United States Patent:   6,027,714

Assignee:  Astra Aktiebolag (SE)

Filed:  January 9, 1998

A dry powder composition comprising budesonide and a carrier substance, both of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml is useful in the treatment of respiratory disorders.

DESCRIPTION OF THE INVENTION

According to the invention there is provided a dry powder composition comprising budesonide and a carrier substance, both of which are in finely divided form, wherein the formulation has a poured bulk density of from 0.28 to 0.38 g/ml, preferably from 0.30 to 0.36 g/ml.

The poured bulk density according to the present invention is measured using known techniques, for example those described in "Powder testing guide: Methods of measuring the physical properties of Bulk powders" L. Svarovsky, Elsevier Applied Science 1987, pp 84-86.

The carrier substance is preferably a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Lactose is particularly preferred, especially in the form of its monohydrate.

The ingredients of the formulation according to the invention must both be in a finely divided form, i.e. their mass median diameter should generally be less than 10 .mu.m, preferably from 1 to 7 .mu.m, as measured by a laser diffraction instrument or a coulter counter. The ingredients may be produced in the desired particle size using methods known to those of skill in the art, e.g. milling, micronisation or direct precipitation.

The composition according to the invention is preferably formulated to comprise, as a daily dose, from 20 to 4300 .mu.g of budesonide (preferably from 80 to 2150 .mu.g). More preferably the composition is formulated to provide unit doses of 200 .mu.g or 400 .mu.g of budesonide. The composition is preferably formulated to comprise in each unit dose from 50 .mu.g to 25 mg of the carrier substance, more preferably from 50 .mu.g to 10 mg, most preferably from 100 to 4000 .mu.g.

According to the invention there is further provided a process for preparing a composition according to the invention which comprises

(a) micronising budesonide and the carrier substance;

(b) optionally conditioning the product; and

(c) spheronizing until the desired bulk density is obtained.

The process preferably further comprises a low energy remicronisation step after step (b).

The formulation according to the invention may be made by conventional techniques known per se. Such production processes generally comprise micronising the ingredients to the required size, removing any amorphous areas on the particles obtained by, for example, the methods described in WO 92/18110 or WO 95/05805 and then agglomerating, spheronising and sieving the powder obtained. The size of the agglomerates obtained is preferably in the range of from 100 to 2000 .mu.m, more preferably from 100 to 800 .mu.m. The bulk density of the formulation produced may be adjusted by varying the components and the process empirically, for example the bulk density can be increased by lengthening the time in which the particles are tumbled in a spheronising device.

In solid-solid mixing, one of the most important features is to ensure content uniformity. The major problem encountered in the powder mixing of fine powders is the inability of mixers to break down powder agglomerates. It has been found that a remicronisation step after the conditioning step of the fine powder with low energy input is advantageous. It should generally be carried out using enough energy to break down powder agglomerates but not with so much energy that the size of the particles themselves is affected. Such a step gives a composition wherein the active substance and carrier substance are substantially uniformly distributed, having for example a relative standard deviation of less than 3% (preferably less than 1%) without disturbing the crystallinity of the fine particles.

The formulation according to the invention may be administered using any known dry powder inhaler, for example the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler, for example Turbuhaler (trade mark). The invention further provides use of a composition according to the invention in the manufacture of a medicament for use in therapy. The composition according to the invention is useful in the treatment of respiratory disorders, particularly asthma. The invention also provides a method of treating a patient suffering from a respiratory disorder which comprises administering to the patient a therapeutically effective amount of a composition according to the invention.

Claim 1 of 14 Claims

1. A dry powder pharmaceutical composition comprising budesonide and a carrier substance,

wherein both the budesonide and the carrier substance consist of particles having a mass median diameter of less than 10 .mu.m, and the composition has a poured bulk density of from 0.28 to 0.38 g/ml.

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