WO2013190445A1

WO2013190445A1 - Inhalable formulations for removal of viscous secretions from the respiratory tract

Info

Publication number: WO2013190445A1
Application number: PCT/IB2013/054944
Authority: WO
Inventors: Luciano GROTTOLA
Original assignee: Ecupharma S.R.L.
Priority date: 2012-06-18
Filing date: 2013-06-17
Publication date: 2013-12-27
Also published as: EP2861211A1; ITMI20121052A1

Abstract

Disclosed are inhalable compositions consisting of an aqueous solution of sodium chloride in concentrations of between 5 and 6.5% by weight and mannitol in concentrations of between 4.7 and 10.4% by weight, having an osmolality of between 2100 and 2400 mOsm/kg.

Description

INHALABLE FORMULATIONS FOR REMOVAL OF VISCOUS SECRETIONS FROM THE RESPIRATORY TRACT

Summary of the invention

The present invention relates to inhalable compositions consisting of an aqueous solution of sodium chloride in concentrations of between 5 and 6.5% by weight and mannitol in concentrations of between 4.7 and 10.4% by weight, having an osmolality of between 2100 and 2400 mOsm/kg.

Background to the invention

Mucociliary clearance is certainly the main protection system of the airways. However, the mucus must have ideal characteristics in order to fully perform its important function of "trapping" foreign substances introduced into the airways.

In a number of disorders of the respiratory system, stagnation of the secretions in the airways and their consequent dehydration leads to conditions predisposing to bacterial colonisation, and consequently to progressive worsening of the disorder. The removal of the mucopurulent secretions is a pharmacological objective of primary importance.

In various genetic disorders, such as cystic fibrosis and Kartagener's syndrome, this stagnation of dehydrated mucus in the airways causes rapid deterioration of the pulmonary function, which can lead to early death. In other disorders, such as chronic obstructive pulmonary disease (COPD), stagnation of the secretions and the consequent broncho-obstruction takes place at a later age, but can still seriously compromise the respiratory function.

In some acute disorders of viral origin, such as influenza, stagnation of mucous secretions is often responsible for worsening respiratory symptoms.

A number of mucolytic drugs, which have a mucolytic mechanism, have been used for years. Said drugs act by depolymerising mucin, due to the presence of SH groups, thus reducing the viscosity of the secretions.

Other molecules act as mucokinetics, increasing the volume of fluid in the airways and consequently inducing coughing, thus facilitating the detachment of mucus from the airways.

Finally, active ingredients such as bromhexine and ambroxol, which stimulate the production of surfactant and therefore facilitate the flow of mucus in the airways, have been used for years.

However, the efficacy of said mucoactive medicaments is limited to modest obstruction syndromes with acute development, and they are not very effective in disorders where the bronchial obstruction is more severe, and above all chronic.

In cystic fibrosis, the non-operation of the CFT channel protein, responsible for the sodium and chlorine ion exchange between the cell and the extracellular space, leads to a reduction in the periciliary liquid layer that lines the respiratory mucosa. Said surface liquid layer, which is kept constant by the water that enters and exits from the cell, following the flow of the Na⁺ and CI^" ions, normally amounts to about 10 μΜ.

Said surface aqueous layer allows the cilia of the epithelium to move while fully immersed in the periciliary liquid layer, and thus fully perform the task of removing secretions and everything trapped in them for elimination. In cystic fibrosis (CF) patients the periciliary liquid layer is reduced by over 50% to about 4 μΜ; this reduction in volume reduces the capacity of the cilia to move adequately, and therefore also reduces mucociliary transport, until it disappears.

Due to the reduction in mucociliary clearance, mucus stagnates in the airways with consequent dehydration, bacterial colonisation and development of the ideal conditions for chronic colonisation by pathogenic, especially Gram-negative, flora.

The consequent activation of the immune system and the impossibility of eradicating the bacterial infection leads to an inflammatory process of the airways and progressive loss of respiratory function.

In other genetic disorders, such as primary ciliary dyskinesia, a variety of causes can lead to a clearance deficiency, but the resulting clinical picture is more or less identical: reduced mucociliary clearance promotes bronchial obstruction, inflammation and the development of bacterial infections, which become chronic with time.

It is therefore possible to act on two fronts to improve mucociliary clearance: improving the rheology of the secretions by reducing their viscosity and increasing their hydration, and using osmolarity-regulating agents to attract water to the epithelium, thereby restoring the periciliary liquid layer.

The former is currently sought by the mucolytics in common use, and also, for example, by Dornase alpha, a molecule of biotechnological origin with enzymatic activity which destroys the DNA filaments trapped in the mucus, leading to the death of inflammatory cells, thereby increasing its viscosity. Osmolarity-regulating agents, such as sodium chloride and mannitol, act by attracting water and restoring the periciliary liquid layer. Said substances have been used both in concentrated solution and as dry powders.

Saline solutions of NaCl, at a concentration of between 3 and 7%, or dry powdered mannitol, have been used by inhalation for some time, especially in CF. Nebulisation of sodium chloride or mannitol in the airways in practice causes water to be attracted from the cell space to the lumen by osmotic action. This flow of water persists on the airways for long enough to allow resumption of mucociliary clearance.

However, unpleasant side effects, especially the bronchospasm caused by the inertial impact of the high saline concentration of the solution in the airways and that of the powder, even micronised, are inherent in inhalation treatment.

In view of the unpleasant salty flavour that remains in the mouth after treatment, the sore throat and the high expectorant effect of osmolarity-regulating preparations, the long-term treatment required, especially in chronic disorders such as COPD, cystic fibrosis and primary ciliary dyskinesia, is impractical.

DESCRIPTION OF THE INVENTION

It has now been found that the administration by inhalation of a specific combination of sodium chloride and mannitol, in aqueous solution, significantly reduces the side effects of the ingredients when administered individually in the form of a solution or dry powder.

Mannitol, administered as a dry powder by inhalation, induces coughing and bronchospasm in a large percentage of patients. Its inhalation must be preceded by the administration of a bronchodilator. Moreover, the inhalation of mannitol in aqueous solution presents considerable drawbacks associated with the high viscosity of the solution and its excessively sweet flavour.

The sodium chloride concentration that has proved effective in clinical trials is 6-7%. A concentration of 7% is recommended by the international guidelines, but it is highly irritant for the airways.

The combination of the two osmolarity-regulating agents at various concentrations is in any event either less effective or unpleasant, regardless of the concentrations.

It has now surprisingly been found that only specific combinations of sodium chloride and mannitol in very narrow concentration ranges present the ideal properties in terms of efficacy, tolerability and organoleptic acceptability. The optimum sodium chloride concentrations range from 5% to 6.5%, and the mannitol concentration from 4.7 to 10.4%. The concentrations of NaCl and d-mannitol are selected so that the osmolality is between 2100 and 2400 mOsm/kg.

Examples of preferred formulations have concentrations of 5% sodium chloride and 10.4% mannitol, 6.1% NaCl and 5.2% mannitol, or 6.5% NaCl and 4.7% mannitol.

The compositions according to the invention could also contain hyaluronic acid or a salt thereof such as the sodium salt, in concentrations approximately ranging from 0.01 to 1%, preferably 0.1%.

Aqueous solutions thus formulated could be administered by aerosol one or more times a day, in volumes of about 4-5 ml per unit dose. The vials are preferably made of low-density polyethylene (PELLD).

The solutions according to the invention present an osmolarity-regulating action accompanied by high tolerability in the airways and a low risk of bronchospasm, as demonstrated by the lower need for premedication with beta-two agonists, and less irritation of the airways.

The solution according to the invention is also characterised by a better after-taste, because it does not leave unpleasant sensations of salinity or excessive sweetness at the time of spraying.

The invention is described in greater detail in the examples below.

Example 1

Single-dose PELLD vials

NaCl 5%

D-mannitol 10.4%

Water q.s. to 4/5 ml

Example 2

Single-dose PELLD vials

NaCl 6.1%

D mannitol 5.2%

Water q.s. to 4/5 ml

Example 3

Single-dose PELLD vials

NaCl 6.1%

D-mannitol 5.2%

sodium hyaluronate 0.1%

Water q.s. to 4/5 ml Example 4

Single-dose PELLD vials

NaCl 6.5%

4.7% D-mannitol

0.1% sodium hyaluronate

Water q.s. to 4/5 ml

Example 5

A test was conducted to compare the acceptability and tolerability of different formulations with an osmolarity-regulating action.

The crossover study was conducted on 10 CF patients of both sexes, aged

14 to 25.

The patients were asked to inhale 4 different solutions with an interval of at least 8 hours between one administration and the next. The patients inhaled the solutions blind.

The parameters investigated were:

Expectorant effect

Sore throat

Unpleasant flavour

Overall opinion.

The first 3 parameters were evaluated with a score of 1 to 4, defined as follows:

1 none 2 slight 3 moderate 4 strong

The overall opinion was expressed on a scale of 1-5, defined as follows: 1 unacceptable 2 very unpleasant 3 unpleasant 4 acceptable 5 neutral. The tables below show the results obtained. Table 1: Expectorant effect

4% NaCl 5% NaCl 6.1% NaCl

7% NaCl

Patient 15.5% mannitol 10.4% mannitol 5.2% mannitol solution

solution solution solution

1 3 3 2 2

2 3 3 3 2

3 1 3 1 1

4 2 1 2 1

5 2 4 2 · 1

6 4 4 2 2

7 3 3 2 2

8 3 3 3 1

9 3 2 2 1

10 3 2 1 1 score 2.7 2.8 2.0 1.4

Table 2: Sore throat

4% NaCl 5% NaCl 6.1% NaCl

7% NaCl

Patient 15.5% mannitol 10.4% mannitol 5.2% mannitol solution

solution solution solution

1 2 3 2 1

2 3 3 2 2

3 3 2 2 1

4 3 3. 2 2

5 2 2 1 2

6 4 3 2 1

7 4 4 3 2

8 3 3 1 1

9 3 3 2 1

10 3 2 2 1 score 3.0 2.8 1.9 1.4

Table 3: Unpleasant flavour

4% NaCl 5% NaCl 6.1% NaCl

7% NaCl

Patient 15.5% mannitol 10.4% mannitol 5.2% mannitol solution

solution solution solution

1 2 4 2 1

2 2 3 2 1

3 3 2 2 2

4 2 2 1 2

5 2 4 2 1

6 4 3 2 1

7 3 3 1 1

8 3 3 2 1

9 3 2 3 2

10 3 3 2 1 score 2.7 2.9 1.9 1.2

Table 4: Overall opinion

4% NaCl 5% NaCl 6.1% NaCl

7% NaCl

Patient 15.5% mannitol 10.4% mannitol 5.2% mannitol solution

solution solution solution

1 2 1 3 4

2 2 2 3 4

3 3 2 2 4

4 2 2 3 3

5 3 2 4 3

6 3 3 4 5

7 3 2 3 5

8 3 3 3 4

9 3 2 2 5

10 2 2 4 3 score 2.6 2.1 3.1 4.0

Claims

1. Inhalatory compositions consisting of sodium chloride aqueous solution in concentrations ranging from 5 to 6.5% by weight and mannitol in concentrations ranging from 4.7 to 10.4% by weight, having osmolality ranging from 2100 to 2400 mOsm/kg.

2. Compositions according to claim 1 wherein the concentration of sodium chloride is 5% and that of mannitol is 10.4% by weight.

3. Compositions according to claim 1 wherein the concentration of sodium chloride is 6.1% and that of mannitol is 5.2% by weight.

4. Compositions according to claim 1 wherein the concentration of sodium chloride is 6.5% and that of mannitol is 4.7% by weight.

5. Compositions according to any one of claims 1-4 wherein the volume of the solution ranges from 4 to 5 ml.

6. Compositions of claims 1-5 for use to improve mucociliary clearance in patients suffering from respiratory diseases.

7. Compositions according to claim 6 wherein the respiratory diseases are cystic fibrosis, chronic obstructive pulmonary disease and DCP.

8. Formulations according to claims 1-7 distributed in low-density polyethylene single-dose vials.

9. Formulations according to claims 1-5 containing sodium hyaluronate.