ITMI20101440A1 - INHALATION FORMULATIONS IN THE FORM OF SOLUTIONS OR DRIED POWDERS, FOR THE REMOVAL OF MUCOSE SECRECTIONS FROM THE RESPIRATORY SYSTEM - Google Patents

Description

â € œINHALATORY FORMULATIONS IN THE FORM OF SOLUTIONS OR DRY POWDERS, FOR THE REMOVAL OF MUCOUS SECRETIONS FROM THE RESPIRATORY SYSTEMâ €

The present invention relates to inhalation formulations in the form of hypertonic solutions or dry powders containing an osmolarizing agent and low molecular weight hyaluronic acid of biotechnological origin or its salts.

State of the art

Ciliary mucus clearance is definitely the main airway protection system. The mucus, however, must have ideal characteristics to be able to fully carry out its important function of â € œtrapâ € of foreign substances that have entered the airways.

In different pathologies of the respiratory system, the stagnation of secretions in the airways and their consequent dehydration determines the establishment of conditions predisposing to bacterial colonization and therefore to the worsening evolution of the disease in progress. The removal of purulent mucus secretions represents a pharmacological goal of primary importance.

In various genetic diseases, such as cystic fibrosis or Kartagener's syndrome, this stagnation of dehydrated mucus in the airways leads to a rapid deterioration of lung function, which can lead to premature death. In other pathologies, such as COPD, the stagnation of secretions and the consequent bronchus obstruction occurs in an older age, but can in any way seriously compromise the respiratory function.

Even in acute pathologies of viral origin, such as a trivial flu, the stagnation of mucous secretions are frequently responsible for the negative evolution of the respiratory picture.

Various mucolytic drugs with muco-lytic mechanisms have been used for years. These drugs act by depolymerizing the mucin, thanks to the presence of SH groups, thus reducing the viscosity of the secretions.

Other molecules act as mucus kinetics by increasing the volume of fluid in the airways and thus inducing cough, thus facilitating the detachment of mucus from the airways.

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

These mucus-active drugs have an efficacy, however, limited to modest obstruction and acute evolution, but are not very effective in diseases where bronchial obstruction is more severe and above all chronic.

In cystic fibrosis, the failure of the CFTR channel protein, responsible for the ionic exchange of Na and Chlorine between the cell and the extracellular environment, causes a reduction in the periciliary liquid layer that covers the respiratory mucosa. This superficial liquid layer, kept constant by the water that enters and exits the cell following the flow of the Na and Cl ions, is normally equal to about 10 µM.

This superficial aqueous layer allows the cilia of the epithelium to move completely immersed in the periciliary liquid layer and thus fully perform the task of removing secretions and everything that has been trapped in it for elimination. In subjects affected by CF the periciliary liquid layer is reduced by more than 50%, settling on 4 µM, this volume reduction reduces the ability of the cilia to move adequately and therefore reduces, to the point of canceling, the ciliary mucus transport.

Due to the reduction of ciliary mucus clearance there is stagnation of mucus in the airways resulting in dehydration, bacterial colonization and development of ideal conditions for chronic colonization by pathogenic flora especially Gram -.

The consequent activation of the immune system, the inability to eradicate the bacterial infection lead to an inflammatory process in the airways and to the progressive loss of respiratory function.

In other genetic diseases, for example DCP, the causes leading to the clearance deficit may be different but the result is not different from that in CF, inflammation and chronic infection.

In fact, it characterizes the evolution of CF, as well as that of DCP and chronic obstructive pathology (COPD), a marked inflammatory process that accompanies the infectious picture. In practice, a vicious cycle known as Obstruction-Infection-Inflammation is established in these pathologies, a vicious cycle in which it is still not clear what the exact sequence is and in which the progressive self-feeding is clear.

For not many years systemic therapy has been accompanied by aerosol therapy, for example with antibiotics such as tobramycin, colimycin, ciprofloxacin, aztreonam and with active mucus such as for example Dornase alfa, an enzyme capable of fragmenting the DNA contained in the mucus thus reducing its stickiness.

The advantage of this route of administration is that of reaching the affected site by reducing systemic involvement, an important fact in consideration of the chronicity of the treatment and the intrinsic toxicity of many of the drugs used.

All the molecules used by inhalation are potentially at risk for two reasons: they can favor the onset of bronchospasm, they can be irritating to the airways and therefore risk nullifying the extent of their pharmacological action by aggravating the pulmonary inflammatory picture. This risk is not linked only to the single active ingredient, but also to the formulation itself, to its chemical and physical characteristics as well as to the presence of any excipients.

The formulation that can be administered by aerosol must be sterile to avoid the risk of carrying potential pathogens into the airways, must have a precise range of pH, osmolarity and must give rise to particles with an average aerodynamic diameter of less than 6 microns in order to reach the airways. peripheral areas.

Among the most effective treatments to facilitate the secretion of the airways, the use of osmotic dry solutions or powders, such as hypertonic saline solutions or mannitol, has long been used. The operating principle of these treatments is linked to their ability to recall water in the airways, favoring the restoration of a superficial aqueous film with consequent restoration of ciliary mucus clearance.

Treatment with osmotic solutions or powders are particularly effective in those pathologies such as CF and DCP which are characterized by a marked bronchial obstruction due to a zero clearance. In these subjects the high ionic concentration of NaCl or the high concentration of mannitol can exert the osmotic pressure for a long time because it is not removed from the ciliary mucus clearance, as would happen in a normal subject, or as it happens in an affected subject. from slowing down of minor ciliary mucus eg chronic obstructive bronchitis.

Solutions from 3 to 9% of NaCl to be nebulized by jet or mesh nebulizer have long been used to hydrate the airways, improve ciliary clearance and therefore facilitate the elimination of purulent mucus secretions. More recently, mannitol-based dry powder formulations for inhalation have been proposed. The advantage of these dry powder formulations is that they reduce the time required for inhalation and can potentially improve treatment compliance, especially in patients where therapy must be chronic.

The inhalation of hyperosmolar solutions of NaCl as well as the inhalation of NaCl in dry powder or the inhalation of mannitol in dry powder, easily cause a bronchial obstruction, an irritation in the throat and cough even of considerable entity, effects that they reduce the possibility of reaching the airways in depth, they reduce the breathable fraction of the product due to the alteration of the respiratory air flows and consequent reduction of the effectiveness of the treatment.

It should also be noted that the palatability of the hyperosmolar saline solution and the acceptability of the inhalation of dry NaCl and mannitol powders is somewhat limited due to the irritative and bronchocontracting effects induced by inhalation with over 30% of patients leaving the treatment.

In fact, a large number of patients are unable to regularly carry out the treatment due to the undesirable effects that accompany the nebulization of hypertonic saline solutions or dry powders of osmotic agents.

The use of excipients and preservatives is highly inadvisable, given the intended use and therefore the room for maneuver to improve the quality of the formulations appears rather limited. The excipients currently used to improve the flowability of powders or to adjust the pH of the solutions or to increase the expiration of both solution and powder formulations, can carry out a pro-inflammatory action on the respiratory epithelium and are therefore not recommended in aerosol formulations.

Hyaluronic acid is a linear polysaccharide composed of glucuronic acid and N-acetylglucosamine belonging to the Glycosaminoglycan family.

Hyaluronic acid is a natural component of the extracellular matrix and is ubiquitously present in many tissues. Hyaluronic acid has been used for years in medicine, in orthopedics, for intraarticular injection to increase the viscosity of the synovial fluid, in ophthalmology, otolaryngology and cosmetic surgery.

Hyaluronic acid, as such, is non-toxic and has no allergenic effects. For each of these activities different hyaluronic acids are recommended both in origin and in molecular weight. More recently, high molecular weight hyaluronic acid has been suggested for respiratory use due to its ability to reduce exercise-induced bronchospasm (G. Petrigni, L. Allegra, Pulmonary Pharmacology & Therapeutics 19 (2006) 166- 171).

In fact, another author (L.I.Z. Kunz et al Pulmonary Pharmacology & Therapeutics 19 (2006) 286â € “291) highlighted how the use of a hyaluronic acid of lower PM had no activity in this sense.

Potential properties of hyaluronic acid, which have yet to be confirmed, have been suggested by various authors on targets such as pulmonary emphysema, chronic bronchitis and streptococcal infection.

DESCRIPTION OF THE INVENTION

The need for inhalation formulations with precise characteristics has so far limited the availability of products with ideal characteristics.

It has now been found that the addition of hyaluronic acid or its sodium salt to NaCl-based formulations, in solution or in dry powder, or of mannitol in dry powder, improves the tolerability characteristics of the inhaled, reducing the bronchospasm induced by inhalation and, in the case of the solution, also the annoying salty taste, which persists long after inhalation causing nausea in the vast majority of patients.

More particularly, it has been found that it is possible to improve the tolerability of inhalation of osmotic substances by adding to them a possibly salified hyaluronic acid of biotechnological origin and of low molecular weight between 50,000 and 500,000. Hyaluronic acid of both animal and vegetable extractive origin was surprisingly less effective. probably due to the presence of contaminants. The molecular weight, which is preferably between 250,000 and 400,000, is also in contrast with what is reported in the literature which highlights only hyaluronic acid with a higher MW (about 1,000 KDa) as effective.

The exotoxin content of the formulations of the invention must be less than 0.1 ppm.

The hypertonic solution contains NaCl in percentages between 6 and 12% w / v, preferably between 6 and 9% w / v and even more preferably 7% w / v. Low molecular weight hyaluronic acid is comprised between 0.05 and 0.3%, preferably between 0.05% and 0.2%, even more preferably equal to 0.1% w / v.

The solution to be inhaled is divided into single-dose vials of 4-5 ml and is free of excipients and buffers.

It was then found that the solution containing hyaluronic acid and NaCl at hyperosmolar concentrations, when divided into single-dose vials in PELLD (low density polyethylene), is less susceptible to pH variation than polyethylene. In this way it was possible not to insert tampons.

The formulations of the invention in the form of hypertonic solutions contain NaCl and biotechnological hyaluronic acid with low molecular weight and are free of excipients ensuring an optimal pH between 5 and 6.5 stable over time and a longer duration of the formulation.

It has also been found that, when inhaled as micronized dry powder formulations, the osmolarizing agents (NaCl and mannitol) are better tolerable, less bronchocontracting and less toxigenic when associated with low molecular weight hyaluronic acid (LMW) in osmolarizing agent ratios: hyaluronic acid between 100: 0.05 and 100: 1.

The addition of hyaluronic acid also improves the flowability of the powders by improving pulmonary distribution.

The invention therefore relates to inhalation formulations in the form of hypertonic solutions or dry powders containing an osmolarizing agent selected from NaCl and mannitol and biotechnological hyaluronic acid of low molecular weight or its salts, free of excipients such as preservatives. The formulations in solution form are preferably distributed in single-dose bottles of low density polyethylene while the powder formulations are preferably distributed in capsules.

The nebulisation of the powder can take place with any commercial device, both PPE and pMDI: PPE, ie devices activated by the patientâ € ™ s breath, are preferred.

The compositions of some formulations of the invention are reported below by way of example.

EXAMPLES

1. 5ml single dose low density PE vial

NaCl 7% w / v

Sodium hyaluronate 0.1% (biotechnological PM 300.000-450.00)

Solution at pH 4.5-5.5.

2. 4 ml single-dose vial

NaCl 7%

Sodium hyaluronate 0.1% (biotechnological PM 250,000-400,000)

Solution pH 4.5-6.5.

3. 5 ml single-dose vial

NaCl 9% w / v

Sodium hyaluronate 0.1% (biotechnological PM 250,000-400,000).

4. Single dose vial of 4 or 5 ml

NaCl 6% w / v

Sodium hyaluronate 0.1% (biotechnological PM 250 000-400.000) pH solution 4 - 6.5.

5. Inhalation capsules of micronized powder

NaCl 350 mg

Hyaluronic acid 3.5 mg (biotechnology 250,000-400,000).

6. Inhaled micronized powder distributed in NaCl capsules 350 mg Hyaluronic acid (biotechnological 250,000-400,000) 0.35 mg.

7. Micronized powder for inhalation distributed in capsules

NaCl 250 mg

Hyaluronic acid (biotechnological 250,000-400,000) 0.25 mg.

8. Inhalation capsules of micronized powder Mannitol 300 mg Hyaluronic acid (biotechnological 250,000-400,000) 3 mg.

9. Micronized powder for inhalation distributed in capsules Mannitol 420 mg

Hyaluronic acid (biotechnological 250,000-400,000) 0.5 mg.

Claims (10)

CLAIMS 1. Inhalation formulations in the form of hypertonic solutions or dry powders containing an osmolarizing agent chosen from NaCl or Mannitol and biotechnological hyaluronic acid of low molecular weight or one of its salt, without preservatives or excipients. 2. Inhalation formulations according to claim 1 in the form of hypertonic saline solutions in which sodium chloride is present in a percentage between 6 and 12% w / V and hyaluronic acid or a salt thereof is present in percentage between 0.05% and 0.3%. 3. Formulations according to claim 2, distributed in single-dose vials of low density polyethylene. 4. Formulations according to claim 2 or 3 in which the osmolarizing agent is present in percentages comprised between 6 and 9%, preferably 7%. 5. Formulations according to one of claims 1 to 4, wherein the molecular weight of the hyaluronic acid or one of its salt is comprised between 50,000 and 500,000. 6. Formulations according to claim 1 in the form of dry powders. 7. Formulations according to claim 6 wherein the osmolarizing agent: hyaluronic acid ratio is between 100: 0.05 and 100: 1. 8. Formulations according to claim 6 or 7 wherein the osmolarizing agent is sodium chloride. 9. Formulations according to claim 6 or 7 wherein the osmolarizing agent is mannitol. 10. Formulations according to any one of claims 1-9 for the removal of bronchial secretions. Milan, 30 July 2010