Field of Invention

The invention relates to a process for the preparation of a sterile suspension to be used in pharmaceutical formulations for inhalation by nebulization which is used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive respiratory diseases.

The background of the invention

Pharmaceutical compositions for inhalation used in the treatment of obstructive respiratory diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and glucocorticosteroids.

Glucocorticosteroids are a class of drug that lowers inflammation in the body. Inhaled glucocorticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.

Among the various types of drug which are administered by inhalation for the treatment of the pulmonary diseases, glucocorticosteroids, such as ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof. They are generally administered in suspension, in an aqueous phase that usually also contains one or more pharmaceutically acceptable excipients, such as dispersing and/or suspending agents, isotonic and/or buffering agents, or in a propellant.

Fluticasone is the most commonly used glucocorticosteroid for inhalation. Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, anti-inflammatory and antipruritic effects. Fluticasone propionate, sold under the brand name Flixotide, is a steroid medication. In order to ensure an effective and save penetration into the low respiratory tract of the patient, i.e. bronchioli and alveoli, one of the most important parameters that must be met by pharmaceutical formulations for inhalation is sterility. This requirement is becoming more and more mandatory as confirmed by the FDA final rule "Sterility Requirement for Aqueous-Based Drug Products for Oral Inhalation" published in the Federal Register of May 26, 2000 (65 FR 34082) governing the quality and safety of pharmaceutical products for a number of reasons, including the fact that the lungs are a particularly vulnerable organ of the human body, and many patients who use inhaled drugs have general health problems.

For introduction of the fluticasone propionate into the lungs, the droplet size of the nebulised formulation is an important parameter. Droplet size depends to some extent on the type of nebuliser used, whether a facemask or a mouthpiece is used and the pressure or flow rate of the compressed gas, as well as on the physical properties of the formulation for nebulisation. The nebulised formulation will be heterodisperse, i.e. droplets will cover a range of sizes.

The current trend is to produce inhalation formulations devoid of preservatives and bacteriostatics, as it has been reported in the literature that some of the substances commonly used for this purpose can induce allergic reactions or give rise to irritation of the respiratory mucosae (Menendez R et al J Allergy Clin Immunol 84, 272-274, 1989; Afferty P et al Thorax 43, 446-450, 1988).

Various processes can be used to manufacture sterile pharmaceutical formulations for inhalation. For example, the active ingredient can be sterilised by dry heating or irradiation, followed by preparation of the formulation under aseptic conditions, or the formulation can be pre-prepared and sterilised by treatment in an autoclave or by filtration.

Chemical sterilization, for the most part, has been based on exposure to toxic compounds, for example, ethylene oxide. However, when used to sterilize glucocorticosteroids, ethylene oxide has been found to leave residual amounts of ethylene oxide in the drug preparation. Ethylene oxide is toxic, and the residual levels are often above the pharmaceutically acceptable limits as set by most regulatory agencies.

Irradiation based sterilization is known and has been recommended for glucocorticosteroids (see Ilium and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However, significant degradation has been reported when irradiation has been used to sterilize micronized glucocorticosteroids. Sterilization by p or y-irradiation is also known. Indeed, Ilium and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2,1974, pp. 167-174 recommend the use of irradiation to sterilize glucocorticosteroids. However, when such irradiation is used to sterilize certain finely divided, e.g., micronized steroids such as glucocorticosteroids, they are significantly degraded.

WO 99/25359 relates to a process for sterilising corticosteroids by heating them at lower temperatures than those reported in some Pharmacopoeias (110-130°C vs 140-180°C) but does not contain any teaching as to how to prepare the relevant pharmaceutical formulations in the form of suspensions.

In the patent application WO 00/25746, the applicant described a process for the preparation of aqueous suspensions for nebulisation based on a micronised active ingredient sterilised with gamma rays.

WO 99/32156 relates to a sterilisation process for pharmaceutical suspensions.

WO 95/31964 discloses suspension formulations suitable for nebulization, for administration by inhalation, comprising fluticasone propionate with a particle size less than 12 microns, one or more surfactants, one or more buffer agents and water.

WO 051/15332 provides a method for the sterilization of a labile glucocorticosteroid, which method comprises heat-treating by moist heat the labile glucocorticosteroid in the form of a suspension for a sterilizing-effective time.

However, the state of art does not include any mention or motivation to reduce the duration of the homogenisation and mixing stage to obtain a homogeneous suspension.

Considering the state of art, there is still a need for innovative processes that will solve the homogeneity problem, and which will provide a standardized method for the fast production of stable inhalation compositions.

Objects and Brief Description of the Invention

The main object of the present invention is to provide a production method for preparing sterile pharmaceutical glucocorticosteroid compositions for inhalation which eliminate all aforesaid problems and bring additional advantages to the relevant prior art. The main object of the present invention is to provide a production method for preparing sterile pharmaceutical glucocorticosteroid compositions for inhalation for use in the prevention, treatment, or in the alleviation of the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.

Another object of the present invention is to obtain sterile pharmaceutical glucocorticosteroid compositions for inhalation having high homogeneity and uniformity with an appropriate concentration of glucocorticosteroids.

Another object of the present invention is to develop a process for preparing a suspension of glucocorticosteroids with enhanced uniformity and homogeneity.

Another object of the present invention is to reduce processing times and obtain a sterile, homogeneous suspension of fluticasone or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the sterilization of a glucocorticosteroid which process comprises heat treating of a suspension of fluticasone or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to produce a much lower level of total impurities than the prior art sterilization.

Detailed description of the invention

In accordance with the objects outlined above, detailed features of the present invention are given herein.

The present invention relates to a process for the preparation of a sterile suspension to be used in pharmaceutical formulations for inhalation by nebulisation, which comprises the following steps:

- preparing a mixture of a glucocorticosteroid suspension comprising a glucocorticosteroid, water and one or more pharmaceutically acceptable excipients,

- homogenizing the mixture in the aqueous suspension,

- sterilising the homogenous suspension comprises the step of heating an aqueous suspension of glucocorticosteroid,

- preparing the second mixture comprising water and one or more pharmaceutically acceptable excipients,

- filtrating the second final mixture, - mixing the glucocorticosteroid suspension with the second filtered mixture, wherein the concentration of the glucocorticosteroid in the glucocorticosteroid suspension is from 1 mg/ml to about 14 mg/ml.

According to one embodiment, said process reduces processing times and gives rise to suspensions with a homogenous, thus producing compositions with a high level of physical stability and therapeutic efficacy.

According to one embodiment, said process of sterilization comprises the step of heating an aqueous suspension of a glucocorticosteroid for a sterilizing-effective time.

As used herein, "glucocorticosteroid" or "glucocorticoid" refers to any of a group of steroid hormones (including derivatives, synthetic analogs, and pro-drugs), such as cortisone, which are produced by the adrenal cortex. These compounds are involved in carbohydrate, protein, and fat metabolism. Additionally, the glucocorticosteroids may have anti-inflammatory properties.

In a preferred embodiment of the invention, said glucocorticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof

According to one embodiment, suspensions obtained with the process according to the invention are used as pharmaceutical formulations for inhalation after being introduced into suitable containers for nebulisation.

According to one embodiment, the concentration of active ingredient in the pharmaceutical formulations is 2 mg/2 mL and 0.5 mg/2 mL.

According to the preferred embodiment, suspensions may be prepared by conventional methods for the preparation of suspension formulations. Typically, the fluticasone propionate is contacted with the dispersing and/or suspending agents so as to "wet" it before addition to the bulk liquid containing the remaining excipients. Constant mixing is essential to maintain a homogeneous suspension. The bulk suspension is sterilised, conveniently by means of thermal sterilisation using steam.

The dispersing or suspending agents used in the formulations of the present invention must be physiologically acceptable upon administration by inhalation. Within this category are included surfactants such as polysorbate 20, sorbitan monolaurate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetra hydrofurfuryl oleate, ethyl oleate, glyceryl mono-oleate, polyethylene glycol 400 and glyceryl monolaurate.

Preferably, the formulation according to the invention contains sorbitan monolaurate and polysorbate 20.

According to the preferred embodiment, suspensions are buffered to a pH of from about 5 to 7, preferably 6. Suitable buffering agents are those which are physiologically acceptable upon administration by inhalation. Such buffers include citric acid buffers and phosphate buffers, of which phosphate buffers are preferred.

Particularly preferred buffering agents for use in the formulations of the invention are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.

According to the preferred embodiment, suspensions will desirably be isotonic. The formulations may be adjusted to isotonicity by addition of a suitable isotonic agents, for example, sodium chloride.

Thus, in a preferred embodiment, the formulations according to the invention additionally comprise sufficient sodium chloride, or another suitable pharmaceutically acceptable salt, to provide an isotonic composition.

According to one embodiment, the present invention relates to a method of sterilizing active pharmaceutical ingredients, such as steroids that are susceptible to higher temperatures. The sterilization is preferably done at temperatures ranging from 100-140°C for 3-30 mins at varying pressures. Generally, the higher the temperature and pressure, the shorter the time required for adequate sterilization. In an embodiment, the glucocorticosteroid is fluticasone, and the step of heating is by autoclaving at about 121°C for about 15 to about 30 minutes or at about 110°C for about 115 to about 150 minutes. Another embodiment contemplates that the glucocorticosteroid is fluticasone propionate, and the step of heating is by autoclaving at about 121°C for about 15 to about 30 minutes or at about 110°C for about 115 to about 150 minutes. The glucocorticosteroid in yet other embodiments is at a concentration of from about 1 mg/ml to about 14 mg/ml.

In a particularly preferred embodiment, the present invention accordingly provides, in a first aspect, a formulation suitable for nebulisation comprising:

- fluticasone propionate,

- polysorbate 20,

- sorbitan monolaurate,

- monosodium phosphate dihydrate,

- dibasic sodium phosphate anhydrous,

- sodium chloride,

- water for injection.

According to all these embodiments, the below given formulation can be used in the suspension subjected to the invention.

Example 1 : Example 2:

The preparation method of the above-mentioned suspension given in example 1 is prepared by following these steps:

- preparing a mixture of a glucocorticosteroid suspension comprising a glucocorticosteroid, water and one or more pharmaceutically acceptable excipients,

- homogenizing the mixture in the aqueous suspension,

- sterilising the homogenous suspension comprises the step of heating an aqueous suspension of glucocorticosteroid,

- preparing the second mixture comprising water and one or more pharmaceutically acceptable excipients,

- filtrating the second final mixture,

- mixing the glucocorticosteroid suspension with the second filtered mixture, wherein the concentration of the glucocorticosteroid in the glucocorticosteroid suspension is from 1 mg/ml to about 14 mg/ml.