Title:  Particulate formulation for administration by inhalation

United States Patent:  6,284,287

Assignee:   Asta Medica AG (Dresden, DE)

Filed:  April 2, 1997

PCT NO:  PCT/EP95/02392

102(e) Date:  April 2, 1997

PCT PUB. Date:  February 1, 1996

Foreign Application Priority Data:  Jul 16, 1994[DE] (44 25 255)

A pharmaceutical formulation for administration by inhalation, a micronized active compound or micronized active compound mixture with a mean particle size of 0.1 .mu.m to 10 .mu.m being applied to a pharmaceutically acceptable excipient having a mean particle size of 200 .mu.m to 1000 .mu.m without the use of binders.

SUMMARY OF THE INVENTION

DE 28 51 489 A1 describes a formulation consisting of beclomethasone dipropionate whose particles to 90% by weight are smaller than 10 .mu.m and of a powder excipient which consists of particles having an effective size of 90% by weight less than 400 .mu.m and of at least 50% by weight greater than 30 .mu.m. In addition to the active compound beclomethasone dipropionate, this formulation can additionally contain a bronchodilator of preferably the same particle size as beclomethasone dipropionate.

Designated bronchodilators are orciprenaline, terbutaline or salbutamol. Conversion to a pharmaceutical preparation is carried out by simple mixing.

WO 91/11179 A1 describes the use of excipient materials such as lactose, polysaccharides and others. As described, these excipient materials have a particle size of 5.0-1000 .mu.m and a surface roughness of less than 1.75. Simple mixing of the excipient material with a pharmaceutical active compound leads to the powder preparation.

The object is thus, for the purposes of inhalation, to develop a powder which is simple to prepare, requires no complicated in-process controls of the moisture content of the active compounds and/or auxiliaries and has a high degree of redispersion. Furthermore, the formulation should have satisfactory flow properties and be easily disintegrable into respirable particles in the inhaler. Under identical conditions, at least 40% should be redispersed.

It has now surprisingly been found that by suitable mixing of the active compound or of the active compound mixture with a pharmaceutically utilizable excipient which has a mean particle size of 200 .mu.m to 1000 .mu.m, preferably between 300 .mu.m and 600 .mu.m, and a roughness of more than 1.75, the active compound particles having a particle size of 0.01 .mu.m to 10 .mu.m adhere to the excipient particles and thereby almost round excipient particles coated with active compound result. In the case of the formulation according to the invention, treatment, for example additional purification processes, of the excipient material employed can be dispensed with.

The particles of the excipient are commercially available or can be obtained by fractionation (sieve) into a specific grain size or grain size range.

The determination of the particle size of the excipient particles was carried out by measurement of scanning electron microscope photographs and/or by sieve analysis. The determination of the particle size of the active compound particles was carried out by measurement of scanning electron microscope photographs and/or by laser diffraction spectrometry.

This powder formulation can be prepared simply and economically and has significantly better flow properties both in comparison to the untreated active compound powder and to the soft pellets. The results in Table 1 show this. A lower bed height means better flow properties of the formulation.

The more similar the bulk and compacted volumes are, the better the flow properties. However, even the emptying and subsequent redispersion is better in comparison to the previously known formulations (mixtures, soft pellets according to GB 1 569 612 or GB 1 520 247 or untreated active compound powder), i.e. the residues in the inhaler are lower and the yield of respirable particles is higher.

The formulation can contain various active compounds, for example analgesics, antiallergics, antibiotics, anticholinergics, antihistaminics, antiinflammatory substances, antipyretics, corticoids, steroids, antitussives, bronchodilators, diuretics, enzymes, cardiovascular substances, hormones, proteins and peptides. Examples of analgesics are codeine, diamorphine, dihydromorphine, ergotamine, fentanyl and morphine; examples of antiallergics are cromoglycic acid and nedocromil; examples of antibiotics are cephalosporins, fusafungin, neomycin, penicillins, pentamidine, streptomycin, sulfonamides and tetracyclines; examples of anticholinergics are atropine, atropine methonitrate, ipratropium bromide, oxitropium bromide and trospium chloride; examples of antihistaminics are azelastine, flezelastine and methapyrilene; examples of antiinflammatory substances are beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, tipredane and triamcinolone; examples of antitussives are narcotine and noscapine; examples of bronchodilators are bambuterol, bitolterol, carbuterol, clenbuterol, ephedrine, epinephrine formoterol, fenoterol, hexoprenaline, ibuterol, isoprenaline, isoproterenol, metaproterenol, orciprenaline, phenylephrine, phenylpropanolamine, pirbuterol, procaterol, reproterol, rimiterol, salbutamol, salmeterol, sulfonterol, terbutalin and tolobuterol; examples of diuretics are amiloride and furosemide; an example of enzymes is trypsin; examples of cardiovascular substances are diltiazem and nitroglycerine; examples of hormones are cortisone, hydrocortisone and prednisolone; examples of proteins and peptides are cyclosporins, cetrorelix, glucagon and insulin. Other active compounds which can be employed are adrenochrome, colchicine, heparin, scopolamine. The active compounds mentioned by way of example can be employed as free bases or acids or as pharmaceutically tolerable salts. Counterions which can be employed are, for example, physiologically tolerable alkaline earth metals or alkali metals or amines, as well as, for example, acetate, benzenesulfonate, benzoate, hydrogen carbonate, hydrogen tartrate, bromide, chloride, iodide, carbonate, citrate, fumarate, malate, maleate, gluconate, lactate, pamoate and sulfate. Esters can also be employed, for example acetate, acetonide, propionate, dipropionate, valerate.

The formulation according to the invention can also consist of a mixture of several finely ground active compounds, for example of sodium cromoglycate and reproterol hydrochloride. As already described, 100% of the active compound particles should be less than 10 .mu.m, preferably in the range from 1 .mu.m to 5 .mu.m.

The excipient employed is a nontoxic material which has a mean particle size of 200 .mu.m to 1000 .mu.m, preferably between 300 .mu.m and 600 .mu.m. Excipients according to the invention inorganic salts such as sodium chloride and calcium carbonate, organic salts such as, for example, sodium lactate and organic compounds such as, for example, urea, monosaccharides such as, for example, glucose and its derivatives such as sorbitol, polyalchohols, sorbitol, mannitol, xylitol, disaccharides such as, for example, lactose, maltose and their derivatives, and polysaccharides such as, for example, starch and its derivatives, oligosaccharides such as, for example, cyclodextrins, and also dextrins can be employed. Mixtures of the auxiliaries can also be employed.

The ratio of active compound to the excipient material depends on the substances employed. By means of the examples, it has been shown that the use of 10 to 80 percent by weight of the active compound to 20 to 90 percent by weight of the excipient, preferably 30 to 70 percent by weight of the active compound to 30 to 70 percent by weight of the excipient, gives satisfactory results.

Additionally to the active compound and excipient, the formulations can also contain other constituents, such as flavor corrigents, for example saccharin or peppermint flavoring. The components can be, for example, 10-20% by weight relative to the active compound or to the active compound mixture.

The preparation of the formulation is carried out by mixing the constituents in a suitable mixer, for example tumble mixer, rotary mixer, high-speed mixer or fluidizing mixer. A possible tumble mixer is, for example, the Turbula mixer, W. A. Bachofen AG, Basle, CH; a high-speed mixer is the Diosna mixer, Dierks und Sohne, Osnabruck, FRG.

The constituents here are added to the mixer and mixed until the excipient crystals are coated with the fine active compound or active compound mixture, the fine fraction gradually disappearing and round, coated particles resulting.

However, other processes such as fluidized bed or vibration processes can also be used for the preparation of the powder formulations according to the invention. In these processes, the excipient particles are set into rotary motion in a container. The active compound particles are thereby able to deposit thereon and thus form the formulation according to the invention.

In order to demonstrate the advantages of the formulation according to the invention in comparison to the mixture of the two active compounds and the soft pellets according to specifications GB 1,569,612 and GB 1,520,247, these formulations were prepared and some physical measurements were determined.

Claim 1 of 16 Claims

What is claimed is:

1. A formulation comprising an active compound mixture having a mean particle size of 0.1 .mu.m to 10 .mu.m in combination with a physiologically acceptable excipient or excipient mixture having a mean particle size of 400 .mu.m to 1000 .mu.m and a rugosity greater than 1.75.

____________________________________________
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.