a) the steroid concentration ranges from 0.01% to 0.1%;
	b) the carrier is a mixture of water and propylene glycol in a ratio ranging from 60:40 to 30:70 v/v;
	c) pH ranges from 3.5 to 5.0 and has been adjusted by using a concentrated strong acid; wherein the osmolarity is not more than 7500 mOsm/l, preferably not more than 7000, even more preferably not more than 6800 and the percentage of nebulised active ingredient particles with MAD below 6 μm is higher than 70% and the nebulisation efficiency after 5 minutes is higher than 20%.

In a particular embodiment of the invention, the formulations are prepared by using a carrier consisting of a water: propylene glycol 50:50 v/v mixture, correcting pH with concentrated strong acids such as hydrochloric acid to values preferably ranging from 4 to 5. It has, in fact, been surprisingly found that if pH, instead of being just corrected, is adjusted by addition of the usual saline buffers such as dibasic sodium phosphate/citric acid couple, the solutions do not remain stable for a pharmaceutically acceptable time. After addition of said buffers, under accelerated stability conditions (40° C., 75% relative humidity [R.H.]), a 10% or higher loss of the assay is in fact observed already after three months. Conversely, the assay of the active ingredient in the solutions whose pH has been simply corrected to 4.0 or 4.5 with HCl remains substantially unchanged after 18 months under long term conditions (25° C., 60% R.H.) and only a slight decrease in the assay is observed after 6 months under accelerated conditions. The solutions of the invention require no addition of stabilizing agents such as metal chelating agents or other antioxidants.

Although it is known from the prior art that the stability of steroids bearing a dihydroxyacetone side chain, such as budesonide and flunisolide, depends on pH and that said steroids are more stable within a pH range of 3-5 (Das Gupta V, J Pharm Sci 12, 1453, 1983; Timmins P et al. J Pharm Pharmacol 35, 175, 1983), stable budesonide in solution in a simple water-alcoholic mixture consisting of water and propylene glycol has never been reported; moreover it has never been disclosed that stability depends so dramatically on the way of adjusting the pH.

Analogously it has never been reported that said solutions can be efficaciously delivered by means of a nebulizer to the lower respiratory tract.

The pH of the formulation also affects the tolerability of the nebulised solution. Aerosol formulations with pH ranging from 4 to 5 are recognizedly well tolerated by the patient (Morén F et al, Aerosol in Medicine, Elsevier, Amsterdam, 1993, page 342). Furthermore, the simple correction of pH with strong acids causes a decrease in the buffering properties of the solution thereby allowing the pH of the droplets to readily change and attain more physiologically acceptable values once the pulmonary area has been reached. On the other hand, the correction of the natural pH of the water to lower values is extremely advantageous when the solution is stored in glass ampoules as the pH inside such containers tends to increase during storage thus adversely affecting the stability of the active ingredient.

The only known solution formulation of budesonide commercially available is a lotion for topical use containing almost 80% w/w of alcohols.

This kind of formulation, due to the so high content of alcohols, is clearly not suitable for inhalatory purposes.

EP 794767 (Falk) discloses budesonide solutions at pH below 6 to be used in the preparation of enemas and rectal foams. The formulations are claimed as stable, but actually if we look at the examples only water-alcoholic formulations involving the use of antioxidants such as sodium edetate or complexing agents such as cyclodextrins are stable for a pharmaceutically acceptable time (at least 6 months).

When such preservatives are not present, the assay of the active ingredient decreases by more than 30% already after 4 weeks at 40° C. The minimum stability requirements prescribed by the Guidelines for medicinal products for human use—Quality and biotechnology, Vol 3A, 1998 Edition, pages 127-134, envision a loss of assay of the active ingredient lower than 5% after storage under accelerated conditions (40° C., 75% R.H.) for six months. In EP 794767, simple 0.0033% solutions in water at different pH values, have been tested only after 14 day of storage. Solutions in propylene glycol alone, which is anyway a carrier unsuitable for the administration via nebulisation, are found to be sufficiently stable only at pH 2.8. Therefore EP 794767 does not teach to prepare pharmaceutically acceptable hydro-alcoholic budesonide solution formulation stable without the aid of stabilizing agents which may be efficiently nebulized.

DE 19625027 claims solutions of drugs such as flunisolide and budesonide, stable by addition of an organic or inorganic acid, for the preparation of pressurized aerosols, using as a propellant a carrier containing at least 70% of ethanol. Said solutions, due to the high percentage of ethanol, which is recognisedly irritant, are not suitable for nebulisation and always contain EDTA.

In the solutions of the invention, consisting of a physiologically acceptable selected range of propylene glycol in a ratio to water ranging from 60:40 to 30:70 v/v it is also possible to avoid the use of preservatives, as it is proved by the bioburden which remains within the limits provided for by the European Pharmacopoeia during the whole stability time of the product.

Since the solutions of the invention are stable without the use of stabilizing agents and preservatives, it is possible to keep their osmolarity to a lower value with respect to known solution formulations, in such a way as to give rise to either an improved efficiency of nebulization and an increased fraction of respirable droplets.

It has in fact been found, and this is a further object of the invention, that the formulations consisting of simple water: propylene glycol solutions are more efficiently nebulised than the corresponding solutions containing sodium chloride and/or salts acting as buffering or stabilizing agents. Furthermore, the formulations of the invention can deliver a higher amount of active ingredient with MAD ranging from 1 to 6 μm therefore providing a larger respirable fraction.

Davis S in Int. J. Pharm. 1, 71-83, 1978 reports that when a water propylene glycol mixture is used for nebulising 0.1% of flunisolide, the optimal percentage of glycol to attain efficient nebulisation is around 50-60% v/v, but no teachings as regards the preparation of stable solutions in said carrier without further addition of stabilizing agents or buffering salt is reported. Furthermore, in Int. J. Pharm. 1, 85-83, 1978, in a study aimed at evaluating as a carrier the water-propylene glycol-ethanol system, Davis suggests that the presence of alcohol would increase the total output from the nebuliser. As it can be appreciated from Table 2 of the same paper, the nebulisation efficiency of the solution with no alcohol is indeed rather low (1 ml in 21 min).

Derbacher J (Atemwegs-Lungenkrank 20, 381-82, 1994), in a study which emphasizes the importance of pH and osmolarity of solutions for the inhalatory route, reports, inter alia, a budesonide isotonic solution (282 mosm/l) with pH 4, but no information are given concerning the composition of the carrier. Moreover it is not reported whether either the concentration or stability of the active ingredient are suitable for a pharmaceutical use. It is in any case unlikely that budesonide dissolves in an aqueous medium at a therapeutic concentration, due to its high lipophilicity.

With respect to the prior art, the compositions of the invention are therefore characterized by the following features:
 

	a steroid, preferably consisting of budesonide in solution at concentrations ranging from 0.001% to 0.1%, preferably from 0.025% to 0.05%;
	a carrier consisting of a water propylene glycol mixture in ratios ranging from 60:40 v/v to 30:70 v/v, preferably 50:50 v/v;
	a pH ranging from 3.5 to 5.0, preferably from 4.0 to 4.5, characterized by a shelf life of at least two years and a reduced osmolarity in such a way as to improve the efficiency of nebulization and the fraction of respirable droplets.

Advantageously the osmolarity is not more than 7500 mOsm/l, preferably not more than 7000, even more preferably not more than 6800, based on the calculation of the depression of the freezing point.

Similar compositions can be prepared with acetonide glucocorticoids and in particular with flunisolide.

Preferred carriers for the formulations of the invention are those consisting of a water: propylene glycol mixture in ratios ranging from 60:40 to 30:70 v/V, preferably in a 50:50 v/v ratio, the concentration of the active ingredient in the solution ranging from 0.001 to 0.1% by weight.

The pH can be corrected by using any concentrated strong acid such as HCl and should range from 3.5 to 5.0, preferably from 4.0 to 4.5. Preferred active ingredients are steroids usually administered in the inhalatory treatment of respiratory diseases. Particularly preferred are acetonide derivatives such as flunisolide. Even more preferred are acetal derivatives such as budesonide or the epimers thereof.

The obtained solutions can be distributed in suitable containers such as multidose vials for nebulisation or preferably in monodose vials, preformed or produced with a technology capable of guaranteeing filling the vials under inert atmosphere. The solution formulations can be advantageously sterilized by filtration.
 

Claim 1 of 14 Claims

1. A stable pharmaceutical formulation for inhalation through nebulisation consisting of a solution of a steroid in which:

a) the steroid concentration ranges from 0.01% to 0.1%;

b) the liquid component of the solution is a mixture of water and propylene glycol in a ratio ranging from 60:40 to 30:70 v/v; and

c) the pH ranges from 3.5 to 5.0, the pH of the formulation having been adjusted by the addition of a concentrated strong acid to the solution; wherein the percentage of nebulised active ingredient particles with MAD below 6 μm is higher than 70% and the nebulisation efficiency is higher than 20%.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.