9%) qb lOOg

Example 2

A formulation of nasal spray suitable for use without preservatives having the following composition per 10Og was thus prepared:

Green Tea 0.005%

Tea Tree Oil 0.05%

PEG-40 hydrogenated castor oil 0.2%

Isopropyl alcohol 0.1%

Glycerol 1.0%

Balsamic Fragrance 0.2% Saline (NaCl 0.9%) qb lOOg

Example 3

A formulation for nasal spray having the following composition per lOOg was thus prepared:

Green Tea 0.005% Tea Tree Oil 0.05% Tween 80 0.3% Ethyl alcohol 0.1% Glycerol 1.0%

Benzalkonium Chloride 0.01% Essential oil of mint 0.2% Saline (NaCl 0.9%) qb 10Og

Example 4

Green Tea 0.005%

Tea Tree Oil 0.1%

PEG-40 hydrogenated castor oil 0.2% Cetostearyl alcohol 0.1%

Glycerol 1.0%

Benzalkonium Chloride 0.01%

Boric acid 0.1%

Essential oil of eucalyptus 0.2% Saline (NaCl 0.9%) qb lOOg

Example 5

The following composition for nasal spray was prepared for use with pressurised devices using compressed air as propellant :

Green Tea 0.005%

Tea Tree Oil 0.1% Sorbitan Trioleate 0.2%

Isopropyl alcohol 0.1%

Glycerol 1.0%

Benzalkonium Chloride 0.01%

Compressed air qb

Eucalyptus fragrance 0.2%

Saline (NaCl 0.9%) qb lOOg

Example 6

A formulation for nasal spray having the following composition per lOOg and dispensable by means of non- pressurised devices for inhalation was thus prepared:

Green Tea 0.005% Tea Tree Oil 0.1%

PEG-40 hydrogenated castor oil 0.2% Isopropyl alcohol 0.1%

Glycerol 1.0%

Benzalkonium Chloride 0.01% Eucalyptus fragrance 0.2%

Saline (NaCl 0.9%) qb lOOg

Example 7

A formulation of nasal spray suitable for use having the following composition per 10Og was thus prepared:

Green Tea 0.005%

Tea Tree Oil 0.1%

Eucalyptus essential oil 0.1%

Benzalkonium chloride 0.01%

Resasol VS 1.08%

Isopropyl alcohol 0.1%

Glycerol 3.0% Balsamic Fragrance 0.02%

Saline (NaCl 0.9%) qb lOOg

The use of extracts of green tea and tea tree oil include the use of the active principles present in the extracts. In particular the active principles or concentrated solutions of these active principles can be used directly in the formulations at the appropriate concentrations as can the catechins present in the tea and the terpinen-4-oil present in the tea tree oil .

Other ingredients can be added to the compositions for nasal spray claimed in the present invention. Particularly suitable are those substances able to break down the disulphide bonds of the nasal secretions thereby reducing the viscosity thereof and encouraging a better elimination of the mucus, such as for example, synthesised products such as cysteine, N-acetylcysteine, S-carboxymethylcysteine or natural substances such as extracts of eucalyptus, polyphenols and the anthocyanidins contained in grape seeds and pine kernels.

Biography

1. Hammer K.A. et al . Antimicrobial activity of essential oil and other plant extracts. J Appl Microbiol 1999, 86: 985- 90.

2. Cox SD et al . Determining the antimicrobial actions of tea tree oil Molecules 2001, 6: 87-91.

3. Nenof f P et al . Antifungal activity of the essential oil of Melaleuca alternifolia (tea tree oil) against pathogenic fungi in vitro Skin Pharmacol 1996, 9: 388-94. 4. Schnitzler P et al . Antiviral activity of Australian tea tree oil and eucalyptus oil against herpes simplex virus in cell culture. Pharmazie 2001, 56(4): 343-7.

5. Katiyar SK et al . Green tea polyphenol (-)-epigal- locatechin-3-gallate treatment of human skin inhibits ultraviolet radiation-induced stress. Carcinogenesis 2001. 22(2) : 287-94.

6. Toschi TG et al . The protective role of different green tea extracts after oxidative damage is related to their catechin composition. J Agric Food Chem 2000, 48(9): 3973- 8.

7. Miyazawa T. Absorption, metabolism and antioxidative effects of tea catechin in humans. Biofactors 2000, 13(1- 4) : 55-9.

8. Wei H et al . Scavenging of hydrogen peroxide and inhibition of ultraviolet light-induced oxidative DNA damage by aqueous extracts from green and black teas. Free Radic Biol Med 1999, 26(11-12): 1427-35.

9. Fritz TM et al . Allergic contact dermatitis to cosmetics containing Melaleuca alternifolia (tea tree oil) . Ann Dermatol Venereol 2001, 120(2): 123-6.

10. Omini c et al . Passive cigarette smoke exposure induces airway hyperreactivity to histamine but not to acetylcholine in guinea-pigs. Pul Pharmacol 1990, 3:145- 50.

11. Daffonchio L et al . Airway hyperreactivity induced by active cigarette smoke exposure in guinea-pigs : possible role of sensory neuropeptides . Pulm Pharmacol 1990, 3:161- 6.

Claims

1. Pharmaceutical composition suitable for endonasal administration comprising active principles present in extracts of Camellia sinensis in combination with active principles present in extracts of Melaleuca alternifolia.

2. A pharmaceutical composition according to Claim 1, comprising in combination as active principles catechins present in extracts of Camellia sinensis and terpinen-4-oil present in extracts of Melaleuca alternifolia.

3. A pharmaceutical composition according to Claims 1 or 2, comprising in combination extract of Camellia sinensis and extract of Melaleuca alternifolia.

4. A pharmaceutical composition according to Claim 3 , in which the concentration of extract of Melaleuca alternifolia ranging between 0.1 and 10% by weight and the concentration of extract of Camellia sinensis ranging between 0.001 and 10% by weight .

5. A pharmaceutical composition according to Claim 4, in which the concentration of extract of Melaleuca alternifolia ranging between 0.05 and 2.5% by weight and the concentration of Camellia sinensis ranging between 0.005 and 2.5% by weight .

6. A pharmaceutical composition according to any preceding claim, in which the said active principles dissolved in aqueous solutions, hydro alcoholic or alcoholic solutions are present in oil-water emulsions.

7. A pharmaceutical composition according to any preceding claim, further comprising as active agents compositions able to break down the disulphide bonds of nasal secretions.

8. A pharmaceutical composition according to Claim 7, characterised in that it comprises as further active principles compositions chosen from cysteine, N-acetyl cysteine, S-carboxymethyl cysteine or mixtures thereof.

9. A pharmaceutical composition according to Claim 7, further comprising natural substance chosen from extracts of eucalyptus, polyphenol and anthocyanidins contained in grape seeds and pine kernels, or mixtures thereof.

10. A pharmaceutical composition according to any preceding claim, packaged in a container, optionally under pressure and provided with pumps and inhalers or distributors connectable or connected to the said container.

11. A pharmaceutical composition according to any preceding claim, packaged in a container provided with mechanical no gas pumps .

12. A pharmaceutical composition according to any preceding claim, substantially as described and illustrated in examples 1 to 7.

13. Use of a pharmaceutical composition according to any preceding claim for the preparation of a medicament administrable by endonasal means for the treatment, prevention or therapy of rhinitic symptoms.

14. Use of a pharmaceutical composition according to any of claims 1 to 12 for preparing a medicament for prevention of pro-inflammatory agent adherence to nasal mucosa, and/or eviromental pollution and/or active and passive cigarette smoke induced nasal mucosa irritation of mammals in the need thereof .